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Liver diseases are a major cause of illness and death worldwide. In China, liver diseases, primarily viral hepatitis, affect approximately 300 million people, thus having a major impact on the global burden of liver diseases. Portal hypertension is the most severe complication of chronic liver diseases, including ascites, hepatic encephalopathy and bleeding from gastroesophageal varices. Transjugular intrahepatic portosystemic shunt (TIPS) represents a very effective treatment of these complications. Since its introduction 30 years ago in China, the use of TIPS has evolved and has played an increasingly important role in the management of the complications of portal hypertension. This review will focus on the history, current application and management of complications of TIPS in China.

Nodular regenerative hyperplasia (NRH) is a rare condition characterized clinically by the development of non-cirrhotic portal hypertension. NRH is the histopathological result in the liver of various systemic disease processes including autoimmune disorders, haematological malignancies and medications. However, natural history of this condition has been limited to small case series while patient outcomes pertaining to different aetiologies of NRH are largely unknown.A retrospective cohort of consecutive patients diagnosed with pathology-confirmed NRH at Mayo Clinic between 2002 and 2017 was identified. The histological diagnosis of NRH was determined by expert liver pathologists. Patients with metastatic liver disease, history of liver transplantation or younger than 18 were excluded. Potential aetiologies of NRH were classified as haematological, rheumatological, drug-associated, miscellaneous or idiopathic. Long-term mortality was analysed using Kaplan-Meier estimation and Cox regression models.One hundred and sixty-seven consecutive patients with pathology-confirmed NRH were analysed over a 15-year period and followed for a median time of 50 months (1-306 months). The mean age at diagnosis was 53 years. No aetiology or risk factor for NRH was identified in the majority of patients (94, 56.3%), whereas an associated, possibly causal, condition was found in 73 patients (secondary NRH). The most common presenting feature was elevated liver tests (80%), but no significant differences in laboratory tests were seen based on aetiology of NRH. Compared to idiopathic NRH, those with an identified cause had a higher rate of splenomegaly at presentation (54% vs. 27%, p = 0.002). Portal hypertension-related complications at diagnosis were common, with ascites present in one-third of patients. Overall transplant-free survival was 63% at 5 years. Median survival in idiopathic NRH was 9.4 years compared to 7.3 years in secondary NRH. Age, renal function and volume status at presentation were significantly associated with survival; however, MELD score was not.The rates of liver-related complications and mortality in NRH are low, and only a small number of patients ultimately require liver transplantation. Most patients do not have an identified risk factor or aetiology for NRH, and liver-related outcomes do not appear to differ based on associated, possibly causal, conditions.

Portal hypertension because of liver cirrhosis is a significant cause of morbidity and mortality. Treatment options in these patients include liver transplant, symptomatic treatment of oesophageal varices via endoscopic treatment and symptomatic management of ascites. Portosystemic shunt creation can be challenging in newborns and infants. We present a newborn with Trisomy 21, severe portal hypertension secondary to neonatal cirrhosis, oesophageal varices and upper GI bleeding, severe ascites refractory to medical management who underwent ductus venosus stenting as a palliative procedure. He demonstrated remarkable clinical improvement with no subsequent upper GI bleed and resolution of ascites till his last follow-up at 12 months of age. To the best of our knowledge, stenting of the patent ductus venosus to create a portosystemic shunt to relieve portal hypertension has not been reported in English literature.

Background and Aim: The study was undertaken in order to compare single injection indocyanine green (ICG)-clearances with the steady-state ICG-clearance (ICGCl) in patients with cirrhosis in order to assess the most accurate estimate for ICG-clearance and to relate the ICG-clearances to established indicators of liver dysfunction. Methods: Thirty-eight patients (male 29) with cirrhosis (Child–Turcotte class A 8, class B 21, and class C 9) were studied during a hemodynamic investigation. A single injection of ICG was followed by blood samples for 5, 10, 15, and 20 min. The dose/plasma area clearance (ClA) and plasma volume · initial slope clearance (ClPV) were determined and compared with the steady-state infusion/plasma concentration ratio clearance (ICGCl). Results: The ClA (310; 214; 502 mL/min) and ClPV (294; 164; 481 mL/min) correlated closely with ICGCl (243; 120; 383 mL/min [median; interquartile range], R = 0.95–0.98, P Cl (P A and ClPV) of the steady-state ICG-clearance as derived from the ICG-retention curve and the plasma volume correlate with ICGCl and established variables of portal hypertension and liver cell bile excretory dysfunction. Therefore, these markers can safely replace the more costly ICGCl.

International audience; Background and aims: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients.Methods: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 μmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation» or « the occurrence of one or more parameters » among: prothrombin time (PT)

In patients affected by myelofibrosis with hepatic myeloid metaplasia (HMM), portal hypertension (PHT) complications may develop. In this case series, we analysed the efficacy and safety of transjugular portosystemic shunt (TIPS) in the treatment of PHT-related complications and its effects on the nutritional status. Six patients were evaluated and the average follow-up period after TIPS was 33 (IQR 5) months. None of the patients developed hepatic failure, nor any recurrence of variceal bleeding was recorded. No additional paracentesis or endoscopic prophylactic treatment for PHT-related complications were required. In all subjects, the average dose of diuretics was almost halved three months after TIPS. Three patients died during the follow-up, but none for liver-related causes. All patients showed an improvement in the global nutritional status. In conclusion, TIPS represent an effective and safe treatment option for patients affected by complications of PHT secondary to HMM and drives to an improvement of the nutritional status.

