Search

Complications of cirrhosis and portal hypertension (PH) can be reduced by statin therapy. The common loss-of-function variant p.V174A in the solute carrier organic anion transporter gene 1B1 (SLCO1B1) gene encoding the organic anion transporting polypeptide 1B1 results in decreased hepatic uptake of statins. Our specific aim was to assess the impact of this variant in patients with cirrhosis and statin treatment while controlling for the stage of cirrhosis and other potential confounders with propensity score matching (PSM), availing of a large cohort of genotyped study patients. In total, from 1,088 patients with cirrhosis in two German academic medical centers, PSM yielded 154 patients taking statins and 154 matched controls. The effect on PH was assessed by the liver stiffness-spleen size-to-platelet score (LSPS), and complications of cirrhosis were retrospectively recorded applying consensus criteria. As hypothesized, patients on statin treatment presented less frequently with signs of PH: Esophageal varices (41% vs. 62%; P < 0.001) were less common, and LSPS (4.8 ± 11.5 vs. 5.6 ± 6.4; P = 0.01) was reduced. Correspondingly, decompensation events were also reduced in patients on statins (odds ratio [OR] = 0.54, 95% confidence interval [CI] 0.32-0.90; P = 0.02). When the variant in SLCO1B1 was present in patients on statins, esophageal varices (OR = 2.68, 95% CI 1.24-5.81; P = 0.01) and bacterial infections (OR = 2.50, 95% CI 1.14-5.47; P = 0.02) were more common as compared with wild type carriers on statins. Conclusion: In this cohort, signs and complications of PH were reduced in patients with cirrhosis treated with statins. Notably, this effect was diminished by the common loss-of-function variant in SLCO1B1. Further prospective studies in independent cohorts are warranted to confirm these genotype-specific observations., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background: Left-sided portal hypertension is usually found in patients undergoing pancreaticoduodenectomy (PD) with spleno-mesenterico-portal (S-M-P) confluence resection. This study is to explore the outcomes of S-M-P confluence reconstruction after resection by using bifurcated allogeneic vein., Methods: Clinicopathologic data of patients who underwent extensive PD with S-M-P confluence resection for carcinoma of pancreatic head/uncinate process in our hospital between December 2011 and August 2018 were retrospectively reviewed and clinical outcomes of vein reconstruction after resection were analyzed., Results: Of the 37 patients enrolled, S-M-P reconstruction by bifurcated allogeneic vein was performed in 24 cases (group 1) and simply splenic vein ligation in 13 cases (group 2). Items including pathological results, blood loss, and complications were comparable between the two groups, operation time was longer in group 1 (573.8 vs. 479.2 min, p = 0.018). Significantly decreased platelet count (205.9 vs. 133.1 × 10 9 /L, p = 0.001) and increased splenic volume (270.9 vs. 452.2 ml, p < 0.001) were observed in group 2 at 6 months after operation. The mean splenic hypertrophy ratio was 1.06 in group 1 and 1.63 in group 2, respectively (p < 0.001). There were four patients with varices were found in group 2, none in group 1., Conclusions: Without increased complications, reconstructing S-M-P confluence by bifurcated allogeneic vein after resection may help to avoid left-sided portal hypertension., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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

Cirrhosis is the fifth leading cause of death in adults. Advanced cirrhosis can cause significant portal hypertension (PH), which is responsible for many of the complications observed in patients with cirrhosis, such as varices. If portal pressure exceeds a certain threshold, the patient is at risk of developing life-threatening bleeding from varices. Variceal bleeding has a high incidence among patients with liver cirrhosis and carries a high risk of mortality and morbidity. The management of variceal bleeding is complex, often requiring a multidisciplinary approach involving pharmacological, endoscopic, and radiologic interventions. In terms of management, three stages can be considered: primary prophylaxis, active bleeding, and secondary prophylaxis. The main goal of primary and secondary prophylaxis is to prevent variceal bleeding. However, active variceal bleeding is a medical emergency that requires swift intervention to stop the bleeding and achieve durable hemostasis. We describe the pathophysiology of cirrhosis and PH to contextualize the formation of gastric and esophageal varices. We also discuss the currently available treatments and compare how they fare in each stage of clinical management, with a special focus on drugs that can prevent bleeding or assist in achieving hemostasis.

Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes and for three miRNAs (miR-192-5p, miR-34a-5p, and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, which was refractory in 18 (50%), and were placed on NSBBs for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient, and an echocardiogram study were performed before and 1 month after NSBBs. Patients with cirrhosis had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p, and miR-29a-5p ( P  < 0.05). Baseline serum miR-452-5p and miR-429 levels were lower in NSBB responders ( P  = 0.006). miR-181b-5p levels were greater in refractory ascites than in diuretic-sensitive ascites ( P  = 0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ = -0.46, P  = 0.007; and ρ = -0.41, P  = 0.01, respectively) and with diminished systolic contractility (ρ = -0.55, P  = 0.02; and ρ = -0.55, P  = 0.02, respectively) in patients with refractory ascites after NSBBs. Conclusion: Analysis of a miRNA signature in serum discriminates between patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade and those more likely to benefit from NSBBs., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: The safety of non-selective β-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA., Methods: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol., Results: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI., Conclusion: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. β-blockade should be used cautiously or even avoided in patients with RA., Lay Summary: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, β-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function., Competing Interests: Conflict of interest The authors have no conflicts of interest that pertain to this 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: Portosystemic shunts (PSS) are associated with recurrent or persistent hepatic encephalopathy (HE), severe portal hypertensive (PHT) complications, and poor survival in cirrhosis patients. Shunt embolization improves HE in patients with recurrent or persistent HE. The role of early shunt embolization (ESE) in comparison with no and late SE (LSE) in cirrhosis patients with PSS and associated clinical outcomes are not studied., Methods: ESE was defined as occlusion of PSS in patients with the first episode of spontaneous HE, while LSE was that when performed in patients with recurrent/persistent PSS-related HE. We retrospectively analyzed (November 2016 to March 2019) clinical outcomes, liver disease severity, and survival between patients undergoing ESE (n = 22) vs. LSE (n = 23) and compared ESE with matched historical controls (n = 22) not undergoing shunt embolization, followed-up for 18 months., Results: Males predominated, and the lienorenal type of shunt was the most frequent. Significantly larger and multiple shunts were noted in the LSE group. Arterial ammonia, total bilirubin, and Child-Pugh scores were significantly higher at baseline in the LSE group. Post-procedure length of stay in the intensive unit (mean 0.6 vs. 2.1 days; p = 0.04), infections (31.8% vs. 66.7% beyond 100 days; p = 0.02), recurrence of HE in first 9 months (4.5% vs. 28.6%; p = 0.03), and liver- and PHT-related clinical events beyond 10 months were significantly higher in LSE compared with those in the ESE group respectively. HE beyond 10 months was comparable between both the groups. 18.2% died in ESE while 60.87% died in the LSE group (p = 0.002). Compared with patients on only standard medical care, the occurrence of ascites, variceal bleeding, recurrence of HE, and portal vein thrombosis were significantly lower in those undergoing ESE, even though differences in survival were not significant., Conclusions: Our study demonstrates the benefits of ESE of large PSS in patients with cirrhosis, probably by improving survival through a reduction in liver and PHT events that warrant validation through prospective randomized controlled multicenter trials.

Background: Portal hypertension after hepatectomy is associated with impaired postoperative recovery. Terlipressin decreased portal vein pressure in patients with variceal bleeding and improved patient survival, but the role of postoperative terlipressin treatment for patients who underwent liver resection is not clear., Methods: We determined the effect of terlipressin on portal vein pressure in patients with portal vein pressure >12 mmHg after hepatectomy. If portal vein pressure was decreased (ie, Responders), a continuous infusion of terlipressin at 2 mg/day for 4 days was given. The incidence of posthepatectomy liver failure, abdominal drainage, acute kidney injury, operative complications, and side-effects of terlipressin in the Responders were compared with those whose portal vein pressure did not decrease (ie, non-Responders) and patients whose portal vein pressure was ≤12 mmHg after hepatectomy (low portal vein pressure group)., Results: We recruited 110 patients, 65 of whom were eligible for terlipressin administration. Portal vein pressure decreased in 46 patients (71%) with the mean portal vein pressure decreasing from 15.8 ± 2.6 mmHg to 14.3 ± 2.9 mmHg (P < .001). The median [interquartile range] postoperative abdominal drainage for the first 3 postoperative days was less in the Responders than in the non-Responders (350 mL [228-573] vs 730 mL [330-980]; P = .004). Incidence of posthepatectomy liver failure in the Responders was less than the non-Responders (26% vs 53%, P = .04). Acute kidney injury, operative complications, and side-effects of terlipressin were not different between groups., Conclusion: Terlipressin decreased posthepatectomy portal vein pressure and may decrease the incidence of posthepatectomy liver failure and postoperative abdominal drainage (NCT03352349)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. This is an updated version of a previously published review., Objectives: To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis., Search Methods: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 November 2019. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 01 January 2020., Selection Criteria: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both)., Data Collection and Analysis: Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review., Main Results: A comprehensive search of the literature did not identify any published eligible randomised controlled trials., Authors' Conclusions: In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: To explore the feasibility of fenestration in the treatment of shunt dysfunction after transjugular intrahepatic portosystemic shunt (TIPS)., Methods: Between February 2012 and December 2017, 12 TIPS patients with shunt dysfunction underwent fenestration to resolve recurrent portal hypertension with gastric variceal bleeding or ascites. The demographic data, operative data, postoperative recovery data, hemodynamic data, and complications were analyzed., Results: Twelve patients underwent TIPS revision by fenestration, with a technical success rate of 100%. After stent reconstruction, the portal vein diameters decreased gradually with time (before the procedure: at 5 days/1 month/3 months/6 months; after procedure: 1.45 ± 0.11 cm/1.38 ± 0.06 cm/1.36 ± 0.05 cm/1.34 ± 0.05 cm/1.32 ± 0.06 cm, respectively, P = 0.057). Additionally, the blood flow velocity and blood flow rapidly increased in the portal veins and shunts after TIPS revision (P < 0.001). Surprisingly, after 3 months of stent reconstruction, the portal blood flow was 4607.99 ± 1304.10 mL/min which was even lower than the shunt flow at 4651.18 ± 612.74 mL/min. The mean pressure gradient (PSG) prior to TIPS revision was 36.71 ± 3.36 mmHg which decreased to 17.42 ± 3.37 mmHg after the procedure (P < 0.001). Clinical improvement was observed in all patients after the shunt reconstruction. Three patients (25%) had mild intra-abdominal hemorrhage at 1 week after the operation. After a mean 11.0 ± 1.24 months follow-up, ascites and bleeding were well controlled, and no stenosis of the stents was found., Conclusions: For patients with failed TIPS revision, fenestration to reconstruct the shunt provides an excellent alternative procedure, which is effective, safe, and has a certain clinical value, for continuing the treatment of portal hypertension.

