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TIPS is the most effective treatment for portal hypertension. Patient selection remains important to achieving optimal post-TIPS outcomes. The study evaluates 1-year mortality factors in cirrhotic patients receiving TIPS., Methods: 87 cirrhotic patients received a TIPS between 2015 - 2021. Predictors of 1-year and overall mortality were assessed by estimating cumulative incidence functions and Grey's test to adjust for liver transplantation as a risk competing with mortality. Variables with p < 0.05 were checked for collinearity and included in the multivariate Cox proportional hazards model. Model discrimination was evaluated by calculating the area under the ROC curve., Results: 87 patients were included (68% men; 22% ≥70 years). ALD was the primary cirrhosis cause. Most patients were Child-Pugh class B, MELD-Na score was 13.6 ± 6.0 points. The most frequent indication for TIPS was bleeding (51.7%), followed by refractory ascites (42.5%). The variables positively associated with mortality in univariate analysis were ascites, clinically overt sarcopenia and MELD-Na score, while ongoing nutritional supplementation improved survival. In the multivariate analysis, only clinically overt sarcopenia and MELD-Na score remained independently associated with mortality. A MELD-Na/sarcopenia model demonstrated a good discrimination, AUROC: 0.86 (95% CI 0.77 - 0.95)., Conclusion: MELD-Na score, and sarcopenia were significantly associated with 1-year survival in cirrhotic patients who received TIPS., Competing Interests: Conflict of Interest The authors declare that there are not conflicts of interest regarding the manuscript “Combination of Model for End-Stage Liver Disease (MELD) and Sarcopenia predicts Mortality after transjugular intrahepatic portosystemic shunt (TIPS)”. The authors have no financial, personal or professional affiliations that could influence or bias the content and findings presented in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG > 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients., Approach and Results: This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664-0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model's performance [C-index of 0.808 (CI95% 0.735-0.882); p =0.032]. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710-0.860), not significantly different from the HVPG-based models including or not metabolites., Conclusions: In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aims: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis., Approach and Results: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events., Conclusions: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aims: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm., Approach and Results: Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome-stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held-out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver-related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML-HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P < 0.001). The ML HVPG score differentiated patients with normal (0-5 mm Hg) and elevated (5.5-9.5 mm Hg) HVPG and CSPH (median: 1.51 vs. 1.93 vs. 2.60; all P < 0.05). The areas under receiver operating characteristic curve (AUROCs) (95% CI) of the ML-HVPG score for CSPH were 0.85 (0.80, 0.90) and 0.76 (0.68, 0.85) in the training and test sets, respectively. Discrimination of the ML-HVPG score for CSPH improved with the addition of a ML parameter for nodularity, Enhanced Liver Fibrosis, platelets, aspartate aminotransferase (AST), and bilirubin (AUROC in test set: 0.85; 95% CI: 0.78, 0.92). Although baseline ML-HVPG score was not prognostic, changes were predictive of clinical events (HR: 2.13; 95% CI: 1.26, 3.59) and associated with hemodynamic response and fibrosis improvement., Conclusions: An ML model based on trichrome-stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis., (© 2021 by the American Association for the Study of Liver Diseases.)

Background & Aims: In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD., Methods: Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle., Results: TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor., Conclusions: Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD., Lay Summary: Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects., Competing Interests: Conflicts of interest C.R., P.B., J-L.J. and G.W. are employees of Inventiva. All other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice., Methods: This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH., Results: A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences of portal hypertension in patients with NASH were maintained across different strata of LSM values. LSM ≥25 kPa was the best cutoff to rule in CSPH in alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, and nonobese patients with NASH, whereas in obese NASH patients, the positive predictive value was only 62.8%. A new model for patients with NASH (ANTICIPATE-NASH model) to predict CSPH considering body mass index, LSM, and platelet count was developed, and a nomogram was constructed. LSM ≤15 kPa plus platelets ≥150 × 10/L ruled out CSPH in most etiologies., Discussion: Patients with cACLD of NASH etiology, especially obese patients with NASH, present lower prevalences of portal hypertension compared with other cACLD etiologies. LSM ≥25 kPa is sufficient to rule in CSPH in most etiologies, including nonobese patients with NASH, but not in obese patients with NASH.

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date., Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality., Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not., Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB., Lay Summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt., Competing Interests: Conflict of interest Christophe Bureau has received speaker fees from GORE and is a board member of Alfawassemran/Norgine. Virginia Hernández - Gea, Álvaro Giráldez, Jaume Bosch, Agustin Albillos, Dominique Thabut, Michael Praktiknjo and Frederik Nevens have received speaker fees from GORE. Juan Carlos Garcia – Pagan has received consultant fees from GORE, Shionogi and Cook grants from GORE and Novartis. Jonel Trebicka has received speaking and/or consulting fees from GORE, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, and Martin Pharmaceutical, and Rafael Bañares has received speaker fees from GORE and Grifols, unrelated to the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Treatment of refractory ascites in liver cirrhosis is challenging. Transjugular intrahepatic portosystemic shunt and alfapump® have been proposed for the management, but few data comparing both exist., Aims: The aim of this study was to evaluate the characteristics and outcomes of patients treated with transjugular intrahepatic portosystemic shunt and alfapump® for refractory ascites at our centre., Methods: All consecutive patients were retrospectively reviewed for baseline characteristics, efficacy of treatment, complications and survival., Results: In total, 19 patients with transjugular intrahepatic portosystemic shunt and 40 patients with alfapump® were included. Patients with transjugular intrahepatic portosystemic shunt had better liver function and less hepatic encephalopathy at baseline. Fifty-eight per cent of patients developed hepatic encephalopathy in the first six months after transjugular intrahepatic portosystemic shunt. In patients with alfapump®, renal function decreased and 58% developed prerenal impairment and 43% hepatorenal syndrome in the first six months. Alfapump® patients with new catheters required less reinterventions (26% versus 57% with old catheters, p  = 0.049). Transplant-free survival at 1 year was 25% in alfapump® and 65% in transjugular intrahepatic portosystemic shunt. Hepatic encephalopathy predicted transplant-free survival in patients with alfapump® (hazard ratio 2.00, 95% confidence interval 0.99-4.02, p  = 0.05). In a sensitivity analysis comparing patients with similar liver function, the rate of hepatorenal syndrome and prerenal impairment was higher in patients with alfapump® and these patients were hospitalised more frequently, whereas the rate of hepatic encephalopathy was similar in both treatment groups., Conclusions: Both transjugular intrahepatic portosystemic shunt and alfapump® were effective treatments for refractory ascites in cirrhosis. Patients treated with transjugular intrahepatic portosystemic shunt had a better one-year transplant-free survival but had less negative prognostic factors at baseline. Selecting patients without hepatic encephalopathy prior to implantation of an alfapump® might improve transplant-free survival.