Noninvasive predictors; Portal hypertension; Cirrhosis Predictores no invasivos; Hipertensión portal; Cirrosis Predictors no invasius; Hipertensió portal; Cirrosi Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg, identifies patients with compensated cirrhosis at a high risk of decompensation. However, HVPG is an invasive and nuanced method. The ANTICIPATE models, which include liver stiffness measurements by transient elastography (TE) and platelet count ± body mass index, are robust noninvasive surrogates of CSPH but required external validation in patients with nonalcoholic steatohepatitis (NASH) cirrhosis. Additionally, TE is not widely available worldwide. The aims of the study were: (1) to externally validate the ANTICIPATE models using baseline data from patients with compensated NASH cirrhosis screened/enrolled in a multicenter international randomized controlled trial; and (2) to develop and externally validate a model using only laboratory values. Regarding aim 1, both ANTICIPATE models showed good calibration and discrimination (area under the curve [AUC] > 0.8) in our cohort (n = 222). Regarding aim 2, a new lab-based model using the Fibrosis-4 index (FIB-4 [age, aspartate aminotransferase, alanine aminotransferase, platelet count]) plus serum albumin was developed. The discrimination in the training cohort (n = 309) was good (AUC of 0.78 [95% confidence interval [CI]:0.72–0.83]). It was then externally validated in a separate cohort of 245 patients with compensated NASH cirrhosis (AUC of 0.8 [95% CI: 0.75–0.86]). Given the difference in the prevalence of CSPH between training (74%) and validation (39%) cohorts, the model required an update of the baseline risk to achieve a good calibration. The updated model was named FIB4+. In conclusion, both ANTICIPATE models performed well in predicting the presence of CSPH in NASH cirrhosis. A model using FIB-4 plus albumin (FIB4+) can be used to predict CSPH where TE is not available. Supported by the Yale Liver Center, National Institutes of Health (P30 DK34989).

Liver cirrhosis and portal hypertension are accompanied by hyperdynamic circulation, angiogenesis and portosystemic collaterals. Matrix metalloproteinases (MMPs) participate in fibrogenesis and angiogenesis, however, whether they can be targeted in cirrhosis treatment is unclear. Therefore, we performed three series of experiments to investigate this issue. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague‐Dawley rats. Sham‐operated rats served as controls. Rats were randomly allocated to receive vehicle, minocycline (a nonselective MMP inhibitor) or SB‐3CT (MMP‐2 and −9 inhibitor) for 28 days in the first and second series, respectively. MMP‐9 knockout mice were used in the third series. The results showed that minocycline ameliorated portal hypertension, hemodynamic abnormalities, reduced collateral shunting, mesenteric vascular density, plasma VEGF level and alleviated liver fibrosis. SB‐3CT attenuated portal hypertension, hemodynamic derangements, reduced shunting, mesenteric vascular density, mesenteric VEGF protein expression, and liver fibrosis. Knockout BDL mice had significantly alleviated portal hypertension, liver fibrosis, liver α‐SMA and mesenteric eNOS protein expressions compared to wild‐type BDL mice. Liver SMAD2 phosphorylation was down‐regulated in all series with MMP inhibition or knock‐out. In conclusion, MMP‐9 inhibition or deletion ameliorated the severity of cirrhosis, portal hypertension, and associated derangements. MMP‐9 may be targeted in the treatment of liver cirrhosis.

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase‐2 (COX‐2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX‐2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX‐2 overexpression by COX‐2‐dependent PGE2‐EP2‐ERK1/2‐NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX‐2‐independent LKB1‐AMPK‐NRF2‐HO‐1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX‐2‐dependent and COX‐2‐independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1–75) kPa] and EOT [21.3(6.7–73.5) kPa; p < .0001] and EOT and FU144 [16(4.1–75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2–4.1) m/s] and FU144 [1.7(0.9–4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (

Background Endoscopic variceal ligation (EVL) is a widely accepted treatment for esophagogastric varices in patients with portal hypertension. It is used for urgent treatment and prophylactic treatment of esophagogastric varices not only in adults, but also in pediatric patients. However, major life-threatening adverse events such as early rebleeding can occur. Although early rebleeding after EVL among children and adolescents has been reported, the risk factors remain obscure. This study evaluated the risk factors for early rebleeding after EVL in children and adolescents. Methods Subjects were children and adolescents with portal hypertension aged less than 18 years who underwent EVL for esophagogastric varices. Early rebleeding was defined as hematemesis, active bleeding or blood retention in the stomach, confirmed by esophagogastroduodenoscopy from 2 hours to 5 days after EVL. Results A total of 50 EVL sessions on 22 patients were eligible for this study. There were 4 episodes of early rebleeding. No other major adverse events have occurred. Multivariate analysis showed that EVL implemented at cardiac varices just below the esophagogastric junction (EGJ); within 5mm from the EGJ, is the independent factor of higher risk of early rebleeding: odds ratio 18.2 (95% Confidence interval: 1.40-237.0), p=0.02. Conclusions Children and adolescents who undergo EVL for cardiac varices just below the EGJ have a higher risk of early rebleeding than those who do not.

BACKGROUND AND AIMS Porto-sinusoidal vascular disease (PSVD) is a rare disease that requires excluding cirrhosis and other causes of portal hypertension for its diagnosis because it lacks a specific diagnostical test. Although it has been occasionally associated with autoimmune diseases, the pathophysiology of PSVD remains unknown. The aim of this study was to evaluate the potential role of autoimmunity in the pathophysiology and diagnosis of PSVD. METHODS Thirty-seven consecutive patients with PSVD and 39 with cirrhosis matched by gender, signs of portal hypertension and liver function were included (training set). By using Indirect Immunofluorescence, ELISA and slot-blot methods data 22 autoantibodies were identified in patients with PSVD and cirrhosis. Presence of anti-endothelial cells antibodies (AECA) was assayed by a cell-based ELISA. Thirty-one PSVD, 40 cirrhosis patients, 15 patients with splenomegaly associated with haematological disease and 14 healthy donors were included in a validation set. FINDINGS The proportion of patients with at least one positive antibody was statistically significantly higher in patients with PSVD compared with cirrhosis (92% vs 56%; P