Background: Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis., Methods: We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459., Findings: The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST -14 IU/L [-91 to 64; p=0·728] and for ALT -8 IU/L [-49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [-804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study., Interpretation: Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis., Funding: Horizon 20/20 European programme., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Transjugular intrahepatic portosystemic shunt (TIPS) has been suggested to reduce portal hypertension-associated complications in cirrhotic patients undergoing abdominal surgery. The aim of this study was to compare postoperative outcome in cirrhotic patients with and without specific preoperative TIPS placement, following elective extrahepatic abdominal surgery., Methods: Patients were retrospectively included from 2005 to 2016 in four centers. Patients who underwent preoperative TIPS (n = 66) were compared to cirrhotic control patients without TIPS (n = 68). Postoperative outcome was analyzed using propensity score with inverse probability of treatment weighting analysis., Results: Overall, colorectal surgery accounted for 54% of all surgical procedure. TIPS patients had a higher initial Child-Pugh score (6[5-12] vs. 6[5-9], p = 0.043) and received more beta-blockers (65% vs. 22%, p < 0.001). In TIPS group, 56 (85%) patients managed to undergo planned surgery. Preoperative TIPS was associated with less postoperative ascites (hazard ratio = 0.330 [0.140-0.780]). Severe postoperative complications (Clavien-Dindo > 2) and 90-day mortality were similar between TIPS and no-TIPS groups (18% vs. 23%, p = 0.392, and 7.5% vs. 7.8%, p = 0.644, respectively)., Conclusions: Preoperative TIPS placement yielded an 85% operability rate with satisfying postoperative outcomes. No significant differences were found between TIPS and no-TIPS groups in terms of severe postoperative complications and mortality, although TIPS patients probably had worse initial portal hypertension.

Purpose: Although ultrasound has been widely used to evaluate transjugular intrahepatic portosystemic shunts (TIPS) patency, several studies have reported conflicting data regarding its performance. Therefore, we aimed to evaluate performance of ultrasound for detection of TIPS dysfunction by performing a meta-analysis., Methods: Literature search was performed for studies evaluating ultrasound for TIPS dysfunction, stenosis, and occlusion using PubMed, EMBASE, Scopus, and Cochrane Library through February 2019. Pooled sensitivity, specificity, log diagnostic odds ratio (LDOR), and area under curve (AUC) of summary receiver-operating characteristic were calculated. Subgroup analyses were performed according to ultrasonographic criteria and type of stent., Results: In total, 21 studies were evaluated. Pooled sensitivity, specificity, and LDOR of ultrasound for detection of TIPS dysfunction were 0.82 (0.67, 0.93), 0.58 (0.46, 0.70), and 1.77 (1.20, 2.35). Pooled sensitivity, specificity, and LDOR for TIPS stenosis were 0.80 (0.69, 0.90), 0.80 (0.69, 0.91), and 2.83 (1.88, 3.78). Pooled sensitivity, specificity, and LDOR for TIPS occlusion were 0.96 (0.92, 0.99), 1 (0.99, 1.00), and 6.28 (4.96, 7.60). AUCs of ultrasound for TIPS dysfunction, stenosis, and occlusion were 0.77, 0.86, and 0.95, respectively., Conclusions: Although ultrasound had excellent performance for TIPS occlusion and acceptable performance for TIP stenosis, most studies utilized bare metal stent, and therefore, application to current practice is limited. Ultrasound for TIPS dysfunction in the setting of covered metal stent appeared to have acceptable sensitivity of 0.82, but limited specificity of 0.58 and low LDOR of 1.77. A new noninvasive tool is needed for detection of TIPS dysfunction in the era of covered metal stent.

Splenic artery (SA) ligation can be performed during liver transplantation (LT) to avoid portal hyperperfusion, which is involved in the pathogenesis of both small-for-size and SA syndrome. The SA can also be used as an inflow for arterial reconstruction. Exceptionally, SA interruption or agenesis has been associated with positive remodeling of collateral arteries supplying the spleen via the left gastric artery (LGA), short gastric vessels, and the gastroepiploic arcade (GEA), with subsequent severe upper gastrointestinal (GI) bleeding. To determine incidence, magnitude, predictors, and clinical implications of vascular remodeling after SA interruption during LT, we identified 465 patients transplanted in the period 2007-2017 who had the SA ligated or interrupted at LT. Among them, 88 had a computed tomography angiography suitable for evaluation of vascular remodeling after LT. The presence of prominent gastric arterial collaterals and the increase in LGA and GEA diameter were evaluated on 2-dimensional axial images and multiplanar reconstructions. Of the 88 patients, 28 (31.8%), 32 (36.4%), and 22 (25.0%) developed gastric collateralization graded as mild, moderate, or severe. Of the patients for whom comparison with pre-LT imaging was possible (n = 54), 51 (94.4%) presented a median 37% and 55% increase in LGA and GEA diameter, respectively. Severe gastric collateralization was associated with lower body mass index (odds ratio, 0.84; 95% confidence interval [CI], 0.71-0.98; P = 0.03), whereas a GEA caliper measurement increase was positively correlated with Model for End-Stage Liver Disease score (r 2 = 0.12; 95% CI, 0.65-4.15; P = 0.008). Out of 465 patients, 2 (0.43%) had severe episodes of arterial upper GI bleeding, possibly exacerbated by vascular remodeling. In conclusion, vascular remodeling after SA interruption during LT is frequent and can aggravate GI bleeding during follow-up., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Purpose: Conflicting data exist regarding the appropriate shunt diameter for transjugular intrahepatic portosystemic shunt (TIPS) creation in cirrhotic patients. This study was designed to compare the clinical efficacy of TIPS using stent-grafts with 8- and 10-mm diameters., Methods: In this retrospective study, cirrhotic patients who underwent TIPS technical successfully for the prevention of variceal rebleeding from December 2011 to June 2015 were included. Thirty-four patients with 8-mm TIPS and 380 patients with 10-mm TIPS were identified. Propensity score matching method produced 32 patients in each group for comparison., Results: Baseline characteristics between two groups were comparable. There was no significant difference in variceal rebleeding rate between the two groups. The cumulative incidence of variceal rebleeding after 1 and 3 years was 6.4% and 35.5% in the 8-mm group, respectively, and 14.2% and 24.9% in the 10-mm group, respectively (P = 0.663). 8-mm TIPS conferred a significant decrease in hepatic encephalopathy (HE) rate compared with the 10-mm TIPS (16.1 vs. 32.6% at 1 year, 27.8 vs. 53.2% at 3 years, P = 0.034). The cumulative survival rates were similar between the two groups: 93.3% and 79.6% at 1 and 3 years, respectively, in the 8-mm TIPS group vs. 87.3% and 72.1% at 1 and 3 years, respectively, in the 10-mm TIPS group (P = 0.451)., Conclusion: The placement of 8-mm TIPS was sufficient to decompress the portal hypertension and prevent variceal rebleeding. The use of the 8-mm stent-graft can decrease HE rates compared with 10-mm stent-graft, although no survival benefit was observed.

Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis, and may impede hepatic fibrogenesis and decompensation. Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management, nutritional optimisation and patient education., Competing Interests: Conflict-of-interest statement: None declared for all authors.

Background: Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis., Methods: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls., Results: In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension., Conclusions: By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

There is a consensus that portal venous pressure (PVP) modulation prevents portal hypertension (PHT) and consequent complications after adult-to-adult living donor liver transplantation (ALDLT). However, PVP-modulation strategies need to be updated based on the most recent findings. We examined our 10-year experience of PVP modulation and reevaluated whether it was necessary for all recipients or for selected recipients in ALDLT. In this retrospective study, 319 patients who underwent ALDLT from 2007 to 2016 were divided into 3 groups according to the necessity and results of PVP modulation: not indicated (n = 189), indicated and succeeded (n = 92), and indicated but failed (n = 38). Graft survival and associations with various clinical factors were investigated. PVP modulation was performed mainly by splenectomy to lower final PVP to ≤15 mm Hg. Successful PVP modulation improved prognosis to be equivalent to that of patients who did not need modulation, whereas failed modulation was associated with increased incidence of small-for-size syndrome (SFSS; P = 0.003) and early graft loss (EGL; P = 0.006). Among patients with failed modulation, donor age ≥ 45 years (hazard ratio [HR], 3.67; P = 0.02) and ABO incompatibility (HR, 3.90; P = 0.01) were independent risk factors for graft loss. Survival analysis showed that PVP > 15 mm Hg was related to poor prognosis in grafts from either ABO-incompatible or older donor age ≥ 45 years (P < 0.001), but it did not negatively affect grafts from ABO-compatible/identical and young donor age < 45 years (P = 0.27). In conclusion, intentional PVP modulation is not necessarily required in all recipients. Although grafts from both ABO-compatible/identical and young donors can tolerate PHT, lowering PVP to ≤15 mm Hg is a key to preventing SFSS and consequent EGL with grafts from either ABO-incompatible or older donors., (© 2018 by the American Association for the Study of Liver Diseases.)

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/aims: Fibrosis and increased intrahepatic vascular resistance are the hallmarks of chronic inflammatory disorders of the liver and cirrhosis. Inhibitors of the enzyme soluble epoxide hydrolase reduce fibrosis in several disease models. The present study aimed at investigating the effects of soluble epoxyhydrolase inhibition with t-TUCB in tetrachloride-induced cirrhosis in rats., Methods: The models were established by CCl 4 (2ml/kg) given subcutaneously for 14 weeks. t-TUCB was concomitantly administered from the tenth week of modelling time. After the models were successfully built, the rats were anesthetized with sodium phenobarbital and portal pressure was determined in the groups. After that, the rats were killed and part of liver tissues were taken for histological analysis. In addition, the levels of intrahepatic inflammatory message factors were measured using real-time polymerase chain reaction (PCR) analysis. The remaining liver samples were processed for assessment of oxidative stress., Results: t-TUCB administration significantly attenuated portal pressure relative to CCl 4 -only rats. This improvement was associated with decreased deposition of collagen in liver, which was supported by reduced mRNA expression of α-smooth muscle actin (α-SMA), Collagen I, Collagen III, transforming growth factor (TGF)-β and tissue inhibitor of metalloproteinase-1 (TIMP-1) and increased matrix metalloproteinase-1, -13 (MMP-1, -13) mRNA expression. In addition, t-TUCB decreased the levels of proinflammatory cytokines, including IL-1β, IL-6, IL-10, tumor necrosis factor-α (TNF-α) and NF-κB, within cirrhotic hepatic tissue. Meanwhile, oxidative stress was also alleviated following inhibition of sEH in CCl 4 -induced models, as evidenced by down-regulated levels of malondialdehyde (MDA) and up-regulated levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)., Conclusion: The soluble epoxyhydrolase inhibitor, t-TUCB alleviates liver fibrosis and portal hypertension through attenuation of inflammatory response and oxidative stress in tetrachloride induced cirrhosis., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

BACKGROUND Major or aggressively-extended hepatectomy (MAEH) may cause secondary portal hypertension (PH), and postoperative liver failure (POLF) and is often fatal. Challenges to prevent secondary PH and subsequent POLF, such as shunt creation and splenic arterial ligation, have been reported. However, these procedures have been performed simultaneously only during the initial MAEH. CASE REPORT A 58-year-old female with chronic hepatitis C developed a solitary hepatic cellular carcinoma with portal tumor thrombosis. Blood examination and imaging revealed a decreased platelet count and splenomegaly. Her liver viability was preserved, and collaterals did not develop, and her tumor thrombosis forced us to perform a right hepatectomy from an oncological standpoint. The estimated volume of her liver remnant was 51.8%. A large volume of ascites and pleural effusion were observed on post-operative day (POD) 3, and ascetic infection occurred on POD 14. Hepatic encephalopathy was observed on POD 16. According to the post-operative development of collaterals due to secondary PH, submucosal bleeding in the stomach occurred on POD 37. Though it is unclear whether delayed portal venous pressure (PVP) modulation after MAEH is effective, a therapeutic strategy for recovery from POLF may involve PVP modulation to resolve intractable PH. We performed a splenectomy on POD 41 to reduce PVP. The initial PVP value was 32 mm Hg, and splenectomy decreased PVP to 23 mm Hg. Thereafter, she had a complete recovery from POLF. CONCLUSIONS Our thought-provoking case is the first successfully-treated case of secondary PH and POLF after MAEH, achieved by delayed splenectomy for PVP modulation.

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 & Aims: Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis., Methods: Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4 ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4 INH ). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions., Results: Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4 ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4 ORAL rats. In CCl4 INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance., Conclusions: Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Superior mesenteric vein-portal vein confluence resection combined with pancreatoduodenectomy (SMPVrPD) is occasionally required for resection of pancreatic head tumors. It remains unclear whether such situations require splenic vein (SV) reconstruction for decompression of left-sided portal hypertension (LSPH)., Methods: The data from 93 of 104 patients who underwent pancreatoduodenectomy (PD) for pancreatic head malignancies were reviewed. Surgical outcomes in three groups-standard PD (control group), PD combined with vascular resection and SV preservation (SVp group), and SMPVrPD with SV resection (SVr group)-were compared. The influence of division and preservation of the two natural confluences (left gastric vein-portal vein and/or inferior mesenteric vein-SV confluences) on portal hemodynamics were evaluated using three-dimensional computed tomographic portography., Results: No mortality occurred. The morbidity rates were not significantly different among the three groups (18/43, 8/21, and 7/29, respectively; p = 0.306). In the SVr group, three patients had gastric remnant venous congestion, and three had esophageal varices without hemorrhagic potential. No patients had splenomegaly, or severe or prolonged thrombocytopenia. These LSPH-associated findings were less frequently observed when the two confluences were preserved., Conclusions: SMPVrPD without SV reconstruction can be safely conducted. Additionally, preservation of these two confluences may reduce the risk of LSPH., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and α alpha smooth muscle actin expression. Moreover, hepatic collagen deposition was markedly decreased in mirtazapine-treated mice as evaluated by Masson's trichrome staining. Mirtazapine provided an antifibrotic environment by decreasing the liver content of transforming growth factor-β1 (TGF-β1), and protein kinase C as well as the expression of phosphorylated-Smad3 (p-Smad) and phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2). Additionally, oxidative stress was largely mitigated by mirtazapine as manifested by decreased liver lipid peroxidation and NADPH oxidase 1 along with glutathione replenishment. The current study indicates that mirtazapine suppressed 5-HT-mediated TGF-β1/Smad3 and ERK1/2 signaling pathways as well as oxidative stress that contribute to the progression of liver fibrosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly., Methods: Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls ( n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) ( n = 10) or everolimus (EVR: 1 mg/kg per day) ( n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated., Results: LV determination by MRI correlated excellent with the ex vivo measurements ( r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis ( P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels., Conclusion: Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression., Competing Interests: Conflict-of-interest statement: None of the authors report a potential conflict of interest regarding this work.

Background & Aims: In cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria-targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension., Methods: Ex vivo: Hepatic stellate cells phenotype was analysed in human precision-cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl 4 - and thioacetamide-cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation., Results: Mitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl 4 -cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide-cirrhotic model., Conclusion: We propose mitochondria-targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Decompensated cirrhosis is characterized by disturbed systemic and splanchnic hemodynamics. Bacterial translocation from the gut is considered the key driver in this process. Intestinal decontamination with rifaximin may improve hemodynamics. This double-blind, randomized, controlled trial (clinicaltrials.gov, NCT01769040) investigates the effects of rifaximin on hemodynamics, renal function, and vasoactive hormones. We randomized 54 stable outpatients with cirrhosis and ascites to rifaximin 550 mg twice a day (n = 36) or placebo twice a day (n = 18). Forty-five patients were male, mean age 56 years (±8.4), average Child score 8.3 (±1.3), and Model for End-Stage Liver Disease score 11.7 (±3.9). Measurements of hepatic venous pressure gradient, cardiac output, and systemic vascular resistance were made at baseline and after 4 weeks. The glomerular filtration rate and plasma renin, noradrenaline, lipopolysaccharide binding protein, troponin T, and brain natriuretic peptide levels were measured. Rifaximin had no effect on hepatic venous pressure gradient, mean 16.8 ± 3.8 mm Hg at baseline versus 16.6 ± 5.3 mm Hg at follow-up, compared to the placebo, mean 16.4 ± 4 mm Hg at baseline versus 16.3 ± 4.4 mm Hg at follow-up, P = 0.94. No effect was found on cardiac output, mean 6.9 ± 1.7 L/min at baseline versus 6.9 ± 2.3 L/min at follow-up, compared to placebo, mean 6.6 ± 1.9 L/min at baseline compared to 6.5 ±2.1 L/min at follow-up, P = 0.66. No effects on the glomerular filtration rate, P = 0.14, or vasoactive hormones were found. Subgroup analyses on patients with increased lipopolysaccharide binding protein and systemic vascular resistance below the mean (1,011 dynes × s/cm 5 ) revealed no effect of rifaximin., Conclusion: Four weeks of treatment with rifaximin did not reduce the hepatic venous pressure gradient or improve systemic hemodynamics in patients with cirrhosis and ascites; rifaximin did not affect glomerular filtration rate or levels of vasoactive hormones. (Hepatology 2017;65:592-603)., (© 2016 by the American Association for the Study of Liver Diseases.)

Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl 4 -caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl 4 -administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl 4 -induced liver injury. DHA also reduced CCl 4 -caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis., (© 2016 Federation of European Biochemical Societies.)

Background: Congenital portosystemic shunts (CPSS) with intrahepatic portal vein (IHPV) hypoplasia or absence cause encephalopathy or pulmonary hypertension (PH). Acute shunt closure may result in postoperative portal hypertension. The aim of this study was to propose a surgical strategy according to the anatomical types of CPSS and IHPV., Methods: Twenty-three CPSS patients were diagnosed from1990 to 2015. All patients were evaluated by computed tomography, angiography, and PV pressure monitoring under a shunt occlusion test. CPSS were categorized into 5 types according to the anatomical shunt location., Results: The median age at diagnosis was 34months. Three of 23 total patients, who had an extrahepatic portosystemic shunt with a hypoplastic IHPV, died before treatment initiation because of severe PH. Fourteen cases received surgical or interventional treatment at the median age of 5years. A total of 6 cases received surgical therapy, including liver transplants for 2 absent IHPV cases. The remaining 8 cases received interventional coiling. All shunt ligations were successfully accomplished in 1-stage ligation without any complications. After the treatment, the hypoplastic IHPV gradually enlarged with an efficient portal inflow., Conclusion: A precise pretreatment anatomical evaluation of CPSS and IHPV types is mandatory for the selection of surgical treatment., Level of Evidence: Diagnostic study - level II and treatment study - level III., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway., Competing Interests: All authors declare no conflict of interests.

Background: MEN1 patients requiring resection of neuroendocrine tumors (pNET) are frequently young, active patients in whom a minimal access approach minimizes perioperative morbidity and splenic preservation decreases the risk of post-splenectomy sepsis. Laparoscopic spleen preserving distal pancreatectomy can be performed with removal (Warshaw's technique) or preservation of the splenic vessels, the later having a higher rate of successful splenic preservation., Patient: This is an active, 16-year-old Jehovah's Witness with trifocal nonfunctioning neuroendocrine tumor in the proximal body and tail of the pancreas as part of MEN1 syndrome. A spleen preserving distal pancreatectomy was performed with the final pathology showing three pNET with low mitotic count and three lymph nodes free of cancer (final stage pT2pN0)., Technique: This video demonstrates patient and trocar positioning as well as operative tactics for a laparoscopic distal pancreatectomy with preservation of splenic vessels. Intraoperative ultrasound is crucial in assessing pNETs' relation to critical vessels, pancreatic duct, and to exclude synchronous lesions. The video focuses on safe laparoscopic creation of the retropancreatic tunnel and dissecting the pancreas off the splenic vessels using novel energy devises to control direct splenic venous branches into the pancreas., Conclusion: Improvements in laparoscopic techniques and technology have enabled surgeons to preserve the major splenic vessels to avoid splenic infarcts, abscesses and re-operations, and minimize the risk of left-sided portal hypertension. Splenic preservation is particularly important in young MEN1 patients undergoing laparoscopic pancreatectomy for pNET due to the increased risk of overwhelming post-splenectomy sepsis.

Treatment with direct-acting antiviral agents has revolutionized the approach to hepatitis C. We are now able to obtain high sustained virological response (SVR) rates, even in the historically difficult-to-treat patient populations. SVR translates into improved clinical outcomes, particularly overall and liver-related mortality, and benefits are more striking in patients with cirrhosis. A 2.5- to 5-fold risk reduction in the incidence of hepatocellular carcinoma and improvement in complications derived from portal hypertension have been reported as well. It is hypothesized that the benefits from SVR occur largely due to regression of fibrosis, which arises from the halt on the fibrogenic stimuli and activation of extracellular matrix reabsorption signals. Non-invasive markers of fibrosis are being utilized to assess regression, but it is still unclear how accurate they are in this clinical scenario. Interventions aiming to improve liver wellness and screening for cirrhosis-related complications should continue to be the norm after SVR.

Thrombosis of the splenoportal axis not associated with liver cirrhosis or neoplasms is a rare disease whose prevalence ranges from 0.7 to 3.7 per 100,000 inhabitants. However, this entity is the second most common cause of portal hypertension. Prothrombotic factors are present as an underlying cause in up to 70% of patients and local factors in 10-50%. The coexistence of several etiological factors is frequent. Clinical presentation may be acute or chronic (portal cavernomatosis). The acute phase can present as abdominal pain, nausea, vomiting, fever, rectorrhagia, intestinal congestion, and ischemia. In this phase, early initiation of anticoagulation is essential to achieve portal vein recanalization and thus improve patient prognosis. In the chronic phase, symptoms are due to portal hypertension syndrome. In this phase, the aim of treatment is to treat or prevent the complications of portal hypertension. Anticoagulation is reserved to patients with a proven underlying thrombophilic factor., (Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.)