Background and Aims: A hepatic venous pressure gradient (HVPG) decrease of 20% or more (or ≤12 mm Hg) indicates a good prognosis during propranolol/nadolol treatment but requires two HVPG measurements. We aimed to simplify the risk stratification after variceal bleeding using clinical data and HVPG., Methods: A total of 193 patients with cirrhosis (62% with ascites and/or hepatic encephalopathy [HE]) who were within 7 days of bleeding had their HVPG measured before and at 1-3 months of treatment with propranolol/nadolol plus endoscopic band ligation. The endpoints were rebleeding and rebleeding/transplantation-free survival for 4 years. Another cohort (n = 231) served as the validation set., Results: During follow-up, 45 patients had variceal bleeding and 61 died. The HVPG responders (n = 71) had lower rebleeding risk (10% vs. 34%, P = 0.001) and better survival than the 122 nonresponders (61% vs. 39%, P = 0.001). Patients with HE (n = 120) had lower survival than patients without HE (40% vs. 63%, P = 0.005). Among the patients with ascites/HE, those with baseline HVPG ≤ 16 mm Hg (n = 16) had a low rebleeding risk (13%). In contrast, among patients with ascites/HE and baseline HVPG > 16 mm Hg, only the HVPG responders (n = 32) had a good prognosis, with lower rebleeding risk and better survival than the nonresponders (n = 72) (respective proportions: 7% vs. 39%, P = 0.018; 56% vs. 30% P = 0.010). These findings allowed us to develop a strategy for risk stratification in which HVPG response was measured only in patients with ascites and/or HE and baseline HVPG > 16 mm Hg. This method reduced the "gray zone" (i.e., high-risk patients who had not died on follow-up) from 46% to 35% and decreased the HVPG measurements required by 42%. The validation cohort confirmed these results., Conclusions: Restricting HVPG measurements to patients with ascites/HE and measuring HVPG response only if the patient's baseline HVPG is over 16 mm Hg improves detection of high-risk patients while markedly reducing the number of HVPG measurements required., (© 2020 by the American Association for the Study of Liver Diseases.)

In the recent years, there have been an increasing number of reports on favourable effects of statins in patients with advanced chronic liver disease. These include reduction in portal pressure, improved liver sinusoidal endothelial and hepatic microvascular dysfunction, decreased fibrogenesis, protection against ischaemia/reperfusion injury, safe prolongation of ex vivo liver graft preservation, reduced sensitivity to endotoxin-mediated liver damage, protection from acute-on-chronic liver failure, prevention of liver injury following hypovolaemic shock and preventing/delaying progression of cirrhosis of any aetiology. Moreover, statins have been shown to have potential beneficial effects in the progression of other liver diseases, such as chronic sclerosing cholangitis and in preventing hepatocellular carcinoma. Because of these many theoretically favourable effects, statins have evolved from being considered a risk to kind of wonder drugs for patients with chronic liver diseases. The present article reviews the current knowledge on the potential applications of statins in chronic liver diseases, from its mechanistic background to objective evidence from clinical studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis., Methods: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes., Results: There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups., Conclusions: Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated., Lay Summary: Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients., Clinical Trial Number: Clinical Trials.gov #NCT02960204., Competing Interests: Conflict of interest Jean L. Chan, James Robinson, and David T. Hagerty are employees of Conatus Pharmaceuticals. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo-controlled trials of simtuzumab. The trials were terminated after 96 weeks because of lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening and at weeks 48 and 96. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha-smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis. Associations with progression to cirrhosis (in patients with F3 fibrosis) and liver-related clinical events (in patients with F4 fibrosis) were determined. Progression to cirrhosis occurred in 22% (48/217) of F3 patients, and liver-related clinical events occurred in 19% (50/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha-smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% confidence interval, 1.28-67.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver-related clinical events in patients with cirrhosis. Disease progression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. Conclusion: In patients with advanced fibrosis due to NASH, the primary determinant of clinical disease progression is fibrosis and its change over time., (© 2019 by the American Association for the Study of Liver Diseases.)

Background & Aims: Patients with hepatic venous pressure gradients (HVPGs) of 10 mm Hg or greater and chronic liver disease often are assumed to have cirrhosis. We investigated the association between HVPGs and cirrhosis, using histologic findings as the reference standard. We also assessed the prevalence and characteristics of patients with HVPGs of 10 mm Hg or greater without cirrhosis., Methods: We performed a retrospective analysis of 157 consecutive patients, 89 with suspected cirrhosis and hepatic hemodynamic data collected from 2015 through 2017. Biopsy specimens collected had 10 or more portal tracts from each patient and were analyzed for features of cirrhosis. Biopsy specimens with histologic features of cirrhosis were excluded and the remaining biopsy specimens were re-reviewed by an expert pathologist. The fibrosis area was calculated digitally by image analysis., Results: HVPG identified patients with cirrhosis with an area under the receiver operating characteristic curve of 0.879: 14 of 89 patients with HVPG of 10 mm Hg or greater (16%) had no histologic features of cirrhosis (METAVIR scores <4 and Ishak scores <6). The median HVPG was 11 mm Hg (range, 10-22 mm Hg). Based on METAVIR scores, 7 patients had fibrosis stage F3, 4 patients had fibrosis stage F2, and 3 patients had fibrosis stages F0 or F1. The mean area of fibrosis in livers was 16.2% ± 6.5%. All 14 patients had perisinusoidal fibrosis and 8 patients had hepatocyte ballooning. The most common diagnoses were nonalcoholic steatohepatitis (n = 5) and nodular regenerative hyperplasia (n = 4). An HVPG cut-off value of 12 mm Hg identified patients with cirrhosis with 92% specificity, misclassifying 5 patients with different etiologies of liver disease., Conclusions: In a retrospective analysis of 89 consecutive patients with chronic liver disease and an HVPG of 10 mm Hg or greater, 16% were not found to have cirrhosis upon biopsy analysis. Most of these patients had nonalcoholic steatohepatitis or nodular regenerative hyperplasia. Perisinusoidal fibrosis and hepatocyte ballooning might increase sinusoidal pressure. An HVPG cut-off value of 12 mm Hg or greater identified patients with cirrhosis with 92% specificity., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Failure to control variceal bleeding with current recommendations occurs in 10 to 20% of cases. This systematic review and meta-analysis analyzes the experience, results, and complications of "bridge" therapies for failure to control acute variceal bleeding: balloon tamponade and esophageal stents. The main outcomes assessed were failure to control bleeding and mortality in the short-term and medium-term follow-up, and adverse events. Balloon tamponade studies had a pooled rate of short-term failure to control bleeding of 35.5%, and adverse events in over 20% of cases; 9.7% resulting in death. Stenting failed to control bleeding in the short term and medium term in 12.7 and 21.5% of cases of severe or refractory variceal bleeding, respectively, despite stent migration in 23.8% of cases. Medium-term mortality rates were similar in both therapies. Although only one trial compared these treatments, the available evidence consistently supports that stents serve as a better and safer bridge therapy in refractory acute variceal bleeding., Competing Interests: Dr. Bosch report grants and personal fees from Conatus, grants from Gilead, personal fees from Actelion, personal fees from Biovie, grants and personal fees from Brudy, personal fees from BLB, personal fees from Exallenz, outside the submitted work; In addition, Dr. Bosch has a patent biofluidixc biosystem licensed to BLB, and a patent CLEVER software licensed to Ymaging., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta-blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners., (© 2018 by the American Association for the Study of Liver Diseases.)

Background & Aims: Although patients with cryptogenic cirrhosis have historically been considered as having "burnt-out" non-alcoholic steatohepatitis (NASH), some controversy remains. The aim of this study was to compare outcomes of patients with cryptogenic cirrhosis and NASH-related cirrhosis from a cohort with longitudinal follow-up data., Methods: Patients with cryptogenic cirrhosis or NASH cirrhosis were screened for a clinical trial. Patients with <5% hepatic steatosis regardless of other histologic features were considered to have cryptogenic cirrhosis. Clinico-laboratory data and adjudicated liver-related events (e.g. decompensation, qualification for transplantation, death) were available., Results: A total of 247 patients with cirrhosis (55.3 ± 7.4 years, 37% male) were included; 144 had NASH cirrhosis and 103 had cryptogenic cirrhosis. During a median follow-up of 29 (IQR 21-33) months (max 45 months), 20.6% of patients had liver-related clinical events. Patients with NASH cirrhosis and cryptogenic cirrhosis were of a similar age and gender, as well as having a similar body mass index, PNPLA3 rs738409 genotype, and prevalence of diabetes (p >0.05). However, patients with cryptogenic cirrhosis had higher serum fibrosis markers and greater collagen content and α-smooth muscle actin expression on liver biopsy. Compared to cirrhotic patients with NASH, patients with cryptogenic cirrhosis experienced significantly shorter mean time to liver-related clinical events (12.0 vs. 19.4 months; p = 0.001) with a hazard ratio of 1.76 (95% CI 1.02-3.06)., Conclusions: Populations with NASH and cryptogenic cirrhosis have similar demographics, but patients with cryptogenic cirrhosis have evidence of more active fibrosis and a higher risk of liver-related clinical events. Thus, we believe these patients belong to the same spectrum of disease, with cryptogenic cirrhosis representing a more advanced stage of fibrosis., Lay Summary: Significant liver damage and cirrhosis of the liver may develop without a known cause - a liver disease referred to as cryptogenic cirrhosis. In this work we found that, in the presence of metabolic abnormalities, cryptogenic cirrhosis may actually be a part of the non-alcoholic fatty liver disease spectrum. Yet, it appears to be more progressive than typical non-alcoholic fatty liver disease, leading to advanced liver disease at a faster rate., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Overt hepatic encephalopathy (OHE) negatively impacts the prognosis of liver transplant candidates. However, it is not taken into account in most prioritizing organ allocation systems. We aimed to assess the impact of OHE on waitlist mortality in 3 cohorts of cirrhotic patients awaiting liver transplantation, with differences in the composition of patient population, transplantation policy, and transplantation rates. These cohorts were derived from two centers in the Netherlands (reference and validation cohort, n = 246 and n = 205, respectively) and one in Spain (validation cohort, n = 253). Competing-risk regression analysis was applied to assess the association of OHE with 1-year waitlist mortality. OHE was found to be associated with mortality, independently of MELD score, other cirrhosis-related complications and hepatocellular carcinoma (HCC; sHR = 4.19, 95% CI = 1.9-9.5, P = 0.001). The addition of extra MELD points for OHE counteracted its negative impact on survival. These findings were confirmed in the Dutch validation cohort, whereas in the Spanish cohort, containing a significantly greater proportion of HCC and with higher transplantation rates, OHE was not associated with mortality. In conclusion, OHE is an independent risk factor for 1-year waitlist mortality and might be a prioritization rule for organ allocation. However, its impact seems to be attenuated in settings with significantly higher transplantation rates., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Cirrhosis and its clinical consequences can be aggravated by bacterial infections, ultimately leading to the development of acute on chronic liver failure (ACLF), characterized by acute decompensation, organ failure, and high mortality within 28 days. Little is known about cellular and molecular mechanisms of ACLF in patients with cirrhosis, so no therapeutic options are available. We developed a sepsis-associated preclinical model of ACLF to facilitate studies of pathogenesis and evaluate the protective effects of simvastatin., Methods: Male Wistar rats inhaled CCl 4 until they developed cirrhosis (at 10 weeks) or cirrhosis with ascites (at 15-16 weeks). Male Sprague-Dawley rats received bile-duct ligation for 28 days or intraperitoneal thioacetamide for 10 weeks to induce cirrhosis. After induction of cirrhosis, some rats received a single injection of lipopolysaccharide (LPS) to induce ACLF; some were given simvastatin or vehicle (control) 4 hours or 24 hours before induction of ACLF. We collected data on changes in hepatic and systemic hemodynamics, hepatic microvascular phenotype and function, and survival times. Liver tissues and plasma were collected and analyzed by immunoblots, quantitative polymerase chain reaction, immuno(fluoro)histochemistry and immunoassays., Results: Administration of LPS aggravated portal hypertension in rats with cirrhosis by increasing the severity of intrahepatic microvascular dysfunction, exacerbating hepatic inflammation, increasing oxidative stress, and recruiting hepatic stellate cells and neutrophils. Rats with cirrhosis given LPS had significantly shorter survival times than rats with cirrhosis given the control. Simvastatin prevented most of ACLF-derived complications and increased survival times. Simvastatin appeared to increase hepatic sinusoidal function and reduce portal hypertension and markers of inflammation and oxidation. The drug significantly reduced levels of transaminases, total bilirubin, and ammonia, as well as LPS-mediated activation of hepatic stellate cells in liver tissues of rats with cirrhosis., Conclusions: In studies of rats with cirrhosis, we found administration of LPS to promote development of ACLF, aggravating the complications of chronic liver disease and decreasing survival times. Simvastatin reduced LPS-induced inflammation and liver damage in rats with ACLF, supporting its use in treatment of patients with advanced chronic liver disease., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis., Methods: We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96., Results: The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (-0.2%, 95% confidence interval [CI] -1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (-0.4%, 95% CI -1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI -1.2 to 1.5, P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups., Conclusion: In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.govNCT01672866 and NCT01672879., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Portal hypertension is a key complication of portal hypertension, which is responsible for the development of varices, ascites, bleeding, and hepatic encephalopathy, which, in turn, cause a high mortality and requirement for liver transplantation., Aim: This review deals with the present day state-of-the-art preventative treatments of portal hypertension in cirrhosis according to disease stage. Two main disease stages are considered, compensated and decompensated cirrhosis, the first having good prognosis and being mostly asymptomatic, and the second being heralded by the appearance of bleeding or non-bleeding complications of portal hypertension., Results: The aim of treatment in compensated cirrhosis is preventing clinical decompensation, the more frequent event being ascites, followed by variceal bleeding and hepatic encephalopathy. Complications are mainly driven by an increase of hepatic vein pressure gradient (HVPG) to values ≥10 mmHg (defining the presence of Clinically Significant Portal Hypertension, CSPH). Before CSPH, the treatment is limited to etiologic treatment of cirrhosis and healthy life style (abstain from alcohol, avoid/correct obesity…). When CSPH is present, association of a non-selective beta-blocker (NSBB), including carvedilol should be considered. NSBBs are mandatory if moderate/large varices are present. Patients should also enter a screening program for hepatocellular carcinoma. In decompensated patients, the goal is to prevent further bleeding if the only manifestation of decompensation was a bleeding episode, but to prevent liver transplantation and death in the common scenario where patients have manifested first non-bleeding complications. Treatment is based on the same principles (healthy life style..) associated with administration of NSBBs in combination if possible with endoscopic band ligation if there has been variceal bleeding, and complemented with simvastatin administration (20-40 mg per day in Child-Pugh A/B, 10-20 mg in Child C). Recurrence shall be treated with TIPS. TIPS might be indicated earlier in patients with: 1) Difficult/refractory ascites, who are not the best candidates for NSBBs, 2) patients having bleed under NSBBs or showing no HVPG response (decrease in HVPG of at least 20% of baseline or to values equal or below 12 mmHg). Decompensated patients shall all be considered as potential candidates for liver transplantation., Conclusion: Treatment of portal hypertension has markedly improved in recent years. The present day therapy is based on accurate risk stratification according to disease stage.