INTRODUCTION Transjugular intrahepatic portosystemic shunt (TIPSS) is an effective modality in reducing portal pressure, and its current main indications are for the management of recurrent ascites and variceal bleeding. The demand and indications for TIPSS are growing. However, it is a complicated and technically demanding procedure with poorer outcomes associated with low volume centres. The aim of this study was, therefore, to review the outcomes of TIPSS at a 'low volume' single centre. Outcomes assessed included indications, safety, efficacy and survival. METHODS A retrospective study was undertaken of all patients who underwent a TIPSS procedure over 10 years at tertiary referral centre for complex liver disease and transplantation. Kaplan-Meier method was used to calculate actuarial survival and log-rank analysis was used to determine significant differences in survival. RESULTS Thirty-eight patients underwent the TIPSS procedure between January 2008 and December 2018. Technical, haemodynamic and clinical success were 95%, 92% and 92% respectively. Cumulative survival at one month, one year and five years were 86.8%, 72% and 44.7% respectively. Results achieved standards published in practice parameters to evaluate TIPSS safety and efficacy. CONCLUSION At a low volume centre, TIPSS usage was associated with high rates of technical, haemodynamic (HPVG reduction) and clinical success. Low volume should not be a contraindication to providing a TIPSS service; however, auditing outcomes and understanding specific institutional factors that influence quality are important requirements for low volume centres.

Disturbed sleep is common among patients with cirrhosis. The extent to which this is associated with the different stages of compensated cirrhosis is unknown. This study examines whether the presence of portosystemic collaterals, an indicator of clinically significant portal hypertension, is associated with sleep disturbance in compensated cirrhosis. We conducted a cross-sectional study among patients with compensated cirrhosis, comparing sleep characteristics, sleep quality, and excessive daytime sleepiness between 21 patients without and 21 patients with portosystemic collaterals. Patients were assessed with wrist actigraphy, Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. Collateral presence was determined by imaging and esophagogastroduodenoscopy. Differences in sleep characteristics were analyzed using t tests and computed effect sizes. Multivariable linear regression analysis was used to evaluate the association between collaterals and sleep disturbance while controlling for possible confounders. The group of patients with collaterals had greater beta-blocker and tobacco use, lower albumin, and higher international normalized ratio compared to the group without collaterals. Patients with collaterals had more sleep fragmentation (Cohen's d = -0.86), lower sleep efficiency (Cohen's d = 0.59), and lower total sleep time (Cohen's d = 0.75) than patients without collaterals. The presence of collaterals was independently associated with greater sleep fragmentation (P = 0.046) and greater daytime sleepiness (P = 0.030). Conclusion: Patients with compensated cirrhosis complicated by portosystemic collaterals experienced more sleep disturbance than those without collaterals.

Refractory ascites is characterized by severe circulatory dysfunction and increased sensitivity to renal impairment by non‐selective beta‐blockers (NSBB). A novel serum microRNA signature, identified in the secretome of human cirrhotic hepatocytes, allows for the molecular characterization of patients with decompensated cirrhosis more prone to develop significant cardiac impairment after NSBB, as well as those more likely to respond to NSBB in terms of HVPG reduction., 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

A patient's hemoglobin is typically expected to rise by 1 g/dL/unit transfused PRBCs. However, it has been theorized that mechanisms such as hyperbilirubinemia and splenomegaly might lead to either a direct lysis or sequestration of red blood cells that could decrease this proportionate response.Patients with resolved GI bleeding but still requiring transfusion to correct anemia were compared in cirrhosis and control groups. A retrospective chart review between 2015 and 2020 was conducted at a single institution. Data collected included age, sex, BMI, GI bleed diagnosis, number of PRBCs transfused, presence of splenomegaly and spleen size, alcohol use history, type of cirrhosis, MELD-Na at admission, GFR, and pre-and post-transfusion labs: total bilirubin, ALT, hemoglobin, hematocrit. A logic regression was performed for each group looking at which factors were associated with a successful response (defined as0.9 g/dL hemoglobin per unit transfused).Mean change in hemoglobin was 0.77 g/dL in patients with cirrhosis compared to 1.46 g/dL in patients without (P .001, N = 103). Odds ratios for presence of splenomegaly (0.22, N = 78) and female sex (4.39, N = 102) in predicting adequate response (0.9 g/dL/unit) were both significant (P = .002) as well as portal hypertensive bleed diagnosis (0.28, N = 85, P = .0015). Factors that did not contribute included: age, race, BMI, alcohol use, GFR, change in ALT, and change in total bilirubin.Patients with cirrhosis have an approximately 50% decreased response to transfusion with PRBCs after resolution of a gastrointestinal bleed in comparison to patients without cirrhosis. Risk factors included splenomegaly, portal hypertension, and male sex.

To describe the technique, complications, and outcome of laparoscopic portosystemic shunt attenuation (LPSSA) in dogs.Retrospective study.Twenty client-owned dogs.Medical records were searched for dogs with a single congenital extrahepatic portosystemic shunt (CEPSS) that was treated with LPSSA. Signalment, clinical signs, CEPSS location, diagnostic imaging, laparoscopic approach, operative technique, complications, and clinical outcome were reviewed.Fourteen dogs with CEPSS located in the epiploic foramen had a right (13/14) or left (1/14) paramedian approach. In 6 dogs a CEPSS was not located in the epiploic foramen, and a left paramedian approach was used. A 3 or 4-port technique was used in 7 and 13 dogs, respectively. A thin film band was used for CEPSS attenuation in all dogs. The median operating time for LPSSA was 62 min (range 27-98 min). Intraoperative complications requiring conversion to an open technique occurred in 5 dogs. Mild perioperative self-limiting portal hypertension occurred in 3 dogs, while severe portal hypertension with surgical revision occurred in 1 case. The complications were resolved, and all dogs had a good outcome.Laparoscopic portosystemic shunt attenuation can be performed in dogs, in particular for a CEPSS located in the epiploic foramen using a right paramedian approach. For CEPSS not located in the epiploic foramen, a left paramedian approach is recommended. Conversion to open celiotomy was required in around a third of cases.Laparoscopic attenuation of CEPSSs can be performed in dogs and has a good clinical outcome, particularly for CEPSS located in the epiploic foramen.

Occlusion of the splenic vein, without occlusion of the portal vein, can lead to a localized, regional splenic hypertension, referred as sinistral or left-sided portal hypertension in the human radiology literature. In people, may cause gastrointestinal hemorrhages from the esophageal and gastric varices and the primary pathology usually includes pancreatitis and pancreatic neoplasms. The final diagnosis of localized splenic hypertension necessitates accompanying normal liver functions and a patent extrahepatic portal vein. Following obstruction, the resultant elevated splenic bed venous pressure causes formation of collateral routes, the extent of which depends upon the level and degree of obstruction. In this retrospective descriptive study, authors assessed the collateral pathways in dogs with isolated splenic vein occlusion and possible regional splenic vein hypertension. Out of the 46 patients initially recruited, 25 were excluded due to the presence of concomitant portal thrombosis and direct/indirect CT signs of portal hypertension. The remaining 21 dogs had clinicopathological tests suggesting normal liver function. The causes of obstruction identified included splenic pedicle torsion, tumoral splenic vein invasion, and splenic vein thrombosis. Four of 21 dogs with isolated splenic vein obstruction showed collateral pathways through the left gastroepiploic vein (4/4), left gastric vein (2/4), and splenogonadal vein (1/4). The diagnosis of isolated, regional splenic hypertension should be based on clinical, biochemical, and radiological evaluation. Computed tomography is an excellent tool to assess the collateral patterns and to determine the underlying cause.

Background and aim Portal hypertensive gastropathy (PHG) is characterized by noninflammatory edema and vasodilatation of the lamina propria of the mucosal epithelium. In addition, the alterations of intercellular junction proteins and dilatation of the endothelial gaps have been reported. In this study, we examined whether irsogladine maleate (IM), a gastric mucosal protective agent, has the potential to improve PHG by restoration of tight junctions (TJs). Methods Twenty-four patients with PHG were registered and randomly assigned into two groups: 12 patients in the IM-administration group and 12 patients in the non-administration group. In the administration group, IM (4 mg/day) was administered orally for 12 weeks. Gastric mucosa with a red color in patients with PHG were obtained endoscopically on the registration day and 12 weeks later. The endoscopic findings were evaluated, an immunohistochemical analysis of claudin-3 (a TJ protein) expression in gastric mucosal tissues by a laser microscope was performed, and claudin-3 expression was quantified by western blot analysis. Results Irsogladine maleate improved the degree of PHG in 2/12 patients endoscopically, in contrast to none of the 12 patients in the non-administration group. Immunohistochemical analysis showed that expression of claudin-3 increased in 8/12 patients in the IM-administration group and 2/12 patients in the non-administration group (P = 0.036). Western blot analysis revealed that the increase in claudin-3 after 12 weeks was significantly higher in the IM-administration group than in the non-administration group (P = 0.010). Conclusions The present pilot study suggested that IM might improve the gastric mucosa in PHG through restoration of TJ-protein claudin-3.

BACKGROUND AND AIMS Portal hypertension is the main consequence of cirrhosis, responsible for the complications defining clinical decompensation. The only cure for decompensated cirrhosis is liver transplantation, but it is a limited resource and opens the possibility of regenerative therapy. We investigated the potential of primary human amniotic membrane-derived mesenchymal stromal (hAMSCs) and epithelial (hAECs) stem cells for the treatment of portal hypertension and decompensated cirrhosis. METHODS In vitro: Primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) from cirrhotic rats (chronic CCl4 inhalation) were co-cultured with hAMSCs, hAECs or vehicle for 24 hours, and their RNA profile was analysed. In vivo: CCl4-cirrhotic rats received 4x106 hAMSCs, 4x106 hAECs, or vehicle (NaCl 0.9%) (intraperitoneal). At 2-weeks we analysed: a) portal pressure (PP) and hepatic microvascular function; b) LSECs and HSCs phenotype; c) hepatic fibrosis and inflammation. RESULTS In vitro experiments revealed sinusoidal cell phenotype amelioration when co-cultured with stem cells. Cirrhotic rats receiving stem cells, particularly hAMSCs, had significantly lower PP than vehicle-treated animals, together with improved liver microcirculatory function. This hemodynamic amelioration was associated with improvement in LSECs capillarization and HSCs de-activation, though hepatic collagen was not reduced. Rats that received amnion derived stem cells had markedly reduced hepatic inflammation and oxidative stress. Finally, liver function tests significantly improved in rats receiving hAMSCs. CONCLUSIONS This preclinical study shows that infusion of human amniotic stem cells effectively decreases PP by ameliorating liver microcirculation, suggesting that it may represent a new treatment option for advanced cirrhosis with portal hypertension.

Portal hypertension is one of the most important causes of morbidity and mortality in cirrhotic patients. A color Doppler evaluation of the left gastric vein (LGV) has proven utility in the prediction of esophageal varices and variceal bleeding in patients with portal hypertension. The purpose of this review is to discuss the ultrasound evaluation, imaging findings, and clinical application of Doppler ultrasound in the assessment of the LGV. Knowledge of the color Doppler technique and imaging findings of the LGV may help clinicians improve the monitoring of portal hypertension and predict patients with a high risk of esophageal varices.

Objectives Our goal was to discuss the role of Doppler ultrasound (US), combined with clinical features, in the diagnosis of transjugular intrahepatic portosystemic shunt (TIPS) dysfunction in the era of covered stents. In light of the lack of research regarding the accuracy of Doppler US in TIPS dysfunction evaluations when using covered stents and a recent major meta-analysis, which primarily reviewed studies with bare metal stents but few with covered stents, we aimed to provide our single-center case study for further investigation. Methods All patients from 2010 to 2019 who underwent angiography for a covered stent preceded by a Doppler US examination in our institution were retrospectively reviewed. Results All of the Doppler US and angiographic examination results showed complete agreement, and 11 of 12 were positive for TIPS dysfunction. Conclusions Combining the presence of positive clinical signs for TIPS dysfunction with Doppler US may increase its accuracy. Considering our results, there may be a need to reinvestigate Doppler US as a noninvasive, inexpensive, and available tool for the diagnosis of TIPS dysfunction in the era of covered stents, despite recent publications depicting Doppler US as inadequate for evaluating a TIPS.

Bleeding related to rectal varices associated with portal hypertension is rare but life-threatening, and requires prompt treatment. We reviewed the literature for patients with this complex presentation and current recommendations, and commented on a case at our institution of a 68-year-old man with Child-Pugh B alcoholic liver cirrhosis and hepatic encephalopathy who presented with profuse life-threatening rectal variceal bleeding. Treatment options for rectal varices in patients with hepatic encephalopathy were reviewed and a management algorithm was devised from current knowledge in the literature. We suggest endoscopic management, and if unsuccessful then to proceed to angioembolization and/or balloon-occluded retrograde transvenous obliteration, which may be used in conjunction with surgical management. The chosen therapeutic option may depend on the clinical condition of the patient, the cause of portal hypertension and clinical expertise or facilities available. Given that transjugular intra-hepatic portosystemic shunting is contraindicated in patients with hepatic encephalopathy, management of life-threatening rectal variceal bleeding should be multimodal.

A 40-year-old woman presented with abdominal pain and jaundice. Past medical history was significant only for splenectomy following a motor vehicle accident. Owing to presence of multiple peritoneal nodules on computerized tomography (CT) and elevated serum CA-125, ovarian peritoneal carcinomatosis was suspected. Ultrasound-guided fine-needle aspiration (FNA) revealed presence of abundant hemosiderin, leukocytes, endothelial cells, and fungal hypha-like structures. No evidence of neoplasia was found. Findings were consistent with Gamna-Gandy bodies (GGBS) within splenic tissue. Based on history of splenectomy and FNA findings, a diagnosis of abdominal splenosis with presence of GGBS was made. Workup for hepatic cirrhosis and portal hypertension was recommended. Liver biopsy confirmed presence of cirrhosis. To our knowledge, this is the first report of GGBS identified within abdominal splenosis. It is important for pathologists to be able to recognize GGBS and to be aware of their relationship to portal hypertension and other conditions associated with severe vascular congestion or hemorrhage. History and pathogenesis of GGBS, their diagnostic morphologic features and a review of cases of GGBS diagnosed via cytology are given.

Objective To explore the effectiveness of gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) in predicting portal hypertension and high-risk esophageal varices (EV) in patients with hepatitis B cirrhosis. Methods In total, 71 and 30 patients comprising the training and validation groups, respectively, were enrolled in the study. Univariate and multivariate analyses were performed to detect their risk of developing high-risk EV to generate a formula for scoring EV. The relationships between the relative enhancement ratio (RE) of Gd-BOPTA-enhanced MRI and portal vein pressure were explored. Results Platelet count, portal vein width and RE were identified as independent predictors of high-risk EV. Based on these parameters, the EV score model were calculated as: -6.483 + 15.612 × portal vein width + 2.251 × RE - 0.176 × platelet count. The area under the receiver operating characteristic curve was 0.903. At a cut-off value of ≤ -2.74, the negative predictive value was 94.00%, while the positive predictive value was as high as 93.80% when the cut-off was set at > 4.00. Gd-BOPTA-enhanced MRI was effective in predicting portal pressure. Its accuracy was confirmed with the validation set. Conclusions Gd-BOPTA-enhanced MRI was successfully applied to evaluate high-risk EV and portal hypertension. These results represent an accurate, non-invasive model for detecting high-risk EV, based on which we propose a cost-effective algorithm for EV management, eliminating the need to perform an endoscopy in all patients with cirrhosis.

Background and aims: To evaluate two-dimensional shear wave elastography (2DSWE) in parallel with transient elastography (TE) for diagnosing clinically significant portal hypertension (CSPH) and high-risk varices (HRV) in patients with chronic liver disease. Patients and methods: Consecutive patients with suspicion of compensated advanced chronic liver disease (cACLD) [liver stiffness measurement (LSM) ≥ 10 kPa by TE, or morphological signs suggestive of cACLD on imaging], with no history of liver decompensation, underwent hepatic venous pressure gradient (HVPG) measurement, transjugular liver biopsy and esophagogastroduodenoscopy, which served as the reference methods for diagnosing CSPH, cACLD and HRV. All patients underwent LSM and spleen stiffness measurements (SSM) by 2DSWE and TE. Results: Seventy-six (76) patients were included (78% men, mean age 62 years, body mass index 28.3 kg/m2 , 36.8% alcoholic, 30.3% non-alcoholic fatty liver disease, 14.5% viral hepatitis). Of them, 80.3%, 69.7%, 52.6% and 22.4% had cACLD, cirrhosis, CSPH and HRV respectively. LSM performed better than SSM in diagnosing CSPH and HRV. For CSPH, AUROCs (0.926 vs. 0.866), optimal cut-offs (20.1 vs. 20.2 kPa) and sensitivity/specificity (80.5%/94.3% vs. 77.5% /86.1%) were comparable for 2DSWE and TE. Ruling-out of CSPH by 2DSWE (LSM at cut-off with ≥90% sensitivity (13.5 kPa) and platelets ≥ 150 x 109 /L) performed comparably to TE, with 1/24 cases falsely classified as negative. For HRV, AUROCs were similar (0.875 2DSWE, 0.851 TE) with similar optimal LSM cut-offs enabling 100% sensitivity and ruling-out HRV. Conclusion: Liver stiffness measurement by 2DSWE appears to perform equally well as TE for diagnosing CSPH and ruling-out HRV in compensated chronic liver disease.