Aim: To investigate the role of diarylpropionitrile (DPN), a selective agonist of estrogen receptor β (ERβ), in liver cirrhosis with portal hypertension (PHT) and isolated hepatic stellate cells (HSCs)., Methods: Female Sprague-Dawley rats were ovariectomized (OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin (HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Collagen gel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition., Results: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance (IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of RhoA and ROCK II, and even suppressed ROCK II activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, and promoted the activities of protein kinase G (PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK II activity in activated HSCs. Finally, in vivo/in vitro experiments demonstrated that MLC activity was inhibited by DPN., Conclusion: For OVX rats with liver cirrhosis, DPN suppressed liver RhoA/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.

Background and Aim: Portal-systemic collaterals lead to dreadful consequences in patients with cirrhosis. Angiogenesis participates in the development of liver fibrosis, hyperdynamic circulation, and portal-systemic collaterals. 2'-Hydroxyflavanone (2'-HF), one of the citrus fruits flavonoids, is known to have antiangiogenesis effect without adverse response. However, the relevant effects in liver fibrosis have not been surveyed., Methods: Male Wistar rats received thioacetamide (TAA, 100 mg/kg tiw, i.p.) for 6 weeks to induce liver fibrosis. On the 29th to 42nd day, rats randomly received 2'-HF (100 mg/kg, qod, i.p.) or vehicle (corn oil). On the 43rd day, after hemodynamic measurements, the followings were surveyed: (i) severity of collaterals; (ii) mesenteric angiogenesis; (iii) mesenteric proangiogenic factors protein expressions; (iv) Mesenteric vascular endothelial cells apoptosis; and (v) Mesenteric expressions of proteins regulating apoptosis., Results: Compared with the vehicle group, 2'-HF did not significantly change body weight, mean arterial pressure, heart rate, and portal pressure in TAA rats. 2'-HF significantly alleviated the severity of collaterals, but the mesenteric phospho-ERK, ERK, phospho-Akt, Akt, COX1, COX2, VEGF, and VEGFR-2 protein expressions were not altered. The apoptotic index of 2'-HF group was significantly higher and the mesenteric protein expressions of pro-apoptotic factors, NFkB 50, NFkB 65, Bax, phospho-p53, 17 kD cleaved caspase 3, and 17 kD casepase 3 were up-regulated., Conclusions: 2'-HF does not influence the hemodynamics but alleviated the severity of collaterals in rats with liver fibrosis and early portal hypertension. This is, at least partly, attributed to enhanced apoptosis of mesenteric vascular endothelial cells., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Portal hypertension is a serious obstacle of partial orthotopic liver transplantation (POLT) with the use of small-for-size liver graft. Several therapeutic strategies including surgical innovations and pharmacological agents to reduce the portal hypertension have been developed. Splenectomy (SP) on POLT is one of surgical procedures to reduce portal pressure. We previously reported a dual cytoprotective mechanism of SP just before POLT, using small-for-size liver graft in a rat model. However, the best timing of SP during POLT has been unclear. We compared liver functions between SP just before and after POLT, using small-for-size rat liver grafts., Methods: With the use of small-for-size liver grafts (20%) in rats previously reported, the rats were assigned to 2 groups: the pre-SP group (SP just before POLT) and the post-SP group (SP just after POLT). Liver tissues and blood were sampled at 6 and 24 hours after POLT for several liver function tests., Results: The serum alanine aminotransferase levels at 24 hours after POLT were significantly decreased in the pre-SP group compared with the post-SP group (226 ± 78 vs 340 ± 71 IU/L). The infiltrations of neutrophil at 6 hours and ED-1-positive cells at 24 hours were significantly suppressed in the pre-SP group compared with the post-SP group. Serum hyaluronic acid levels, indicating attenuation of endothelial damage, were lower in the pre-SP group than in the post-SP group., Conclusions: SP before POLT, which directly eliminates splenic inflammatory leukocytes, inhibits inflammatory leukocyte infiltration, which leads to impaired liver function as compared with SP after POLT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To develop a device intended for gradual venous occlusion over 4 to 6 weeks., Sample: Silicone tubing filled with various inorganic salt and polyacrylic acid (PAA) formulations and mounted within a polypropylene or polyether ether ketone (PEEK) outer ring., Procedures: 15 polypropylene prototype rings were initially filled with 1 of 5 formulations and placed in PBSS. In a second test, 10 polypropylene and 7 PEEK prototype rings were filled with 1 formulation and placed in PBSS. In a third test, 2 formulations were loaded into 6 PEEK rings each, placed in physiologic solution, and incubated. In all tests, ring luminal diameter, outer diameter, and luminal area were measured over 6 weeks., Results: In the first test, 2 formulations had the greatest changes in luminal area and diameter, and 1 of those had a greater linear swell rate than the other had. In the second test, 6 of 7 PEEK rings and 6 of 10 polypropylene rings closed to a luminal diamater < 1 mm within 6 weeks. Polypropylene rings had a greater increase in outer diameter than did PEEK rings between 4.5 and 6 weeks. In the third test, 11 of 12 PEEK rings gradually closed to a luminal diameter < 1 mm within 6 weeks., Conclusions and Clinical Relevance: A PAA and inorganic salt formulation in a prototype silicone and polymer ring resulted in gradual occlusion over 4 to 6 weeks in vitro. Prototype PEEK rings provided more reliable closure than did polypropylene rings.

