Unsolved Questions in Salvage TIPSS: Practical Modalities for Placement, Alternative Therapeutics, and Long-Term Outcomes

Salvage transjugular intrahepatic portosystemic shunt (TIPSS) has proven its efficacy to treat refractory variceal bleeding for patients with cirrhosis. However, this procedure is associated with very poor outcomes. As it is used as a last resort to treat a severe complication of cirrhosis, it seems essential to improve our practice, with the aim of optimizing management of those patients. Somehow, many questions are still unsolved: which stents should be used? Should a concomitant embolization be systematically considered? Is there any alternative therapeutic in case of recurrent bleeding despite TIPSS? What are the long-term outcomes on survival, liver transplantation, and hepatic encephalopathy after salvage TIPSS? Is this procedure futile in some patients? Is prognosis with salvage TIPSS nowadays as bad as earlier, despite the improvement of prophylaxis for variceal bleeding? The aim of this review is to summarize those data and to identify the lacking ones to guide further research on salvage TIPSS

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

Background: Hepatic encephalopathy (HE) is highly prevalent in patients with liver diseases. The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation. However, some data suggest altered functioning of the blood–brain barrier (BBB). Assessing BBB function is challenging in clinical practice and at the bedside. Protein-S-100 Beta (PS100-Beta) could be a useful peripheral marker of BBB permeability in HE. This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit (ICU) with decompensated cirrhosis with and without overt HE. Methods: We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement. Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded. Overt HE was defined as West-Haven grades 2 to 4. The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes. After ICU discharge, the patients were followed for at least 3 months for the occurrence of overt HE. Adverse outcomes (liver transplantation or death) were collected. The ability of PS100-Beta – in combination with other factors – to predict overt HE was evaluated in a multivariate analysis using logistic regression. Likelihood ratios were used to determine the effects and calculate odds ratios (OR). Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test. Results: A total of 194 ICU patients and 207 outpatients were included in the study. Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients ([0.15±0.01] mg/L vs. [0.08±0] mg/L, P <0.001). ICU patients with overt HE had higher levels of PS100-Beta ([0.19±0.03] mg/L) compared with the ICU patients without overt HE ([0.13±0.01] mg/L) (P=0.003). PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis (P=0.670). PS100-Beta values were correlated with Child-Pugh score (P <0.001), Model for End-Stage Liver Disease (MELD) score (P=0.004), C-reactive protein (P <0.001), ammonemia (P <0.001), and chronic liver failure consortium (CLIF-C) organ failure (P <0.001) and CLIF-C acute-on-chronic (P=0.038) scores, but not with leukocytes (P=0.053), procalcitonin (PCT) (P=0.107), or the lymphocyte-to-neutrophil ratio in ICU patients (P=0.522). In a multivariate model including age, ammonemia, PS100-Beta, PCT, MELD, presence of transjugular portosystemic shunt, and sodium level, the diagnostic performance was 0.765 for the diagnosis of overt HE. Patients with a PS100-Beta level <0.12 mg/L had a better overall survival (P=0.019) and a better survival without liver transplantation (P=0.013). Conclusions: Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis, and even more so in those displaying overt HE, and the levels are correlated with outcome. This suggests an increase in the permeability of the BBB in these patients

Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies

International audienceBiochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N-terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T-cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single-molecule assay (Simoa) to distinguish the full-length CXCL101-77 from the NH2-truncated CXCL103-77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103-77 concentration, a reciprocal increase in CXCL101-77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors

Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy

International audienceBACKGROUND & AIMS:Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort.METHODS:We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results.RESULTS:We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication.CONCLUSION:These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infectio

Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing

International audienceDespite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival

Background and aims. Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies.Methods. Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx).Results. A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival.Conclusions. This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival

Impact of IL28B, APOH and ITPA polymorphisms on efficacy and safety of TVR- or BOC-based triple therapy in treatment-experienced HCV-1 patients with compensated cirrhosis from the ANRS CO20_CUPIC study

Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1

Prevalence of minimal hepatic encephalopathy in patients with liver cirrhosis: a multicenter study

Objectives: The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high-risk and to pave the way for personalized screening approaches. Methods: In this study, data of patients recruited at 10 centers across Europe and the US were analyzed. Only patients without clinical signs of HE were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. Results: In total, 1868 patients with cirrhosis with a median MELD of 11 were analyzed (Child-Pugh stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 (35%) patients. After excluding patients with a history of overt HE, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), while it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (spearman's rho=-0.16, p<0.001). Conclusions: The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches