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BACKGROUND AND AIMS Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

Patients with cirrhosis are at risk of both thrombotic and hemorrhagic events. Traditional hemostatic tests are inadequate to assess the complex and fragile balance of hemostasis in this setting, especially in advanced stages of disease such as decompensated cirrhosis or acute on chronic liver failure (ACLF). Furthermore, the indiscriminate use of pro-hemostatic agents for prophylaxis and treatment of bleeding episodes is still debated and often contraindicated. Alongside, splanchnic, and peripheral thrombotic events are frequent in this population and require management that involves a careful balance between risks and benefits of antithrombotic therapy.This review aims to address the state of the art on the clinical management of the hemostatic balance of cirrhosis in terms of established knowledge and future challenges.The old paradigm of cirrhosis as a naturally anticoagulated condition has been challenged by more sophisticated global tests of hemostasis. Integrating this information in the clinical decision-making is still challenging for physicians and experts in hemostasis.

Despite vaccination programs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a public health problem. Identifying key prognostic determinants of severity of the disease may help better focus health resources. The negative prognostic role for metabolic and hepatic alterations is established; however, the interplay among different metabolic comorbidities and their interconnections with the liver have never been explored.The objective of this study is to evaluate the impact of liver alterations in addition to metabolic comorbidities as a predictor of SARS-CoV-2 severity. 382 SARS-CoV-2 patients were enrolled. Severe SARS-CoV-2 was diagnosed according to international consensus. Transaminases > 2 times the upper limit of normality (2ULN), hepatic steatosis (by ultrasound and/or computed tomography in 133 patients), and FIB-4 defined liver alterations. All data were collected on admission. The results are severe SARS-CoV-2 infection in 156 (41%) patients (mean age 65 ± 17; 60%males). Prevalence of obesity was 25%; diabetes, 17%; hypertension, 44%; dyslipidaemia, 29%; with 13% of the cohort with ≥ 3 metabolic alterations. Seventy patients (18%) had transaminases > 2ULN, 82 (62%) steatosis; 199 (54%) had FIB-4 3.25. At multivariable analysis, ≥ 3 metabolic comorbidities (OR 4.1, CI 95% 1.8–9.1) and transaminases > 2ULN (OR 2.6, CI 95% 1.3–6.7) were independently associated with severe SARS-CoV-2. FIB-4

© 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved, Background & aims: Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis. Methods: In this IPD meta-analysis, we selected studies comparing anticoagulation vs. no treatment in patients with cirrhosis and portal vein thrombosis from PubMed, Embase, and Cochrane databases (until June 2020) (PROSPERO no.: CRD42020140026). IPD were subsequently requested from authors. The primary outcome - the effect of anticoagulation on all-cause mortality - was assessed by a one-step meta-analysis based on a competing-risk model with liver transplantation as the competing event. The model was adjusted for clinically relevant confounders. A multilevel mixed-effects logistic regression model was used to determine the effect of anticoagulation on recanalization. Results: Individual data on 500 patients from five studies were included; 205 (41%) received anticoagulation and 295 did not. Anticoagulation reduced all-cause mortality (adjusted subdistribution hazard ratio 0.59; 95% CI 0.49-0.70), independently of thrombosis severity and recanalization. The effect of anticoagulation on all-cause mortality was consistent with a reduction in liver-related mortality. The recanalization rate was higher in the anticoagulation arm (adjusted odds ratio 3.45; 95% CI 2.22-5.36). The non-portal-hypertension-related bleeding rate was significantly greater in the anticoagulation group. Conclusions: Anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization, but at the expense of increasing non-portal hypertension-related bleeding. Prospero registration number: CRD42020140026. Impact and implications: Anticoagulation is effective in promoting recanalization of portal vein thrombosis in patients with cirrhosis, but whether this benefit translates into improved survival is controversial. Our individual patient data meta-analysis based on a competing-risk model with liver transplantation as the competing event shows that anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization. According to our findings, portal vein thrombosis may identify a group of patients with cirrhosis that benefit from long-term anticoagulation.

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.

The reference standard for assessing transjugular intrahepatic portosystemic shunt (TIPS) function is venography with portosystemic pressure gradient (PPG) measurement. This procedure is invasive and expensive; thus, we assessed the feasibility, reproducibility and diagnostic accuracy of color-Doppler ultrasound (CDUS) and spleen and liver stiffness (LS) measurements for identifying TIPS dysfunction. Twenty-four patients (15 undergoing TIPS placement and nine undergoing TIPS revision) consecutively underwent CDUS examination and LS and spleen stiffness (SS) determination by transient elastography (TE) and point shear-wave elastography (pSWE). All parameters were taken before TIPS placement/revision (1–15 d before) and 24 h after, just before revision by venography. pSWE inter-observer agreement was assessed by intra-class correlation coefficient (ICC). CDUS and elastographic data were correlated (Pearson coefficient) with pressure gradients (hepatic venous pressure gradient [HVPG], PPG). Main determinants of TIPS dysfunction were investigated by linear regression. Forty-nine paired examinations were performed in total: 49 (100%) SS reliable measurements by pSWE and 38 (88%) by TE. The ICC for pSWE values was 0.90 (95% confidence interval [CI] 0.81‒0.94). SS values significantly correlated with HVPG and PPG (R = 0.51, p = 0.01). The area under the Receiver-Operating Characteristic (AUROC) curve of SS for diagnosing TIPS dysfunction was 0.86 (95% CI 0.70‒0.96) using a 25 kPa cutoff. At multivariate analysis, the flow direction of the intrahepatic portal vein branches and SS values were independently associated to TIPS dysfunction. The intrahepatic portal vein branches flow direction and SS value are two simple, highly sensitive parameters accurately excluding TIPS dysfunction. SS measurement by pSWE is feasible, reproducible and both positively and significantly correlates with HVPG and PPG values.

Background & Aims Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. Methods This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. Results One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23–37%) on US and 47.7% (95% CI 39–56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38–62%) and 85.3% (95% CI 75–92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. Conclusion While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. Lay summary Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is anticipated that it could become even more prevalent in parallel with an increase in the incidence of metabolic diseases closely related to NAFLD, such as obesity, type II diabetes, dyslipidemia, and arterial hypertension. In addition to liver impairment, NAFLD is associated with cardiovascular diseases. Fibrosis, atherosclerosis, and venous thrombosis are basically the pathogenic mechanisms behind these clinical manifestations, and all are plausibly associated with hypercoagulability that may, in turn, develop because of an imbalance of pro- vs. anticoagulants and the presence of such procoagulant molecular species as microvesicles, neutrophil extracellular traps (NETs), and inflammation. The assessment of hypercoagulability by means of thrombin generation is a global procedure that mimics the coagulation process occurring in vivo much better than any other coagulation test, and is considered to be the best candidate laboratory tool for assessing, with a single procedure, the balance of coagulation in NAFLD. In addition to defining the state of hypercoagulability, the assessment of thrombin generation could also be used to investigate, in clinical trials, the best approach (therapeutic and/or lifestyle changes) for minimizing hypercoagulability and, hence, the risk of cardiovascular diseases, progression to atherosclerosis, and liver fibrosis in patients with NAFLD.

Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.

Nonselective β-blockers improve decompensation-free survival in viremic hepatitis C virus compensated cirrhotic patients with clinically significant portal hypertension, but their protective role after sustained virological response by direct-acting antiviral (DAA) is undefined. We evaluated the incidence of decompensation in DAA-cured Child-A patients without high-risk varices. During the 49-month (12-60) follow-up, only one of 148 patients decompensated (ascites), with a 4-year cumulative risk of 1%, but decompensation was associated with hepatocellular carcinoma. The risk of decompensation in DAA cured hepatitis C virus compensated Child-A cirrhotic patients with clinically significant portal hypertension but without high-risk varices is negligible; thus, questioning the need for nonselective β-blocker treatment in this setting (see Visual abstract, Supplemental Digital Content, 1, http://links.lww.com/AJG/B861). JOURNAL/ajgast/04.03/00000434-202106000-00035/inline-graphic1/v/2021-05-28T144026Z/r/image-tiff.

Background Liver stiffness measurement (LSM) 150,000/mm3 exclude varices needing treatment (VNT) in viral compensated advanced chronic liver disease (cACLD), saving-up to 20–25% endoscopies (Baveno VI criteria). Refinements of such criteria to further reduce endoscopies and an approach without LSM (Platelet 150/MELD 6) were later proposed. Aims To assess LSM 25/platelet 125, LSM 25/platelet 110 (Expanded-Baveno VI) and Platelet 150/MELD 6 accuracy versus Baveno VI criteria, and the impact of platelet count variability on criteria accuracy in all-etiologies cACLD. Methods cACLD patients undergoing screening endoscopy with laboratory data within 6 months and LSM within one year. Results Of 442 patients, 31% had varices (7% with VNT). Baveno VI criteria had 100% sensitivity (Se) and negative predictive value (NPV) and spared 19.5% endoscopies. “LSM 25/platelet 125” and “Expanded-Baveno VI” criteria maintained such accuracy, sparing 15% and 24% more endoscopies, respectively (p Conclusions Both “Expanded-Baveno VI” and “LSM 25/platelet 125” criteria are accurate in cACLD, but the former are more advantageous. Platelet 150/MELD 6 proved inadequate.

Background & Aims Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. Methods In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. Conclusions In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. Lay summary While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

We hereby report on the case of F.C., a 17 years old male patient, who was initially referred to our Unit on the advice of his cardiologist at a tertiary referral center. He presented with an anatomic single ventricle, also known as univentricular heart, a condition known since birth. The univentricular heart is defined as the presence of only one well-developed ventricle and the other rudimentary ventricle (if present) with less than 30% of its expected volume. The patient underwent a first surgical procedure by Glenn in 2005, followed by Fontan surgery in 2008. The Fontan procedure, firstly described as a surgical palliation for a single ventricle with tricuspid atresia, has become the standard operation for all patients with single-ventricle physiology (e.g., hypoplastic left-heart syndrome, pulmonary atresia, unbalanced atrio-ventricular canal defects) [1–4].

Portal hypertension and ascites are two crucial events in the natural history of liver cirrhosis, whose appearance marks a downward shift in the prognosis of the disease. Over the years, several international and national societies have issued clinical practice guidelines for the diagnosis and management of portal hypertension and ascites. The present document addresses the needs of an updated guidance on the clinical management of these conditions. Accordingly, the AISF Governing Board appointed a multi-disciplinary committee of experts for drafting an update of the most recent EASL Clinical Practice Guidelines. The aim of this work was to adapt the EASL recommendations to national regulations and resources, local circumstances and settings, infrastructure, and cost/benefit strategies to avoid duplication of efforts and optimize resource utilization. The committee defined the objectives, the key issues and retrieved the relevant evidence by performing a systematic review of the literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines’ key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes). For each of the PICO questions, the systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase)

Background This study aimed to determine the feasibility, safety and effectiveness of combined percutaneous transhepatic obliteration (PTO) and balloon-occluded retrograde transvenous obliteration (BRTO) therapy for the treatment of patients with high-risk bleeding gastric varices. Methods Ten patients were retrospectively reviewed. All the patients presented gastric varices, according to the Sarin classification, at high risk of bleeding, and not otherwise manageable. Patients with portal vein thrombosis were excluded. All patients were treated with a combination of PTO and BRTO. In all cases the gastric varices were embolized with glue, combined with coils or not, with an occlusion balloon inflated into the shunt. In 7 cases, embolization was immediate; in the remaining 3 the balloon remained inflated for 4 h and in 2 of them embolization of the shunt was required. Technical success was defined as complete obliteration of the gastric varices observed during a contrast-enhanced computed tomography study and endoscopy within 1 month following treatment. Clinical success was defined as absence of bleeding of gastric varices during the follow-up period. Major and minor complications during the follow up were recorded. Results Twelve sessions of combined PTO and BRTO procedures were performed in 10 patients; in 2 patients a new combined treatment was required during the follow up. Technical and clinical success was 100%. Neither major nor minor procedure-related complications were observed. Conclusion Combined PTO and BRTO therapy is safe and effective for the treatment of gastric varices that cannot be managed otherwise.

Preemptive TIPS Individual Data Metanalysis, International Variceal Bleeding Study and Baveno Cooperation Study groups., [Background & Aims] Compared with drugs plus endoscopy, placement of transjugular portosystemic shunt within 72 hours of admission to the hospital (early or preventive transjugular intrahepatic portosystemic shunt [TIPS], also called preemptive TIPS) increases the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survive for 1 year. However, the benefit of preemptive TIPS is less clear for patients with a Child-Pugh score of B and active bleeding (CP-B+AB). We performed an individual data meta-analysis to assess the efficacy of preemptive TIPS in these patients and identify factors associated with reduced survival of patients receiving preemptive TIPS., [Method] We searched publication databases for randomized controlled trials and observational studies comparing the effects of preemptive TIPS versus endoscopy plus nonselective beta-blockers in the specific population of high-risk patients with cirrhosis and acute variceal bleeding (CP-B+AB or Child-Pugh C, below 14 points), through December 31, 2019. We performed a meta-analysis of data from 7 studies (3 randomized controlled trials and 4 observational studies), comprising 1327 patients (310 received preemptive TIPS and 1017 received drugs plus endoscopy). We built adjusted models to evaluate risk using propensity score for baseline covariates. Multivariate Cox regression models were used to assess the factors associated with survival time. The primary endpoint was effects of preemptive TIPS versus drugs plus endoscopy on 1-year survival in the overall population as well as CP-B+AB and Child-Pugh C patients., [Results] Overall, preemptive TIPS significantly increased the proportion of high-risk patients with cirrhosis and acute variceal bleeding who survived for 1 year, compared with drugs plus endoscopy (hazard ratio [HR] 0.443; 95% CI 0.323–0.607; P < .001). This effect was observed in CP-B+AB patients (HR 0.524; 95% CI 0.307–0.896; P = .018) and in patients with Child-Pugh C scores below 14 points (HR 0.374; 95% CI 0.253–0.553; P < .001). Preemptive TIPS significantly improved control of bleeding and ascites without increasing risk of hepatic encephalopathy in Child-Pugh C and CP-B+AB patients, compared with drugs plus endoscopy. Cox analysis of patients who received preemptive TIPS showed that patients could be classified into 3 categories for risk of death, based on age, serum level of creatinine, and Child-Pugh score. In each of these risk categories, preemptive TIPS increased the proportion of patients who survived for 1 year, compared with drugs plus endoscopy., [Conclusions] In a meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10 and 13 points or CP-B+AB, preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy., Juan Carlos García-Pagán received support in part through grants from the Spanish Ministry of Education and Science (SAF-2016–75767-R and PIE 15/00027) and from the “Commissioner for Universities and Research of the Generalitat de Catalunya” (AGAUR SGR 2017). CIBERehd is funded by the Instituto de Salud Carlos III. Edilmar Alvarado-Tapias and Anna Baiges are recipients of a "Río Hortega" fellowship grant from the Instituto de Salud Carlos III. The study was partially supported by a GORE grant for statistical support.

BACKGROUND In cirrhosis, a decrease in hepatic venous pressure gradient (HVPG) > 10% after acute iv propranolol (HVPG response) is associated with a lower risk of decompensation and death. Only a part of patients are HVPG responders and there are no accurate non-invasive markers to identify them. We aimed at discovering metabolomic biomarkers of HVPG responders to propranolol. METHODS Sixty-six patients with cirrhosis and HVPG ≥ 10 mm Hg in whom the acute HVPG response to propranolol was assessed, were prospectively included. A targeted metabolomic serum analysis using ultrahigh-performance liquid chromatography coupled to mass spectrometry was performed. Different combinations of 2-3 metabolites identifying HVPG responders (HVPG reduction > 10%) were obtained by stepwise logistic regression. The best of these model (AUROC, Akaike criterion) underwent internal cross-validation and cut-offs to classify responders/non-responders was proposed. RESULTS A total of 41/66 (62%) patients were HVPG responders. Three hundred and eighty-nine metabolites were detected and 177 were finally eligible. Eighteen metabolites were associated to the HVPG response at univariate analysis; at multivariable analysis, a model including a phosphatidylcholine (PC(P-16:0/22:6)) and a free fatty acid (20:2(n-6), eicosadienoic acid) performed well for HVPG response, with an AUROC of 0.801 (0.761 at internal validation). The cut-off 0.629 was the most efficient for overall classification (49/66 patients correctly classified). Two cut-off values allowed identifying responders (0.688, PPV 84%) and non-responders (0.384, NPV 82%) with undetermined values for 17/66 patients. Clinical variables did not add to the model. CONCLUSIONS The combination of two metabolites helps at identifying HVPG responders to acute propranolol. It could be a useful non-invasive test to classify the HVPG response to propranolol.

Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, anti-inflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.

Management of ascites ranges from diuretic treatment to liver transplantation. This chapter will describe the widely accepted strategies of treatment for uncomplicated and complicated ascites.

The abnormal accumulation of peritoneal fluid in the abdomen is a frequent complication in patients with cirrhotic and non-cirrhotic portal hypertension which is defined as ascites whose appearance heralds worsening of prognosis in such chronic diseases of the liver. Ascites can be also associated with acute liver failure, hepatic and extra-hepatic malignancies, infections (among them tuberculosis), pancreatitis, malnutrition or malabsorption or other rare inflammatory conditions. Therefore, peritoneal fluid analysis is mandatory to differentiate these clinical conditions in order to guide the best clinical management and treatment. This chapter summarizes the most important principles of peritoneal fluid analysis to best differentiate the etiological diagnosis of ascites.

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p 83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS., Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, CRC1382), Cellex Foundation and European Union’s Horizon 2020 research and innovation program GALAXY study (No. 668031), LIVERHOPE (No. 731875) and MICROB-PREDICT (No. 825694) and the Cellex Foundation. Joan Genescà is a recipient of a Research Intensification grant from Instituto de Salud Carlos III, Spain. The study was partially funded by grants PI15/00066, and PI18/00947 from Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future”). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivasis supported by Instituto de Salud Carlos III. Macarena Simón-Talero is a recipient of the grant JR 17/00029 from Instituto de Salud Carlos III

This revision was aimed to report the evidences on the treatment of patients with cirrhosis and refractory ascites. Mainly, we wished to explore which of the predicting variables could be used to prefer large-volume paracentesis or TIPS.

Background & aims Portal vein thrombosis (PVT) is frequently observed in cirrhosis and may be a clinically important complication. In vitro assays for endogenous thrombin potential (ETP) demonstrated that in cirrhosis plasma has intrinsic resistance to the anticoagulant action of thrombomodulin (TM-R). This study retrospectively explores the association of TM-R with de novo PVT and its clinical impact on cirrhosis. Methods Fifty-three patients with cirrhosis were tested for ETP-ratio with/without thrombomodulin. Clinical, endoscopic variables, presence/absence of PVT by Doppler-US and/or CT examination were collected at baseline and up to 4 years from baseline. The de novo PVT was the primary clinical end-point. Portal hypertension (PHT)-related complications and transplantation free survival were secondary end-points. ETP-ratio higher than the 95° percentile of the distribution in 173 healthy controls defined TM-R. Results During 48 months of follow-up, 11 patients developed de novo PVT, with preference for the 36 patients with TM-R after adjusting for Child-Pugh class (HR: 8.354; 90%CI:1.475 - 47.305; P = 0.009). Seventeen patients experienced PHT-related complications, 23 either died or underwent liver transplantation. PHT complications and transplantation free survival were associated with TM-R, but were independently predicted by Child-Pugh class, only. Same results were obtained by considering the MELD score. Conclusions Owing to PVT results from the pro-coagulant imbalance occurring in patients with advanced cirrhosis, TM-R might serve as a predictor and could possibly be a biological mediator of adverse outcome in patients with advanced cirrhosis.

Fibrosis is the main consequence of any kind of chronic liver damage. Coagulation and thrombin generation are crucial in the physiological response to tissue injury; however, the inappropriate and uncontrolled activation of coagulation cascade may lead to fibrosis development due to the involvement of several cellular types and biochemical pathways in response to thrombin generation. In the liver, hepatic stellate cells and sinusoidal endothelial cells orchestrate fibrogenic response to chronic damage. Thrombin interacts with these cytotypes mainly through protease-activated receptors (PARs), which are expressed by endothelium, platelets and hepatic stellate cells. This review focuses on the impact of coagulation in liver fibrogenesis, describes receptors and pathways involved and explores the potential antifibrotic properties of drugs active in hemostasis in studies with cells, animal models of liver damage and humans.