Background: Variceal bleeding is a major complication of portal hypertension, which is associated with significant mortality. Moreover, patients surviving a variceal bleeding episode have very high risk of rebleeding, which is associated with mortality as high as that of the first bleed. Because of this, prevention of bleeding from gastroesophageal varices has been one of the main therapeutic goals since the advent of the first effective therapies for portal hypertension., Aim: This review deals with the present day state-of-the-art pharmacological prevention of variceal bleeding in primary and secondary prophylaxis., Results: Pharmacological therapy aims to decrease portal pressure (PP) by acting on the pathophysiological mechanisms of portal hypertension such as increased hepatic vascular tone and splanchnic vasodilatation. Propranolol and nadolol block the beta-1 in the heart and the peripheral beta-2 adrenergic receptors. Beta-1 blockade of cardiac receptors reduces heart rate and cardiac output and subsequently decreases flow into splanchnic circulation. Beta-2 blockade leads to unopposed alpha-1 adrenergic activity that causes splanchnic vasoconstriction and reduction of portal inflow. Both effects contribute to reduction in PP. Carvedilol is more powerful in reducing hepatic venous pressure gradient (HVPG) than traditional nonselective beta-blockers (NSBBs) and achieves good hemodynamic response in nearly 75 % of cases. Simvastatin and atorvastatin improve endothelial dysfunction mainly by enhancing endothelial nitric oxide synthase (eNOS) expression and phosphorylation and NO production. In addition, statins deactivate hepatic stellate cells and ameliorate hepatic fibrogenesis. These effects cause a decrease in HVPG and improve liver microcirculation and hepatocyte perfusion in patients with cirrhosis. In addition, several promising drugs under development may change the management of portal hypertension in the coming years., Conclusion: This review provides a background on the most important aspects of the treatment of portal hypertension in patients with compensated and decompensated liver cirrhosis. However, despite the great improvement in the prevention of variceal bleeding over the last years, further therapeutic options are needed.

Endoscopic variceal ligation plus beta-blockers (EVL+BB) is currently recommended for variceal rebleeding prophylaxis, a recommendation that extends to all patients with cirrhosis with previous variceal bleeding irrespective of prognostic stage. Individualizing patient care is relevant, and in published studies on variceal rebleeding prophylaxis, there is a lack of information regarding response to therapy by prognostic stage. This study aimed at comparing EVL plus BB with monotherapy (EVL or BB) on all-source rebleeding and mortality in patients with cirrhosis and previous variceal bleeding stratified by cirrhosis severity (Child A versus B/C) by means of individual time-to-event patient data meta-analysis from randomized controlled trials. The study used individual data on 389 patients from three trials comparing EVL plus BB versus BB and 416 patients from four trials comparing EVL plus BB versus EVL. Compared with BB alone, EVL plus BB reduced overall rebleeding in Child A (incidence rate ratio 0.40; 95% confidence interval, 0.18-0.89; P = 0.025) but not in Child B/C, without differences in mortality. The effect of EVL on rebleeding was different according to Child (P for interaction <0.001). Conversely, compared with EVL, EVL plus BB reduced rebleeding in both Child A and B/C, with a significant reduction in mortality in Child B/C (incidence rate ratio 0.46; 95% confidence interval, 0.25-0.85; P = 0.013)., Conclusion: Outcomes of therapies to prevent variceal rebleeding differ depending on cirrhosis severity: in patients with preserved liver function (Child A), combination therapy is recommended because it is more effective in preventing rebleeding, without modifying survival, while in patients with advanced liver failure (Child B/C), EVL alone carries an increased risk of rebleeding and death compared with combination therapy, underlining that BB is the key element of combination therapy. (Hepatology 2017;66:1219-1231)., (© 2017 by the American Association for the Study of Liver Diseases.)

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.