The value of noninvasive tools in the diagnosis of autoimmune hepatitis (AIH)-related cirrhosis and the prediction of clinical outcomes is largely unknown. We sought to evaluate (1) the utility of liver stiffness measurement (LSM) in the diagnosis of cirrhosis and (2) the performance of the Sixth Baveno Consensus on Portal Hypertension (Baveno VI), expanded Baveno VI, and the ANTICIPATE models in predicting the absence of varices needing treatment (VNT). A multicenter cohort of 132 patients with AIH-related cirrhosis was retrospectively analyzed. LSM and endoscopies performed at the time of cirrhosis diagnosis were recorded. Most of the patients were female (66%), with a median age of 54 years. Only 33%-49% of patients had a LSM above the cutoff points described for the diagnosis of AIH-related cirrhosis (12.5, 14, and 16 kPa). Patients with portal hypertension (PHT) had significantly higher LSM than those without PHT (15.7 vs. 11.7 kPa; P = 0.001), but 39%-52% of patients with PHT still had LSM below these limits. The time since AIH diagnosis negatively correlated with LSM, with longer time being significantly associated with a lower proportion of patients with LSM above these cutoffs. VNT was present in 12 endoscopies. The use of the Baveno VI, expanded Baveno VI criteria, and the ANTICIPATE model would have saved 46%-63% of endoscopies, but the latter underpredicted the risk of VNT. Conclusions: LSM cutoff points do not have a good discriminative capacity for the diagnosis of AIH-related cirrhosis, especially long-term after treatment initiation. Noninvasive tools are helpful to triage patients for endoscopy.

Background Congenital porto-systemic shunt (CPSS) is a rare disease and can cause fatal complications. Accurate angiographic assessment is mandatory for proper treatment. Although technically difficult, we developed assessment techniques and assessed their accuracy. One technique came from evaluating patients with extrahepatic portal vein obstruction (EHPVO). Methods We conducted a single center retrospective study to evaluate the efficacy of angiographic diagnostic procedure for the assessment of CPSS and EHPVO, and its impact on patients' subsequent interventions and clinical course. Eight patients with CPSS and two patients with EHPVO who underwent diagnostic angiography were included. Assessment of intrahepatic portal vein was performed in all patients. The route of the shunt, and portal vein pressure under shunt occlusion were also evaluated for patients with CPSS. Evaluation was first attempted with balloon angiographic catheter (standard method). Three additional techniques, 1) direct wedge-catheter injection without balloon inflation, 2) use of occlusion balloon in two patients, and 3) hybrid angiography with sheath placement directly into the superior mesenteric vein were performed as needed. Results The standard method was sufficient in four patients. Contrarily, all three techniques were required in two patients each. One lost contact during follow up, but all other patients underwent optimal intervention. There was no complication related to the angiographic procedure. Conclusions Use of direct wedge-catheter injection without balloon inflation, occlusion balloon, and hybrid catheterization improved the diagnostic yield in patients with CPSS or EHPVO.

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Background Anaemia is common in advanced chronic liver disease (ACLD) as a result of various risk factors. Aims & Methods We evaluated the prevalence and severity of anaemia as well as the impact of anaemia on clinical outcomes in consecutive patients with ACLD and portal hypertension. Results Among 494 patients, 324 (66%) patients had anaemia. Anaemic patients showed higher MELD (12 ± 4 vs 9 ± 3; P

Background and Aim This study aims to evaluate and compare the survival and other portal hypertension‐related complications of patients with portal pressure gradient (PPG) ≥ 25 mmHg using transjugular intrahepatic portosystemic shunt (TIPS) as the first‐line and second‐line therapies in secondary prophylaxis of variceal hemorrhage. Methods Fifty patients diagnosed with liver cirrhosis were enrolled in this retrospective study, with 35 of whom received TIPS as the first‐line therapy in secondary prophylaxis of variceal hemorrhage and 15 of whom as second‐line treatment. We observed and analyzed the survival, occurrence of variceal rebleeding and hepatic encephalopathy (HE) of patients in the two groups during the follow up. Results The technical success rate was 100%. In a median follow‐up time of 12 (1–37) and 15 (2–27) months, respectively, significant statistical difference was observed between the first‐line group and the second‐line group concerning cumulative survival rate (94.3% vs 66.7%, log–rank P = 0.01). But that was not the case when it comes to the cumulative rate of variceal rebleeding (8.6% vs 26.7%, log–rank P = 0.164) and HE (22.9% vs 20.0%, log–rank P = 0.793). And multivariate analysis indicated that group assignment (hazard ratio = 8.250, 95% confidence interval = 1.383–49.213, P = 0.021) was the only predictor of survival. Interestingly, we found that spleen diameter (hazard ratio = 0.578, 95% confidence interval = 0.393–0.849, P = 0.005) could be regarded as independent predictor of the occurrence of HE. Conclusions For patients with PPG ≥ 25 mmHg who have recovered from an episode of acute esophageal variceal hemorrhage, utilizing TIPS as the first‐line therapy to prevent rebleeding is demonstrated effective in improving the survival and therefore should be recommended to a wider range of clinical practice.