Transarterial chemoembolization (TACE) is the standard of care for the treatment of patients with an intermediate (Barcelona Clinic Liver Cancer [BCLC] B) hepatocellular carcinoma and to bridge patients with an early cancer to liver transplantation (LT). We explored the efficacy of TACE with drug-eluting beads (DEB) in BCLC A patients. Included are all BCLC A patients unsuitable for resection or locoregional ablation who underwent a DEB TACE between 2006 and 2012. Treatment was carried out "a la demande" until complete tumor devascularization or progression beyond Milan criteria. In patients with a complete response (CR), a contrast computed tomography (CT) scan was repeated at 3-month intervals during the first 2 years and then every 6 months alternating with abdominal ultrasound in the subsequent 3 years. Fifty-five patients had 79 tumor nodules ranging 7 to 50 mm; 32 (58%) achieved a CR that was maintained up to 4 and 7 months in 21 (38%) and 17 (31%) patients, respectively. The 24- and 36-month tumor-free survivals were 21% and 9%, respectively. The overall cumulative progression beyond Milan criteria at 3, 6, 12, and 24 months was 2%, 5%, 30%, and 54%. LT eligibility was maintained for a median of 19 months (range, 2-63 months). CR to first TACE was the strongest independent predictor of Milan-in maintenance. In conclusion, DEB TACE may effectively bridge patients with an early cancer to LT, and a CR to the first procedure may guide patient prioritization during the waiting list.

Portal hypertension is the haemodynamic abnormality associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy and bleeding from gastroesophageal varices. Variceal bleeding is a medical emergency associated with a mortality that, in spite of recent progress, is still in the order of 10–20% at 6 weeks. The evaluation of diagnostic tools and the design and conduct of good clinical trials for the treatment of portal hypertension have always been difficult. Awareness of these difficulties has led to the organisation of a series of consensus meetings. The first one was organised by Andrew Burroughs in Groningen, the Netherlands in 1986 [1]. After Groningen, other meetings followed, in Baveno, Italy in 1990 (Baveno I) [2], and in 1995 (Baveno II) [3,4], in Milan, Italy in 1992 [5], in Reston, U.S.A. [6] in 1996, in Stresa, Italy, in 2000 (Baveno III) [7,8], again in Baveno in 2005 (Baveno IV) [9,10], in Atlanta in 2007 [11], and again in Stresa in 2010 (Baveno V) [12,13]. The aims of these meetings were to develop definitions of key events in portal hypertension and variceal bleeding, to review the existing evidence on the natural history, the diagnosis and the therapeutic modalities of portal hypertension, and to issue evidence-based recommendations for the conduct of clinical trials and the management of patients. All these meetings were successful and produced consensus statements on some important points, although several issues remained unsettled. To continue the work of the previous meetings, a Baveno VI workshop was held on April 10–11, 2015. The workshop was attended by many of the experts responsible for most of the major achievements of the last years in this field. Many of them had attended the previous meetings as well. A concept that has gained wide acceptance over the past few years is the fact that patients in different stages of cirrhosis have different risks of developing complications and of dying. Accordingly, the Baveno VI workshop was entitled ‘‘Stratifying

Background & Aims: Spontaneous portosystemic shunts (SPSS) have been associated with hepatic encephalopathy (HE). Little is known about their prevalence among patients with cirrhosis or clinical effects. We investigated the prevalence and characteristics of SPSS in patients with cirrhosis and their outcomes. Methods: We performed a retrospective study of 1729 patients with cirrhosis who underwent abdominal computed tomography or magnetic resonance imaging analysis from 2010 through 2015 at 14 centers in Canada and Europe. We collected data on demographic features, etiology of liver disease, comorbidities, complications, treatments, laboratory and clinical parameters, Model for End-Stage Liver Disease (MELD) score, and endoscopy findings. Abdominal images were reviewed by a radiologist (or a hepatologist trained by a radiologist) and searched for the presence of SPSS, defined as spontaneous communications between the portal venous system or splanchnic veins and the systemic venous system, excluding gastroesophageal varices. Patients were assigned to groups with large SPSS (L-SPSS, ≥8 mm), small SPSS (S-SPSS