Obesity increases the risk of clinical decompensation in cirrhosis, possibly by increasing portal pressure. Whether weight reduction can be safely achieved through lifestyle (LS) changes (diet and exercise) in overweight/obese patients with cirrhosis, and if weight loss reduces portal pressure in this setting, is unknown. This prospective, multicentric, uncontrolled pilot study enrolled patients with compensated cirrhosis, portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mm Hg), and body mass index (BMI) ≥26 kg/m 2 in an intensive 16-week LS intervention program (personalized hypocaloric normoproteic diet and 60 min/wk of supervised physical activity). We measured HVPG, body weight (BW) and composition, adipokines, health-related quality of life, and safety data before and after the intervention. Changes in HVPG and BW were predefined as clinically relevant if ≥10% and ≥5%, respectively. Safety and BW were reassessed after 6 months. 60 patients were included and 50 completed the study (56 ± 8 years old; 62% male; nonalcoholic steatohepatitis etiology 24%; BMI 33.3 ± 3.2 kg/m 2 ; Child A 92%; HVPG ≥10 mm Hg, 72%). LS intervention significantly decreased BW (average, -5.0 ± 4.0 kg; P < 0.0001), by ≥5% in 52% and ≥10% in 16%. HVPG also significantly decreased (from 13.9 ± 5.6 to 12.3 ± 5.2 mm Hg; P < 0.0001), by ≥10% in 42% and ≥20% in 24%. A ≥10% BW loss was associated with a greater decrease in HVPG (-23.7 ± 19.9% vs. -8.2 ± 16.6%; P = 0.024). No episodes of clinical decompensation occurred. Weight loss achieved at 16 weeks was maintained at 6 months; Child and Model for End-Stage Liver Disease scores did not change., Conclusion: Sixteen weeks of diet and moderate exercise were safe and reduced BW and portal pressure in overweight/obese patients with cirrhosis and portal hypertension. (Hepatology 2017;65:1293-1305)., (© 2016 by the American Association for the Study of Liver Diseases.)

Variceal haemorrhage is a major complication of portal hypertension that still causes high mortality in patients with cirrhosis. Improved knowledge of the pathophysiology of portal hypertension has recently led to a more comprehensive approach to prevent all the complications of this condition. Thus, optimal treatment of portal hypertension requires a strategy that takes into account the clinical stage of the disease and all the major variables that affect the risk of progression to the next stage and death. In patients with compensated liver disease, the correction of factors influencing the progression of fibrosis, in particular aetiologic factors, is now feasible in many cases and should be achieved to prevent the development or progression of gastroesophageal varices and hepatic decompensation. Once gastroesophageal varices have developed, non-selective beta-blockers remain the cornerstone of therapy. Carvedilol provides a greater decrease in portal pressure and is currently indicated as a first-choice therapy for primary prophylaxis. The treatment of acute variceal haemorrhage includes a combination of vasoactive drugs, antibiotics and endoscopic variceal band ligation. In high-risk patients, the early use of transjugular intrahepatic portosystemic shunt (TIPS) lowers the risk of re-bleeding and improves survival. Transjugular intrahepatic portosystemic shunt is the choice for uncontrolled variceal bleeding; a self-expandable metal stent or balloon tamponade can be used as a bridging measure. The combination of non-selective beta-blockers and endoscopic variceal band ligation reduces the risk of recurrent variceal bleeding and improves survival. In these cases, statins seem to further improve survival. Transjugular intrahepatic portosystemic shunt is indicated in patients who rebleed during secondary prophylaxis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Counteracting splanchnic vasodilatation and increased portal-collateral blood flow has been the mainstay for the treatment of portal hypertension (PH) over the past three decades. However, there is still large room for improvement in the treatment of PH., Areas Covered: The basic mechanism leading to portal hypertension is the increased hepatic vascular resistance to portal blood flow caused by liver structural abnormalities inherent to cirrhosis and increased hepatic vascular tone. Molecules modulating microvascular dysfunction which have undergone preclinical and clinical trials are summarized, potential drug development issues are addressed, and situations relevant to design of clinical trials are considered., Expert Opinion: Experimental and clinical evidence indicates that molecules modulating liver microvascular dysfunction may allow for 30-40% reduction in portal pressure. Several agents could be utilized in the earlier stages of cirrhosis (antifibrotics, antiangiogenics, etiological therapies) may allow reduction of fibrosis and halt progression of PH. This 'nip at the bud' policy, by combining therapies with existing agents used in advanced phase of cirrhosis and novel agents which could be used in early phase of cirrhotic spectrum, which are likely to hit the market soon would be the future strategy for PH therapy.

Background & Aims: The combination of β-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis., Methods: We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a β-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding)., Results: The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group (P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15-0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group (P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group (P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group (P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis., Conclusions: In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Vascular endothelial growth factor (VEGF) regulates angiogenesis, yet therapeutic strategies to disrupt VEGF signaling can interfere with physiologic angiogenesis. In a search for ways to inhibit pathologic production or activities of VEGF without affecting its normal production or functions, we investigated the post-transcriptional regulation of VEGF by the cytoplasmic polyadenylation element-binding proteins CPEB1 and CPEB4 during development of portal hypertension and liver disease., Methods: We obtained transjugular liver biopsies from patients with hepatitis C virus-associated cirrhosis or liver tissues removed during transplantation; healthy human liver tissue was obtained from a commercial source (control). We also performed experiments with male Sprague-Dawley rats and CPEB-deficient mice (C57BL6 or mixed C57BL6/129 background) and their wild-type littermates. Secondary biliary cirrhosis was induced in rats by bile duct ligation, and portal hypertension was induced by partial portal vein ligation. Liver and mesenteric tissues were collected and analyzed in angiogenesis, reverse transcription polymerase chain reaction, polyA tail, 3' rapid amplification of complementary DNA ends, Southern blot, immunoblot, histologic, immunohistochemical, immunofluorescence, and confocal microscopy assays. CPEB was knocked down with small interfering RNAs in H5V endothelial cells, and translation of luciferase reporters constructs was assessed., Results: Activation of CPEB1 promoted alternative nuclear processing within noncoding 3'-untranslated regions of VEGF and CPEB4 messenger RNAs in H5V cells, resulting in deletion of translation repressor elements. The subsequent overexpression of CPEB4 promoted cytoplasmic polyadenylation of VEGF messenger RNA, increasing its translation; the high levels of VEGF produced by these cells led to their formation of tubular structures in Matrigel assays. We observed increased levels of CPEB1 and CPEB4 in cirrhotic liver tissues from patients, compared with control tissue, as well as in livers and mesenteries of rats and mice with cirrhosis or/and portal hypertension. Mice with knockdown of CPEB1 or CPEB4 did not overexpress VEGF or have signs of mesenteric neovascularization, and developed less-severe forms of portal hypertension after portal vein ligation., Conclusions: We identified a mechanism of VEGF overexpression in liver and mesentery that promotes pathologic, but not physiologic, angiogenesis, via sequential and nonredundant functions of CPEB1 and CPEB4. Regulation of CPEB4 by CPEB1 and the CPEB4 autoamplification loop induces pathologic angiogenesis. Strategies to block the activities of CPEBs might be developed to treat chronic liver and other angiogenesis-dependent diseases., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Cirrhotic cardiomyopathy may lead to heart failure in stressful circumstances, such as after transjugular intrahepatic portosystemic shunt (TIPS) placement., Aim: To examine whether acute volume expansion predicts haemodynamic changes after TIPS and elicits signs of impending heart failure., Methods: We prospectively evaluated refractory ascites patients (group A) and compensated cirrhotics (group B), who underwent echocardiography, NT-proBNP measurement, and heart catheterization before and after volume load; group A repeated measurements after TIPS., Results: 15 patients in group A (80% male; 54±12.4 years) and 8 in group B (100% male; 56±6.2 years) were enrolled. Echocardiography disclosed diastolic dysfunction in 30% and 12.5%, respectively. In group A, volume load and TIPS induced a significant increase in right atrial, mean pulmonary, capillary wedge pressure and cardiac index, and a decrease in systemic vascular resistance (respectively, 4.7±2.8 vs. 9.9±3.6 mmHg; 13.3±3.5 vs. 21.9±5.9 mmHg; 8.3±3.4 vs. 15.4±4.7 mmHg; 3.7±0.7 vs. 4.6±11 t/min/m2; 961±278 vs. 767±285 dynscm(-5); and 10.1±3.3 vs. 14.2±3.4 mmHg; 17.5±4 vs. 25.2±4.2 mmHg; 12.3±4 vs. 19.3±3.4 mmHg; 3.4±0.8 vs. 4.5±0.91l t/min/m2; 779±62 vs. 596±199 dynscm(-5), p<0.001 for all pairs). At 24h, cardiopulmonary pressures returned towards baseline., Conclusions: Acute volume expansion predicted haemodynamic changes immediately after TIPS. All patients had adequate haemodynamic adaptation to TIPS; none developed signs of heart failure., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The management of portal hypertension in cirrhosis has evolved over time, leading to improvements in the care and survival of patients with varices and variceal hemorrhage, particularly in patients who achieve a significant reduction in portal pressure. In addition to better treatment strategies and improved therapeutic options, the issue of risk stratification has become essential to identify different patient subpopulations that require a different treatment. We now recognize that the management of varices and variceal hemorrhage must be taken in the context of other complications of cirrhosis (ascites, encephalopathy, jaundice) and that the goals of therapy should be based on the presence of such complications. Evolving knowledge of the predominant pathophysiological mechanisms at each of the stages of cirrhosis also has evolved and will continue to lead to improvements in therapy. This review focuses on the management of varices and variceal hemorrhage with respect to refinements in the risk stratification of patients with cirrhosis., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Hepatic venous pressure gradient (HVPG), the difference between wedged (WHVP) and free hepatic vein pressure (FHVP), predicts survival in patients with cirrhosis. It has been suggested for the use of inferior vena cava (IVC) value instead of FHVP to calculate HVPG when the difference between proximal FHVP (obtained at 2 cm from the hepatic vein outlet) and IVC (measured at the level of the hepatic ostium) is >2 mm Hg. However, there are no data supporting this recommendation. The main aim of the study was to establish which gradient, WHVP-FHVP (HVPG-Free) or WHVP-IVC (HVPG-IVC), better correlates with orthotopic liver transplantation (OLT)-free survival. This work was a retrospective evaluation of hepatic hemodynamic studies of 380 consecutive patients with cirrhosis performed from January 2006 to December 2012 with follow-up until December 2013. Patients had a mean age of 56±10 years and 64.7% were men. Mean Child-Pugh was 7±2. HVPG-Free (16±5 mm Hg) was significantly lower than HVPG-IVC (17±5.5 mm Hg; P<0.001). During a mean follow-up of 43 months, 40 patients were transplanted and 111 died. A total of 285 (75%) patients had an FHVP-IVC difference within ±2 mm Hg (no discrepancy) and 95 (25%) patients<-2 mm Hg or >2 mm Hg (discrepancy). In patients without discrepancy, 16 mm Hg was the best cut-off value predicting survival, independently of being calculated as HVPG-Free or HVPG-IVC. However, in those patients with discrepancy, 16 mm Hg was still the best cut-off value for HVPG-Free, but not for HVPG-IVC, among which 25 patients (26%) were misclassified regarding their risk of OLT/death., Conclusions: Given that WHVP-FHVP was more accurate in assessing prognosis than WHVP-IVC, HVPG should be calculated as the gradient between WHVP and FHVP, but not with IVC, in order to optimize its prognostic value and in identifying different risk population., (© 2015 by the American Association for the Study of Liver Diseases.)

Increased hepatic vascular resistance is the primary factor in the development of portal hypertension. Metformin ameliorates vascular cells function in several vascular beds. Our study was aimed at evaluating the effects, and the underlying mechanisms, of metformin on hepatic and systemic hemodynamics in cirrhotic rats and its possible interaction with the effects of propranolol (Prop), the current standard treatment for portal hypertension. CCl4-cirrhotic rats received by gavage metformin 300 mg/kg or its vehicle once a day for 1 wk, before mean arterial pressure (MAP), portal pressure (PP), portal blood flow (PBF), hepatic vascular resistance, and putative molecular/cellular mechanisms were measured. In a subgroup of cirrhotic rats, the hemodynamic response to acute Prop (5 mg/kg iv) was assessed. Effects of metformin ± Prop on PP and MAP were validated in common bile duct ligated-cirrhotic rats. Metformin-treated CCl4-cirrhotic rats had lower PP and hepatic vascular resistance than vehicle-treated rats, without significant changes in MAP or PBF. Metformin caused a significant reduction in liver fibrosis (Sirius red), hepatic stellate cell activation (α-smooth muscle actin, platelet-derived growth factor receptor β polypeptide, transforming growth factor-βR1, and Rho kinase), hepatic inflammation (CD68 and CD163), superoxide (dihydroethidium staining), and nitric oxide scavenging (protein nitrotyrosination). Prop, by decreasing PBF, further reduced PP. Similar findings were observed in common bile duct ligated-cirrhotic rats. Metformin administration reduces PP by decreasing the structural and functional components of the elevated hepatic resistance of cirrhosis. This effect is additive to that of Prop. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs clinical evaluation., (Copyright © 2015 the American Physiological Society.)

