[Liver transplantation in viral and autoimmune liver diseases]. / Lebertransplantation bei viralen und autoimmunen Lebererkrankungen.

BACKGROUND: Despite substantial progress in the management of viral and autoimmune liver diseases, these entities remain relevant indications for liver transplantation. AIMS: To provide an overview of the current knowledge regarding the management of viral and autoimmune liver diseases before and after liver transplantation. MATERIALS AND METHODS: Selective literature search, including current guidelines and abstracts of key scientific meetings. RESULTS AND DISCUSSION: Viral and autoimmune liver disease can be effectively treated in most cases, which has resulted in an overall decline in liver transplantations for this indication group. However, hepatitis D infection and primary sclerosing cholangitis remain difficult-to-treat liver diseases in some patients and may progress to end-stage liver disease despite best possible management. Viral or autoimmune hepatitis can lead to fulminant liver failure requiring emergency liver transplantation. In patients who are transplanted due to viral or autoimmune liver disease, specific measures to prevent recurrence of these diseases after transplantation are mandatory. In view of effective treatment modalities for chronic hepatitis B and C, even liver grafts from donors infected with these viruses can be considered for liver transplantation under certain circumstances.

Thyroid hormone receptor alpha modulates fibrogenesis in hepatic stellate cells.

OBJECTIVE: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or ß (TRα/ß). Here, we evaluated the influence of TH in hepatic fibrogenesis. DESIGN: Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFß in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. RESULTS: TRα and TRß expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFß-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFß signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. CONCLUSION: These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFß signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.

Imaging-Derived Biomarkers Integrated with Clinical and Laboratory Values Predict Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Purpose: To investigate the prognostic value of computed tomography (CT) derived imaging biomarkers in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and develop a predictive nomogram model. Patients and Methods: This retrospective study included 178 patients with histopathologically confirmed HCC who underwent liver transplantation between 2007 and 2021 at the two academic liver centers. We evaluated dedicated imaging features from baseline multiphase contrast-enhanced CT supplemented by several clinical findings and laboratory parameters. Time-to-recurrence was estimated by Kaplan-Meier analysis. Univariable Cox proportional hazard regression and multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to assess independent prognostic factors for recurrence. A nomogram model was then built based on the independent factors selected through LASSO regression, to predict the probabilities of HCC recurrence at one, three, and five years. Results: The rate of HCC recurrence after LT was 17.4% (31 of 178). The LASSO analysis revealed six independent predictors associated with an elevated risk of tumor recurrence. These predictors included the presence of peritumoral enhancement, the presence of over three tumor lesions, the largest tumor diameter greater than 3 cm, serum alpha-fetoprotein (AFP) levels exceeding 400 ng/mL, and the presence of a tumor capsule. Conversely, a history of bridging therapies was found to be correlated with a reduced risk of HCC recurrence. In addition, Kaplan-Meier curves showed patients with irregular margin, satellite nodules, or small lesions displayed shorter time-to-recurrence. Our nomogram demonstrated good performance, yielding a C-index of 0.835 and AUC values of 0.86, 0.88, and 0.85 for the predictions of 1-year, 3-year, and 5-year TTR, respectively. Conclusion: Imaging parameters derived from baseline contrast-enhanced CT showing malignant behavior and aggressive growth patterns, along with serum AFP and history of bridging therapies, show potential as biomarkers for predicting HCC recurrence after transplantation.

Primary Biliary Cholangitis (PBC)-Autoimmune Hepatitis (AIH) Variant Syndrome: Clinical Features, Response to Therapy and Long-Term Outcome.

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

Bilobar Radioembolization Carries the Risk of Radioembolization-Induced Liver Disease in the Treatment of Advanced Hepatocellular Carcinoma: Safety and Efficacy Comparison to Systemic Therapy with Atezolizumab/Bevacizumab.

Recommended treatment options for advanced-stage hepatocellular carcinoma (HCC) include systemic therapy (ST) and trans-arterial radioembolization (TARE) with Yttrium-90 (Y90). Before the approval of immune-checkpoint inhibitors, a similar safety profile was reported for TARE and ST with tyrosine kinase inhibitors (TKI). However, whole-liver treatment and underlying cirrhosis were identified as risk factors for potentially lethal radioembolization-induced liver disease (REILD). Therefore, the safety and efficacy of TARE and ST with atezolizumab/bevacizumab were compared in patients with advanced HCC involving at least both liver lobes in a retrospective real-world cohort. In total, 74 patients with new or recurrent advanced-stage HCC (BCLC stage B/C) were included if treated with either bilobar TARE (n = 33) or systemic combination therapy with atezolizumab plus bevacizumab (n = 41). Most patients had compensated liver function (90.5% were classified as Child-Pugh Score A, 73% as ALBI Grade 1) at baseline. Although not significant, patients treated with ST showed a more prolonged overall survival than those treated with Y90 TARE (7.1 months vs. 13.0 months, p = 0.07). While a similar disease control rate could be achieved with bilobar TARE and atezolizumab/bevacizumab, in the TARE group, overall survival was curtailed by the occurrence of REILD. In patients with underlying liver cirrhosis, the liver function at baseline was a predictor for REILD.

Changing treatment landscape associated with improved survival in advanced hepatocellular carcinoma: a nationwide, population-based study.

BACKGROUND AND AIMS: The treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort. METHODS: A nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed. RESULTS: We identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9-8.9) and in period A was 5.3 months (95% CI: 4.5-6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3-18.4) versus 4.8 months with sorafenib (95% CI: 4.0-7.1, p = 0.008). Costs for prescription drugs per patient increased from €6150 in 2015 to €9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from €1646 to €2149 (p = 0.0240). CONCLUSION: The approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs.

Outcome of Children with Transjugular Intrahepatic Portosystemic Shunt: A Meta-Analysis of Individual Patient Data.

PURPOSE: The purpose of the study was to investigate outcome after pediatric transjugular intrahepatic portosystemic shunt (TIPS) with respect to survival MATERIAL AND METHODS: After searching for studies on TIPS in children in Ovid, Medline, Embase, Scopus and Cochrane published between 2000 and 2022, individual patient data were retrieved from five retrospective cohorts. Overall survival (OS) and transplant-free survival (TFS) were calculated using Kaplan-Meier analysis and log-rank test and compared to the indication (ascites vs. variceal bleeding) as well as to the level of obstruction (pre-hepatic vs. hepatic vs. post-hepatic). Additionally, TIPS patency was analyzed. RESULTS: n = 135 pediatric patients were included in the final analysis. Indication for pediatric TIPS creation was heterogeneous among the included studies. TIPS patency decreased from 6 to 24 months, subsequent pediatric liver transplantation was performed in 22/135 (16.3%) of cases. The presence of ascites was related with poorer TFS (HR 2.3, p = 0.023), while variceal bleeding was not associated with impaired survival. Analysis of the level of obstruction (pre-hepatic, hepatic and post-hepatic) failed to prove significantly reduced OS for post-hepatic obstruction (HR 3.2, p = 0.092) and TFS (HR 1.3, p = 0.057). There was no difference in OS and TFS according to age at time of TIPS placement. CONCLUSIONS: The presence of ascites associates with impaired survival after TIPS in children, with no differences in survival according to the age of the child. Interventional shunt procedures can be considered feasible for all ages. LEVEL OF EVIDENCE: Level 2a.

Limited access to liver transplantation and TIPS despite high mortality, healthcare resource use and costs of cirrhosis in Germany.