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.)

Background and Aim: Extrahepatic portal vein obstruction (EHPVO) is an important cause of portal hypertension in children. The aim of this study was to describe the clinical presentation, possible risk factors, upper gastrointestinal endoscopic findings, and treatment modalities of children with EHPVO., Methods: After ethical approval of our study protocol by our institution review board, we analyzed available data from medical records of patients with EHPVO presenting to the Pediatric Hepatology Unit, Cairo University Pediatric Hospital, Egypt, for a period of 15 years from January 1996 to December 2010., Results: The study included 169 patients. Their ages at presentation ranged from 1 month to 12 years (median 2.5 years, interquartile range 5); 101 were boys. Hematemesis was a presenting symptom in 58%, splenomegaly was present in 87%, esophageal varices were present in 94%, and fundal varices were present in 23%. Possible risk factors, in the form of umbilical catheterization, umbilical sepsis, and exchange transfusion, were elicited in 18%. Propranolol was associated with reduction in bleeding episodes (P < 0.001), but was associated with increased chest symptoms (P < 0.01). Both injection sclerotherapy and band ligation were effective in the management of bleeding varices and for primary and secondary prophylaxis; however, injection sclerotherapy was associated with the development of secondary gastric varices (P = 0.03)., Conclusions: This large study of children with EHPVO demonstrates the efficacy of propranolol in the reduction of gastrointestinal bleeding in children with EHPVO. Both injection sclerotherapy and band ligation were effective in the management of esophageal varices, although the former was associated with the development of secondary gastric varices. Randomized clinical trials to choose the best modalities for the management of portal hypertension in children are still lacking.

Portal hypertension is the main complication of cirrhosis and represents a leading cause of death in patients with chronic liver disease. Therapeutic agents to improve portal hypertension should ameliorate the underlying mechanisms of portal hypertension: the elevated hepatic resistance and the hyperdynamic circulation. In the present issue of Clinical Science, Hsu and co-workers show the beneficial effects of GTPs (green tea polyphenols) in improving portal hypertension. Long-term administration of GTPs inhibited the development of cirrhosis and portal hypertension by decreasing both hepatic resistance and splanchnic hyperdynamic circulation. The main underlying mechanism of the benefits of GTPs appears related to the down-regulation of splanchnic angiogenesis. The present study adds further evidence supporting the potential of natural compounds for an effective nutriceutical approach to the treatment of patients with cirrhosis of the liver.

Background: Resection of the superior mesenteric vein (SMV)-portal vein (PV)-splenic vein (SV) confluence during pancreatectomy for pancreatic cancer requires management of the SV., Discussion: Simple SV ligation can result in sinistral portal hypertension if the inferior mesenteric vein (IMV) enters the confluence and is thereby resected, or if the IMV is insufficient to drain the SV. We describe herein three patients whose clinical course confirms the importance of the IMV decompressing the SV to avoid sinistral hypertension.

Abnormal angiogenesis in liver cirrhosis often leads to severe complications such as variceal haemorrhage and encephalopathy. Furthermore, splanchnic angiogenesis elevates portal pressure, in which angiogenic factors play pivotal roles. GTP (green tea polyphenol) extracted from Camellia sinensis has anti-angiogenic properties, but the effects on the parameters described above in cirrhosis have not been investigated. The aim of the present study was to determine the effects of GTP in cirrhosis and to investigate the underlying mechanism. Liver cirrhosis was induced in Spraque-Dawley rats by common BDL (bile duct ligation). They randomly received GTP or DW (distilled water, vehicle) for 28 days, then haemodynamic parameters, portosystemic shunting, mesenteric window vascular density, intrahepatic angiogenesis, liver fibrosis, plasma VEGF (vascular endothelial growth factor) concentration, mesenteric angiogenic factor and receptor protein expression, and serum and mesenteric oxidative stress parameters were assessed. Compared with the DW group, GTP significantly decreased portosystemic shunting, liver fibrosis, intrahepatic angiogenesis, mesenteric window vascular density, VEGF concentration and down-regulated the mesenteric HIF (hypoxia-inducible factor)-1α, VEGF and phospho-Akt expression. In conclusion, GTP ameliorates the severity of portosystemic shunting and mesenteric angiogenesis via the suppression of HIF-1α, Akt activation and VEGF. GTP appears to be an appropriate agent in controlling portal hypertension-related complications via anti-angiogenesis.

Unlabelled: Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner., Conclusion: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status., (Copyright © 2014 by the American Association for the Study of Liver Diseases.)

A major cause of cirrhosis related morbidity and mortality is the development of variceal bleeding, a direct consequence of portal hypertension. Less common causes of gastrointestinal bleeding are peptic ulcers, malignancy, angiodysplasia, etc. Upper gastrointestinal bleeding has been classified according to the presence of a variceal or non-variceal bleeding. Although non-variceal gastrointestinal bleeding is not common in cirrhotic patients, gastroduodenal ulcers may develop as often as non-cirrhotic patients. Ulcers in cirrhotic patients may be more severe and less frequently associated with chronic intake of non-steroidal anti-inflammatory drugs, and may require more frequently endoscopic treatment. Portal hypertensive gastropathy (PHG) refers to changes in the mucosa of the stomach in patients with portal hypertension. Patients with portal hypertension may experience bleeding from the stomach, and pharmacologic or radiologic interventional procedure may be useful in preventing re-bleeding from PHG. Gastric antral vascular ectasia (GAVE) seems to be different disease entity from PHG, and endoscopic ablation can be the first-line treatment.