BACKGROUND & AIMS In cirrhosis, hepatic venous pressure gradient (HVPG) and imaging body composition assessment can influence prognosis. We assessed whether adipose and skeletal muscle tissues reflect the severity of portal hypertension (PH), and whether they improve non-invasive prediction of decompensation and death. METHODS We included 84 cirrhosis patients with HVPG and computed tomography (CT) within 12 weeks of HVPG at a single centre. L3 vertebra CT images were used for body composition indexes (cm2 /m2 ): total adipose tissue index (TATI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), intramuscular adipose tissue index (IMATI), skeletal muscle index (SMI) and psoas muscle index (PMI). Correlations were calculated between indexes, HVPG and standard non-invasive tests for PH. Twelve-month decompensation and death predictors were determined. RESULTS The following were the characteristics for the patients included in the study: male 61%; BMI 28 ± 5 kg/m2 ; alcoholic liver disease in 51%, non-alcoholic steatohepatitis in 24%; HVPG 14 ± 6 mm Hg; 45% compensated. The median follow-up was 11 (4-17) months. HVPG correlated with SATI (r = -0.282, P = 0.01), TATI (r = -0.220, P = 0.045) and SATI/VATI index (r = -0.240, P = 0.03). In compensated patients, lower VATI (HR 0.94 (0.90-0.99), P = 0.01) was associated with 12-month decompensation. Combining TATI and liver stiffness × spleen size over-platelet count risk score added discriminative capacity for 12-month decompensation (AUROC 0.91 vs 0.87). IMATI was independently associated with mortality in decompensated patients. MELD-Na combined with IMATI discriminated excellently for mortality (AUROC 0.94; P

Background & Aims Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. Methods Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. Results Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. Conclusion Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.

Background and aim Upper gastrointestinal bleeding (UGIB) is a serious complication of portal hypertension in cirrhotic patients. The objective of this study is to identify the risk factors for morbidity and mortality occurring after an UGIB attack. Methods A total of 1097 UGIB attacks in 690 patients with liver cirrhosis were studied. Their clinical, laboratory, and endoscopic data were reviewed. Results Mean age 53.2 ± 10.6 (20-90) years, 78% men and the main cause of liver disease was hepatitis C (94.9%). Complications occurred after 467 attacks (42.6%): hepatic encephalopathy 31.4%, spontaneous bacterial peritonitis 18%, renal impairment 13.2%, and re-bleeding in 7.8%, while 199 patients (18.1%) died. Complications followed 78.4% of bleeding from gastric varices, 75% of post-interventional ulcers, 10.8% of peptic ulcers, and 5.9% of telangiectasias. By univariate analysis: packed red blood cells units transfused, transaminases, Child-Pugh (CP), model of end-stage liver disease (MELD), and albumin-bilirubin (ALBI) scores, beside the presence of hepatocellular carcinoma (HCC), previous hemorrhage in the previous 6 months, and the source of bleeding, were associated with occurrence of complications. By multivariate analysis, independent predictors of complications were CP, MELD, and ALBI scores (odds ratio, 95% confidence interval: 5.63, 3.55-8.93; 1.15, 1.11-1.19; and 2.11, 1.4-3.19, respectively) beside the presence of HCC (4.89, 2.48-9.64). Mortality predictors were packed red blood cells units transfused (1.11, 1.01-1.24), CP (5.1, 1.42-18.25) MELD (1.27, 1.21-1.32) scores, and presence of HCC (6.62, 2.93-14.95). Conclusion High CP, MELD, and ALBI scores beside the presence of HCC could predict poor outcome of UGIB. In the absence of these risk factors, early discharge could be considered if the source of bleeding is peptic ulcer or telangiectasia.

BACKGROUND & AIMS: Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced cirrhosis and acute decompensation is unclear and investigated in this study.METHODS: Patients with decompensated cirrhosis from the prospective NEPTUN cohort (ClinicalTrials.gov Identifier: NCT03628807), who underwent transjugular intrahepatic portosystemic shunt procedure were included. Clinical and laboratory parameters, PRO-C4 and C4M levels were measured in blood samples from portal and hepatic veins just before transjugular intrahepatic portosystemic shunt placement.RESULTS: Levels of C4M and PRO-C4 are significantly lower in patients with massive ascites and impaired renal sodium excretion. C4M and PRO-C4 show gender-specific profiles with significantly lower levels in females compared to males. Females with higher C4M levels show higher mortality. By contrast, males with higher C4M levels show lower mortality. In multivariate Cox regression analysis, C4M is an independent predictor of survival in female patients.CONCLUSION: This study shows that markers of collagen type IV remodelling do not accumulate in severe renal dysfunction. Although collagen type IV degradation markers derive from the liver, portal venous C4M levels are relevant for survival. Moreover, it demonstrates that circulating C4M shows gender-specific profiles, which can independently predict survival in female patients with decompensated cirrhosis.

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.

Gut microbiota is the largest collection of commensal micro-organisms in the human body, engaged in reciprocal cellular and molecular interactions with the liver. This mutually beneficial relationship may break down and result in dysbiosis, associated with disease phenotypes. Altered composition and function of gut microbiota has been implicated in the pathobiology of nonalcoholic fatty liver disease (NAFLD), a prevalent condition linked to obesity, insulin resistance and endothelial dysfunction. NAFLD may progress to cirrhosis and portal hypertension, which is the result of increased intrahepatic vascular resistance and altered splanchnic circulation. Gut microbiota may contribute to rising portal pressure from the earliest stages of NAFLD, although the significance of these changes remains unclear. NAFLD has been linked to lower microbial diversity and weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defence and inflammation. Moreover, disrupted host-microbial metabolic interplay alters bile acid signalling and the release of vasoregulatory gasotransmitters. These perturbations become prominent in cirrhosis, increasing the risk of clinically significant portal hypertension and leading to bacterial translocation, sepsis and acute-on-chronic liver failure. Better understanding of the gut-liver axis and identification of novel microbial molecular targets may yield specific strategies in the prevention and management of portal hypertension.