BACKGROUND AND AIMS: Data on number of patients with cirrhosis in Germany are limited. We therefore aimed to estimate prevalence, comorbidities, mortality, utilization of healthcare resources and costs of patients with cirrhosis and incidence of decompensation of cirrhosis in Germany. METHODS: This longitudinal observational study was based on an anonymized representative claims database including 4.9 million persons insured by a statutory health insurance (SHI) between 2015-2020. Patients with decompensated and compensated cirrhosis were selected via diagnostic ICD codes and followed for 2 years. RESULTS: Prevalence of cirrhosis in 2015 was 250/100 000, resulting in 201 747 (95% CI: 197 540-206 040) patients extrapolated to the German population. Out of all patients with compensated cirrhosis in 2015 who did not deceased, 16.0% developed a decompensation within 3 years. Overall, 978 patients (Ø-age: 68 years; 60% male) were included in the decompensated, and 5135 patients (Ø-age: 66 years; 59% male) in the compensated cirrhosis cohort. Patients with decompensated cirrhosis had a higher burden of comorbidities (Charlson Comorbidity Index 7.3 vs. 4.4) and 3 times higher costs per quarter (7172 € vs. 2213 €) than patients with compensated cirrhosis. 1-year mortality after decompensation was 51% compared to 8% in compensated cirrhosis. Of note, only few patients with decompensated cirrhosis received a liver transplantation or transjugular intrahepatic portosystemic shunts (TIPS) (1% and 5%). CONCLUSION: Patients with cirrhosis have a high healthcare burden in especially decompensated stage. Accordingly, 1-year mortality of decompensated cirrhosis in Germany is high. Despite high health resource utilization, only few patients have access to liver transplantation or TIPS.

Nuclear translocation of YAP drives BMI-associated hepatocarcinogenesis in hepatitis B virus infection.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)-dependent neoplastic transformation. METHODS: Liver tissue and hepatocytes from HBsAg-transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV-related HCC biopsies. RESULTS: Hepatic expression signatures in HBsAg-transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg-transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16INK4a , p19ARF , p53 and Caspase 3 as well as increased Cyclin D1 and γ-H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual-luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non-tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof-of-concept, treatment of HBsAg-transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1-related cell cycle. CONCLUSION: HBV-associated proliferative HCC might be related to the HBsAg-YAP-BMI1 axis and offer a potential target for the development of new therapeutic approaches.

Regional transplant rates depend more on physician-dependent variables than on proximity to transplant center.

PURPOSE: The objective of this work was to uncover inequalities in access to liver transplantation in Bavaria, Germany. METHODS: For this purpose, the annual transplantation rate per 1 million inhabitants for the respective districts was determined from the aggregated postal codes of the place of residence of transplanted patients. The variables examined were proximity and travel time to the nearest transplant center, as well as the care category of the regional hospital. In addition, we assessed whether the head of gastroenterology at the regional hospital through which liver transplant candidates are referred was trained at a liver transplant center. RESULTS: We could not demonstrate a direct relationship between proximity or travel time to the nearest transplant center and access to liver transplantation. Multivariate regression analysis shows that liver transplant training (p < 0.0001) of the chief physician (gastroenterologist) of the regional hospital was the most decisive independent factor for access to liver transplantation within a district. CONCLUSION: We show that the transplant training experience of the head of gastroenterology at a regional hospital is an independent factor for the regional transplantation rate. Therefore, it appears important to maintain some liver transplant expertise outside the transplant centers in order to properly identify and assign potential transplant candidates for transplantation.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

BISCIT: Biliary interventions in critically ill patients with secondary sclerosing cholangitis-a study protocol for a multicenter, randomized, controlled parallel group trial.

BACKGROUND: Progress of cholangitis to cholangiosepsis is a frequent observation in patients with secondary sclerosing cholangitis in critically ill patients (SSC-CIP). Adequate biliary drainage may reduce episodes of cholangiosepsis and therefore stabilize liver function and improve survival. The primary objective of the BISCIT study is to demonstrate that scheduled biliary interventions will reduce incidence of cholangiosepsis, liver transplantation, or death in patients with SSC-CIP. METHODS: A total of 104 patients will be randomized at ten study sites. Patients with SSC-CIP, confirmed by endoscopic retrograde cholangiography (ERC), will be randomized 1:1 either in the intervention group which will be treated with scheduled biliary interventions (i.e., therapeutic ERC) every 8 weeks for 6 months or in the control group which will receive standard of care. The randomization will be stratified by center. The composite primary efficacy endpoint is defined as (1) occurrence of death, (2) necessity of liver transplantation, or (3) occurrence of cholangiosepsis within 6 months following randomization. DISCUSSION: Prospective evaluation of endoscopic treatment procedures is urgently needed to establish an evidence-based therapeutic treatment algorithm in SSC-CIP. A positive trial result could change the current standard of care for patients with SSC-CIP. The results of this study will be disseminated through presentations at international congresses, workshops, and peer-reviewed publications. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT05396755, date of registration: May 31, 2022, last update: May 31, 2022).