Objective: In the liver, the transcription factor, Kruppel-like factor 2 (KLF2), is induced early during progression of cirrhosis to lessen the development of vascular dysfunction; nevertheless, its endogenous expression results insufficient to attenuate establishment of portal hypertension and aggravation of cirrhosis. Herein, we aimed to explore the effects and the underlying mechanisms of hepatic KLF2 overexpression in in vitro and in vivo models of liver cirrhosis., Design: Activation phenotype was evaluated in human and rat cirrhotic hepatic stellate cells (HSC) treated with the pharmacological inductor of KLF2 simvastatin, with adenovirus codifying for this transcription factor (Ad-KLF2), or vehicle, in presence/absence of inhibitors of KLF2. Possible paracrine interactions between parenchymal and non-parenchymal cells overexpressing KLF2 were studied. Effects of in vivo hepatic KLF2 overexpression on liver fibrosis and systemic and hepatic haemodynamics were assessed in cirrhotic rats., Results: KLF2 upregulation profoundly ameliorated HSC phenotype (reduced α-smooth muscle actin, procollagen I and oxidative stress) partly via the activation of the nuclear factor (NF)-E2-related factor 2 (Nrf2). Coculture experiments showed that improvement in HSC phenotype paracrinally ameliorated liver sinusoidal endothelial cells probably through a vascular endothelial growth factor-mediated mechanism. No paracrine interactions between hepatocytes and HSC were observed. Cirrhotic rats treated with simvastatin or Ad-KLF2 showed hepatic upregulation in the KLF2-Nrf2 pathway, deactivation of HSC and prominent reduction in liver fibrosis. Hepatic KLF2 overexpression was associated with lower portal pressure (-15%) due to both attenuations in the increased portal blood flow and hepatic vascular resistance, together with a significant improvement in hepatic endothelial dysfunction., Conclusions: Exogenous hepatic KLF2 upregulation improves liver fibrosis, endothelial dysfunction and portal hypertension in cirrhosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.

Objective: Antiangiogenic strategies have been proposed as a promising new approach for the therapy of portal hypertension and chronic liver disease. Pigment epithelium-derived factor (PEDF) is a powerful endogenous angiogenesis inhibitor whose role in portal hypertension remains unknown. Therefore, we aimed at determining the involvement of PEDF in cirrhotic portal hypertension and the therapeutic efficacy of its supplementation., Design: PEDF expression profiling and its relationship with vascular endothelial growth factor (VEGF), neovascularisation and fibrogenesis was determined in bile duct-ligated (BDL) rats and human cirrhotic livers. The ability of exogenous PEDF overexpression by adenovirus-mediated gene transfer (AdPEDF) to inhibit angiogenesis, fibrogenesis and portal pressure was also evaluated in BDL rats, following prevention and intervention trials., Results: PEDF was upregulated in cirrhotic human and BDL rat livers. PEDF and VEGF protein expression and localisation in mesentery and liver increased in parallel with portal hypertension progression, being closely linked in time and space with mesenteric neovascularisation and liver fibrogenesis in BDL rats. Furthermore, AdPEDF increased PEDF bioavailability in BDL rats, shifting the net balance in the local abundance of positive (VEGF) and negative (PEDF) angiogenesis drivers in favour of attenuation of portal hypertension-associated pathological neovascularisation. The antiangiogenic effects of AdPEDF targeted only pathological angiogenesis, without affecting normal vasculature, and were observed during early stages of disease. AdPEDF also significantly decreased liver fibrogenesis (through metalloproteinase upregulation), portosystemic collateralisation and portal pressure in BDL rats., Conclusions: This study provides compelling experimental evidence indicating that PEDF could be a novel therapeutic agent worthy of assessment in portal hypertension and cirrhosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Unlabelled: Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis., Conclusion: Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis., (© 2014 by the American Association for the Study of Liver Diseases.)

Cirrhosis can be sub-classified in clinical stages with distinct differences in prognosis and can even be reversed in some cases with successful etiological treatment. In this article, we review potential future therapies of cirrhosis, mainly focusing in the expansion of indications of currently licensed drugs. We strongly advocate that future therapies should focus on preventing the advent of complications and further progression of liver disease and should involve both primary and secondary care physicians. Such strategies could be based on the combination of currently licensed, relatively safe and inexpensive drugs and such randomized controlled trials should be prioritized in patients with advanced liver disease. The paradigm should be similar to that of prevention in cardiovascular diseases and long-term follow-up trials are needed.

Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background & Aims: Hepatic blood flow (HBF) is best estimated by the Fick's method during indocyanine green constant infusion (ICG-HBF) on hepatic vein catheterization. We investigated the consistency and agreement of HBF measured by Doppler ultrasound (US-HBF) as compared with ICG-HBF in portal hypertensive patients with cirrhosis., Methods: In 50 patients observed for HVPG measurement (56% compensated; Child score 7 ± 2; HVPG 16.6 ± 6.0 mmHg; varices in 75%) US-HBF (Sequoia-512-Acuson; 4.5-7 MHz convex probe; US-HBF = hepatic artery blood flow+portal vein blood flow) and ICG-HBF (Fick's method after an equilibration period of at least 45 min of ICG bolus of 5 mg + constant rate infusion of 0.2 mg/min). Intraclass correlation coefficient (ICC) for consistency and absolute agreement between US-HBF and ICG-HBF were calculated., Results: Mean ICG-HBF and US-HBF were similar, being respectively 1004 ± 543 ml/min and 994 ± 494 ml/min (p = 0.661 vs. ICG-HBF). However, results in individual patients disclosed marked differences between the two methods (386 ± 415 ml/min) and showed only moderate consistency (ICC 0.456; p < 0.0001), absolute agreement (ICC 0.461; p < 0.0001) and linear correlation (R = 0.464; p < 0.0001). The discrepancy between the two methods was maximal in patients with poor liver function, high HBF by any technique and more arterialized liver circulation. Hepatic artery blood flow ≥40% of US-HBF indicated, with 90% specificity, a discrepancy ≥20% between US-HBF and ICG-HBF., Conclusions: HBF estimations by Doppler-ultrasound and ICG are significantly correlated, but their discrepancy in individual cases is high. Estimation of HBF by Doppler-US should be considered unreliable in patients with poor hepatic function and large liver arterialization., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Cirrhosis recurrence is frequent after orthotopic liver transplantation for hepatitis C virus (HCV). Because transplantation causes liver denervation, we hypothesized that the response to propranolol might differ in transplant patients versus nontransplant patients with cirrhosis and portal hypertension. Twenty-one patients with cirrhosis recurrence after orthotopic liver transplantation with portal hypertension were compared to 20 nontransplant patients with cirrhosis, HCV, and portal hypertension, and they were matched by sex, age, presence of varices, and Child-Pugh score. The patients underwent systemic and hepatic hemodynamic measurements at the baseline and 20 minutes after intravenous propranolol (0.15 mg/kg). At the baseline, the transplant patients with cirrhosis had a lower hepatic venous pressure gradient (HVPG) than the nontransplant patients with cirrhosis (14.8 ± 2.9 versus 17.3 ± 4.4 mm Hg, P = 0.03) but a higher mean arterial pressure (MAP; 100.3 ± 12.3 versus 91.8 ± 11.6 mm Hg, P = 0.04) and higher systemic vascular resistance (2253 ± 573 versus 1883 ± 525 dyn/second/cm(-5) , P = 0.03). There were no differences in the cardiac index (CI). Propranolol significantly decreased HVPG to similar extents in transplant patients and nontransplant patients with cirrhosis (-14.1% ± 8.0% versus -16.9% ± 9.5%, P > 0.99). MAP tended to increase in transplant patients with cirrhosis, whereas it slightly decreased in nontransplant patients (5.1% ± 14.2% versus -4.8% ± 6.4%, P = 0.007); however, the reduction in CI was less marked in transplant patients with cirrhosis (-18.6% ± 7.6% versus -26.9% ± 9.0%, P = 0.005). In conclusion, patients with HCV-related cirrhosis and portal hypertension after orthotopic liver transplantation have lower baseline HVPG values but similar HVPG responses to propranolol infusions in comparison with nontransplant patients with cirrhosis. In contrast to nontransplant patients, propranolol increases the systemic vascular resistance and arterial pressure in transplant patients with cirrhosis and attenuates the fall in CI., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Background & Aims: Noninvasive methods are needed to identify clinically significant portal hypertension (CSPH) and esophageal varices (EVs) in patients with compensated cirrhosis. We looked for markers of the presence of CSPH and EVs in patients with cirrhosis., Methods: We performed a cross-sectional study that included a training set of 117 patients with compensated cirrhosis, confirmed by histology, from a tertiary referral center. Spleen diameter was measured by ultrasound, and liver stiffness (LS) was measured by transient elastography; endoscopy was used as the standard for detection of EVs, and measurements of hepatic venous pressure gradient were used as the standard for identifying CSPH. We assessed the ability of platelet count, spleen diameter, LS, and combinations of these factors (ie, ratio of platelet count to spleen size, and LS × spleen size/platelet count [LSPS]) to identify patients with CSPH and EV. The analysis included 2 new statistical models: the PH risk score and the varices risk score. Results were validated using an independent series of 56 patients with compensated patients from another center., Results: LS was the best single noninvasive variable for identifying patients with CSPH (area under the receiver operating characteristic, 0.883; 95% confidence interval [CI], 0.824-0.943; P < .0001). The area under the receiver operating characteristic value increased when LS was combined with platelet count and spleen size, either as LSPS (0.918; 95% CI, 0.872-0.965; P < .0001) or PH risk score (0.935; 95% CI, 0.893-0.977; P < .0001). More than 80% of patients were accurately classified using LSPS and PH risk score. Analyses of the varices risk score and LSPS were superior to all other noninvasive tests for identifying patients with EVs (area under the receiver operating characteristic, 0.909; 95% CI, 0.841-0.954 and 0.882; 95% CI, 0.810-0.935, respectively); they correctly classified 85% of patients in the training set and 75% in the validation set., Conclusions: Combined data on LS, spleen diameter, and platelet count can be used to identify patients with compensated cirrhosis most likely to have CSPH and EV., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: In a recent randomized international clinical trial (RCT) in high-risk cirrhotic patients with acute variceal bleeding, the early use of transjugular intrahepatic portosystemic shunt (TIPS) was associated with marked and significant reductions in both treatment failure and mortality. The aim of this study was to confirm these results in clinical practice in the same centers of the RCT study., Methods: We retrospectively reviewed patients admitted for acute variceal bleeding and high risk of treatment failure (Child C <14 or Child B plus active bleeding), treated with early-TIPS (n=45) or drugs+endoscopic therapy (ET) (n=30)., Results: Patients treated with early-TIPS had a much lower incidence of failure to control bleeding or rebleeding than patients receiving drug+ET (3 vs. 15; p <0.001). The 1-year actuarial probability of remaining free of this composite end point was 93% vs. 53% (p <0.001). The same was observed in mortality (1-year actuarial survival was 86% vs. 70% respectively; p=0.056). Actuarial curves of failure to control bleeding+rebleeding and of survival were well within the confidence intervals of those observed in the RCT., Conclusions: This study supports the early use of TIPS in patients with cirrhosis and a high-risk variceal bleeding., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Cardiovascular risk factors (CVRF) lead to systemic endothelial dysfunction. It has been suggested that in cirrhosis, cardiovascular risk is low and systemic endothelial function is enhanced. However, there is no prospective study evaluating the relationship between cardiovascular risk and systemic endothelial function in cirrhosis, which was investigated here., Methods: In 47 patients with cirrhosis (33 males; median Child-Pugh score 8; median age 55 years), we evaluated: laboratory parameters, hepatic and systemic hemodynamics, CVRF, 10-year global cardiovascular risk by Framingham score, and presence of carotid plaques. Systemic endothelial dysfunction was investigated non-invasively by flow-mediated dilatation (FMD) of the brachial artery by ultrasound and defined as FMD <10%., Results: Cardiovascular risk (median 7%) was low in 25%, moderate in 26%, moderately high in 40%, and high in 9%. Fifty-three percent of patients had systemic endothelial dysfunction. Systemic endothelial dysfunction (low FMD) increased in parallel with CV risk (linear trend P=0.039) and was higher in patients overweight or obese. Conversely, FMD increased in parallel with Child-Pugh/Mayo Clinic Model for End-stage Liver Disease (MELD) score, bilirubin, serum sodium, plasma renin activity, leukocyte count, platelet count, and with lower arterial pressure, suggesting that enhanced FMD is a feature of advanced liver failure and inflammation. Cardiovascular risk, bilirubin, leukocyte count, and arterial pressure remained independently associated with systemic endothelial dysfunction., Conclusions: CV risk was not low in our studied patients with cirrhosis, and systemic endothelial dysfunction was frequent in this population. In cirrhosis, similar to general population, cardiovascular risk impaired systemic FMD, although liver failure attenuated endothelial dysfunction.

Background and Aims: Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population., Methods: In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured., Results: Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes., Conclusions: Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.

Cirrhosis is a major health problem, being the 5th cause of death in the U.K. and 12th in the U.S., but 4th in the 45 to 54 age group. Until recently cirrhosis was considered a single and terminal disease stage, with an inevitably poor prognosis. However, it is now clear that 1-year mortality can range from 1% in early cirrhosis to 57% in decompensated disease. As the only treatment for advanced cirrhosis is liver transplantation, what is urgently needed is strategies to prevent transition to decompensated stages. The evidence we present in this review clearly demonstrates that management of patients with cirrhosis should change from an expectant algorithm that treats complications as they occur, to preventing the advent of all complications while in the compensated phase. This requires maintaining patients in an asymptomatic phase and not significantly affecting their quality of life with minimal impairment due to the therapies themselves. This could be achieved with lifestyle changes and combinations of already licensed and low-cost drugs, similar to the paradigm of treating risk factors for cardiovascular disease. The drugs are propranolol, simvastatin, norfloxacin, and warfarin, which in combination would cost £128/patient annually-equivalent to U.S. $196/year. This treatment strategy requires randomized controlled trials to establish improvements in outcomes. In the 21st century, cirrhosis should be regarded as a potentially treatable disease with currently available and inexpensive therapies., (Copyright © 2012 American Association for the Study of Liver Diseases.)