Background Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein thrombosis. Therefore, prevention is important. Band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding in children. However, primary prophylaxis is not the current standard of care in paediatric patients because it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children and adolescents. Objectives To determine the benefits and harms of beta-blockers compared with placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Search methods We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 2020). We screened the reference lists of the retrieved publications and manually searched the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstract books from 2008 to December 2019. We searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search. Selection criteria We planned to include randomised clinical trials, irrespective of blinding, language, or publication status to assess benefits and harms. We included observational studies, retrieved with the searches for randomised clinical trials, for a narrative report of harm. Data collection and analysis We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to asses risk of bias and use GRADE to assess the certainty of evidence. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and health-related quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to use intention-to-treat principle. We planned to analyse data with RevMan Analysis. Main results We found no randomised clinical trials that assessed beta-blockers compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We found four observational studies that reported on harms. As a systematic search for observational studies was not planned, we only listed the reported harms in a table. Authors' conclusions Randomised clinical trials assessing the benefits or harms of beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of beta-blockers versus placebo on patient-relevant clinical outcomes, such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.

BACKGROUND Evaluation of pulmonary arterial pressure is crucial among cirrhotic patients, considering that moderate portopulmonary hypertension (POPH) is a contraindication for liver transplantation. Although right heart catheterization (RHC) is the most accurate method to diagnose POPH, it is invasive. OBJECTIVE The aim of the study is to evaluate the performance of echocardiography in detecting POPH in liver transplant candidates. METHODS A Literature search was performed, and pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and area under the summary receiver operating curve (AUC) were calculated. Subgroup analyses were performed based on different cutoff values for echocardiography and diagnostic criteria of RHC. RESULTS Sensitivity, specificity, positive LR, negative LR, and AUC of echocardiography for detection of POPH were 0.86 (0.74, 0.94), 0.87 (0.84, 0.90), 7.17 (3.59, 14.31), 0.22 (0.13, 0.38), and 0.807 while they were 0.82 (0.74, 0.89), 0.81 (0.78, 0.84), 117.75 (16.03, 865.08), 0.28 (0.16, 0.50), and 0.876for detection of moderate POPH, respectively. Performance of echocardiography was not significantly different in the subgroup analyses of stringency of POPH criteria and pulmonary arterial systolic pressure (ePASP) cutoffs. CONCLUSIONS Our meta-analysis supports utilization of echocardiography for screening of POPH. However, RHC remains essential in highly suspicious cases. Echocardiographic data other than ePASP should be evaluated in future studies.

14‐3‐3ζ, a phosphopeptide‐binding molecule, is reportedly overexpressed in the cancerous tissues of patients with hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) protein X (HBx) draws intensive attention in HBV‐related HCC because it not only regulates HBV replication, but also promotes carcinogenesis by interacting with various tumor or antitumor molecules. This study is performed to investigate whether and how 14‐3‐3ζ interacts with HBx. The coimmunoprecipitation (Co‐IP) results showed that 14‐3‐3ζ bond to HBx in HBV‐infected Hep3B HCC cells and CSQT‐2 portal vein tumor thrombosis (PVTT) cells. By performing Co‐IP assay in HBV‐free Huh7 cells expressing wild‐type HBx, mutant HBx‐S31A, or HBx‐S31D (serine31 was mutated into alanine31 or aspartic acid31), we found that the phosphorylated serine31 with its near amino acid residues constituted a RPLphosphoS31 GP (R, arginine; P, proline; L, leucine; S, serine; G, glycine) motif in HBx for 14‐3‐3ζ docking. This 14‐3‐3ζ‐HBx interaction was partly impaired when Akt signaling transduction was blocked by LY294002. Furthermore, 14‐3‐3ζ silencing augmented HBx ubiquitination and decreased its expression in cancer cells and xenograft tumor. The migratory and invasive abilities of CSQT‐2 cells were inhibited upon 14‐3‐3ζ silencing, whereas partly restored by HBx overexpression. Additionally, 14‐3‐3ζ positively correlated with HBx to be overexpressed in the primary HCC tissues (r = 0.344) and metastatic PVTT (r = 0.348). In summary, findings of this study reveal a novel 14‐3‐3ζ‐HBx interaction in HCC cells and suggest 14‐3‐3ζ as a candidate target for treating HBV‐related HCC.

BACKGROUND The test-retest/interobserver repeatability and diagnostic value of 4D flow MRI in liver disease is underreported. PURPOSE To determine the reproducibility/repeatability of flow quantification in abdominal vessels using a spiral 4D flow MRI sequence; to assess the value of 4D flow parameters in diagnosing cirrhosis and degree of portal hypertension. STUDY TYPE Prospective. SUBJECTS Fifty-two patients with chronic liver disease. FIELD STRENGTH/SEQUENCE 1.5T/spiral 4D flow acquired in one breath-hold. ASSESSMENT Thirteen abdominal vessels were identified and segmented by two independent observers to measure maximum and time-averaged through-plane velocity, net flow, and vessel cross-section area. Interobserver agreement and test-retest repeatability were evaluated in 15 and 4 cases, respectively. Prediction of the presence and severity of cirrhosis and portal hypertension was assessed using 4D flow parameters. STATISTICAL TESTS Cohen's kappa coefficient, coefficient of variation (CV), Bland-Altman, Mann-Whitney tests, logistic regression. RESULTS For all vessels combined, measurements showed acceptable agreement between observers, with Cohen's kappa = 0.70 (P

BACKGROUND & AIMS Pulmonary transit time (PTT) is the transit time of blood from the right side of the heart to the left side of the heart. The aim of the present study was to evaluate the role of the PTT derived from pulmonary angiography in the diagnosis of hepatopulmonary syndrome (HPS). METHODS From December 2014 to September 2015, all patients with chronic liver disease and/or portal hypertension undergoing a venous interventional radiologic procedure at our institution were eligible for inclusion in this prospective study. Pulmonary angiography was performed in all patients, and the PTT, which was defined as the time between opacification of the pulmonary trunk and the right border of the left atrium, was determined. RESULTS A total of 53 patients were included, 20 of whom had a positive contrast-enhanced echocardiography result and an elevated alveolar-arterial oxygen gradient were considered to have HPS. PTT was significantly shorter in patients with HPS than in those without [median, 3.34 (interquartile range, 3.01-3.67) seconds vs 4.0 (interquartile range, 3.67-4.17) seconds; P