Indocyanine green clearance predicts outcome in patients undergoing transcatheter valve intervention for severe atrio-ventricular valve regurgitation.

OBJECTIVES: Severe mitral regurgitation (MR) and tricuspid regurgitation (TR) aggravate haemodynamic stress leading to congestive heart failure with impaired hepatic function, also known as cardiohepatic syndrome (CHS). Current perioperative risk calculators do not sufficiently consider CHS and serum liver function parameters lack sensitivity to diagnose CHS. Indocyanine green and its elimination (measured by the LIMON® test) represent a dynamic and non-invasive test which correlates with the hepatic function. Nevertheless, its utility in the setting of transcatheter valve repair/replacement (TVR) to predict CHS and outcome remains unknown. METHODS: We analysed liver function and outcomes of patients undergoing TVR for MR or TR between August 2020 and May 2021 at the Munich University Hospital. RESULTS: Out of a total of 44 patients treated at the University Hospital of Munich, 21 (48%) were treated for severe MR, 20 (46%) for severe TR and 3 (7%) for both diseases. Procedural success defined as MR/TR ≤2+ was 94% among MR patients and 92% among TR patients. While classical serum liver function parameters did not change after TVR, there was a significant improvement in liver function as assessed by the LIMON® test (P ≤ 0.001). Patients with baseline indocyanine green plasma disappearance rate <12.95%/min showed significantly increased 1-year mortality (hazard ratio: 1.54, 95% confidence interval: 1.05-2.25, P = 0.027) and lower New York Hear Association class improvement (P = 0.05). CONCLUSIONS: Especially in the context of the recently stressed importance of a careful patient selection prior to the interdisciplinary treatment of valvular heart disease, the LIMON® test may provide further real-time information on the patients' cardiohepatic injury and prognosis.

Evolution of non-thyroidal illness syndrome in acute decompensation of liver cirrhosis and acute-on-chronic liver failure.

Background and aims: Non-thyroidal illness syndrome (NTIS) is frequent in critically ill patients and associated with adverse outcomes. We aimed to characterize the evolution of NTIS in patients with acute decompensation (AD) of cirrhosis and acute-on-chronic liver failure (ACLF), since NTIS is not well described in these newly defined syndromes. Methods: Thyroid hormones (TH) were quantified at baseline in consecutive patients with cirrhosis. In addition, 76 inflammatory mediators were quantified by proximity extension analysis assay in a subgroup of patients. Associations between TH, cirrhosis stage, mortality and inflammation were assessed. Results: Overall, 437 patients were included, of whom 165 (37.8%), 211 (48.3%), and 61 (14%) had compensated cirrhosis (CC), AD, and ACLF. FT3 concentrations were lower in AD versus CC, and further decreased in ACLF. Importantly, NTIS was present in 83 (39.3%) patients with AD and in 44 (72.1%) patients with ACLF (P<0.001). Yet, TSH and TSH-based indexes (TSH/FT3-ratio, thyroid index) showed an U-shaped evolution during progression of cirrhosis, suggesting a partially preserved responsiveness of the hypothalamus and pituitary in AD. Infections were associated with lower FT3 concentrations in AD, but not in ACLF. Low FT3 concentrations correlated significantly with 90-day mortality. Both, AD/ACLF and NTIS, were associated with signatures of inflammatory mediators, which were partially non-overlapping. Conclusion: NTIS is frequent already in AD and therefore precedes critically illness in a subgroup of patients with decompensated cirrhosis. This might constitute a new paradigm of TH signaling in cirrhosis, offering opportunities to explore preventive effects of TH in AD.

Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments. METHODS: The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed. RESULTS: Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80%) HCC and a preserved liver function as defined by Child-Pugh A (80%). At a median follow-up of 15.3 months, ORR for ipilimumab and nivolumab was 30% with a DCR of 40%. Median PFS was 2.9 months and the median OS was 7.4 months. CONCLUSION: This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination therapies and provides a rationale for the prospective clinical evaluation of this treatment sequencing.

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells.

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

Pathological neutrophil migration predicts adverse outcomes in hospitalized patients with liver cirrhosis.

BACKGROUND AND AIMS: Given the early response of neutrophil granulocytes to infections, detection of pathological neutrophil migration might help in predicting adverse events in patients with liver cirrhosis. METHODS: Migration of blood neutrophils in hospitalized patients with cirrhosis was characterized by a novel standardized migration assay. Pathological neutrophil migration patterns were associated with a composite endpoint of ACLF, sepsis or death within 7 or 30 days. RESULTS: Overall, 125 patients were included, of whom 11 (8.8%) had compensated cirrhosis, 84 (67.2%) had acute decompensation (AD) and 30 (24%) had acute-on-chronic liver failure (ACLF). The migration response of neutrophils from patients with AD or ACLF to stimulation with the chemotactic formylpeptide f-Met-Leu-Phe (fMLP) was significantly impaired, while the response to chemokine (C-X-C motif)-ligand 8 (CXCL8) was affected less pronouncedly. In contrast, no relevant differences in response to CXCL1 were observed. Of note, neutrophils of a number of patients with AD and ACLF were largely immotile at resting and stimulated conditions. Patients with non-migrating neutrophils at unstimulated conditions were at high risk to develop the composite endpoint of ACLF, sepsis or death. Moreover, expression of chemokine receptors CXCR1 and CXCR2 was significantly decreased in patients with ACLF. Interestingly, the expression of chemokine receptors did not correlate with neutrophil migration patterns, but-based on the increased expression of the cell surface markers CD66b and CD177-neutrophils of patients with AD and ACLF were strongly pre-activated. CONCLUSION: Pathological neutrophil migration in patients with cirrhosis indicates a high risk of developing adverse outcomes.

[Use of Thrombopoetin-Receptor-Agonists (TPO-RA) in patients with liver cirrhosis before invasive procedures]. / Einsatz von Thrombopoetin-Rezeptor-Agonisten (TPO-RA) vor invasiven Eingriffen bei Patienten mit Leberzirrhose.

Advanced chronic liver disease is accompanied with relevant changes in the corpuscular and plasmatic coagulation system. Due to thrombocytopenia that is regularly observed in these patients, platelet transfusions are often performed prior invasive procedures to prevent possible bleeding complications. However, platelet transfusions are associated with clinically significant adverse events and economically relevant health care costs. Thus, avoiding unnecessary platelet transfusions remains pivotal in daily clinical practice. The first step is to carefully check if increasing platelet counts prior to a planned invasive procedure is really necessary. Nowadays, two well-tolerated thrombopoetin-receptor agonists (TPO-RAs), Avatrombopaq and Lusutrombopaq, to treat thrombocytopenia preemptively before an invasive procedure in patients with liver cirrhosis are available. This review provides a guide for clinician when to increase platelet counts prior an invasive procedure in patients with liver cirrhosis and helps to identify situations in which the use of TPO-RA may be reasonable.

Prediction of left lobe hypertrophy after right lobe radioembolization of the liver using a clinical data model with external validation.

In cirrhotic patients with hepatocellular carcinoma (HCC), right-sided radioembolization (RE) with Yttrium-90-loaded microspheres is an established palliative therapy and can be considered a "curative intention" treatment when aiming for sequential tumor resection. To become surgical candidate, hypertrophy of the left liver lobe to > 40% (future liver remnant, FLR) is mandatory, which can develop after RE. The amount of radiation-induced shrinkage of the right lobe and compensatory hypertrophy of the left lobe is difficult for clinicians to predict. This study aimed to utilize machine learning to predict left lobe liver hypertrophy in patients with HCC and cirrhosis scheduled for right lobe RE, with external validation. The results revealed that machine learning can accurately predict relative and absolute volume changes of the left liver lobe after right lobe RE. This prediction algorithm could help to estimate the chances of conversion from palliative RE to curative major hepatectomy following significant FLR hypertrophy.