Pregnancy in Patients with Non-cirrhotic Portal Hypertension: A Literature Review / Gravidez em pacientes com hipertensão portal não cirrótica: Uma revisão da literatura

Abstract Pregnancy in non-cirrhotic portal hypertension (NCPH) is an uncommon condition. Its management is challenging both to the obstetricians as well as to the gastroenterologists due to the lack of more extensive studies and standard clinical practice guidelines. These patients are at increased risk of portal hypertension (PTH) complications, especially variceal bleeding, and with an increased incidence of adverse maternal and fetal outcomes. Hence, a multidisciplinary approach is required for management of pregnancy in NCPH. This short review describes the different aspects of pregnancy with NCPH, emphasizing specific strategies for preventing and managing PTH from the preconceptional period to postpartum.

Resumo A gravidez na hipertensão portal não cirrótica (HPNC) é uma condição incomum. Seu manejo é desafiador tanto para os obstetras quanto para os gastroenterologistas devido à falta de estudos mais extensos e diretrizes de prática clínica padrão. Esses pacientes apresentam risco aumentado de complicações da hipertensão portal (PTH) especialmente sangramento por varizes e têm maior incidência de desfechos maternos e fetais adversos. Portanto uma abordagem multidisciplinar é necessária para o manejo da gravidez na NCPH. Esta breve revisão descreve os diferentes aspectos da gravidez com HPNC enfatizando estratégias específicas para prevenção e manejo do PTH desde o período pré-concepcional até o pós-parto.

Protective Effects of Statin Therapy in Cirrhosis Are Limited by a Common SLCO1B1 Transporter Variant.

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

Enzymatic liver function measured by LiMAx is superior to current standard methods in predicting transplant-free survival after TIPS implantation.

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

Reconstructing spleno-mesenterico-portal cofluence by bifurcated allogeneic vein in local advanced pancreatic cancer-a feasible method to avoid left-sided portal hypertension.

BACKGROUND: Left-sided portal hypertension is usually found in patients undergoing pancreaticoduodenectomy (PD) with spleno-mesenterico-portal (S-M-P) confluence resection. This study is to explore the outcomes of S-M-P confluence reconstruction after resection by using bifurcated allogeneic vein. METHODS: Clinicopathologic data of patients who underwent extensive PD with S-M-P confluence resection for carcinoma of pancreatic head/uncinate process in our hospital between December 2011 and August 2018 were retrospectively reviewed and clinical outcomes of vein reconstruction after resection were analyzed. RESULTS: Of the 37 patients enrolled, S-M-P reconstruction by bifurcated allogeneic vein was performed in 24 cases (group 1) and simply splenic vein ligation in 13 cases (group 2). Items including pathological results, blood loss, and complications were comparable between the two groups, operation time was longer in group 1 (573.8 vs. 479.2 min, p = 0.018). Significantly decreased platelet count (205.9 vs. 133.1 × 109 /L, p = 0.001) and increased splenic volume (270.9 vs. 452.2 ml, p < 0.001) were observed in group 2 at 6 months after operation. The mean splenic hypertrophy ratio was 1.06 in group 1 and 1.63 in group 2, respectively (p < 0.001). There were four patients with varices were found in group 2, none in group 1. CONCLUSIONS: Without increased complications, reconstructing S-M-P confluence by bifurcated allogeneic vein after resection may help to avoid left-sided portal hypertension.

Pathophysiology and Management of Variceal Bleeding.

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

Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature.

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

Early, late, or no shunt embolization in patients with cirrhosis- and portosystemic shunt-related hepatic encephalopathy.

BACKGROUND: Portosystemic shunts (PSS) are associated with recurrent or persistent hepatic encephalopathy (HE), severe portal hypertensive (PHT) complications, and poor survival in cirrhosis patients. Shunt embolization improves HE in patients with recurrent or persistent HE. The role of early shunt embolization (ESE) in comparison with no and late SE (LSE) in cirrhosis patients with PSS and associated clinical outcomes are not studied. METHODS: ESE was defined as occlusion of PSS in patients with the first episode of spontaneous HE, while LSE was that when performed in patients with recurrent/persistent PSS-related HE. We retrospectively analyzed (November 2016 to March 2019) clinical outcomes, liver disease severity, and survival between patients undergoing ESE (n = 22) vs. LSE (n = 23) and compared ESE with matched historical controls (n = 22) not undergoing shunt embolization, followed-up for 18 months. RESULTS: Males predominated, and the lienorenal type of shunt was the most frequent. Significantly larger and multiple shunts were noted in the LSE group. Arterial ammonia, total bilirubin, and Child-Pugh scores were significantly higher at baseline in the LSE group. Post-procedure length of stay in the intensive unit (mean 0.6 vs. 2.1 days; p = 0.04), infections (31.8% vs. 66.7% beyond 100 days; p = 0.02), recurrence of HE in first 9 months (4.5% vs. 28.6%; p = 0.03), and liver- and PHT-related clinical events beyond 10 months were significantly higher in LSE compared with those in the ESE group respectively. HE beyond 10 months was comparable between both the groups. 18.2% died in ESE while 60.87% died in the LSE group (p = 0.002). Compared with patients on only standard medical care, the occurrence of ascites, variceal bleeding, recurrence of HE, and portal vein thrombosis were significantly lower in those undergoing ESE, even though differences in survival were not significant. CONCLUSIONS: Our study demonstrates the benefits of ESE of large PSS in patients with cirrhosis, probably by improving survival through a reduction in liver and PHT events that warrant validation through prospective randomized controlled multicenter trials.

Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites.

BACKGROUND & AIMS: The safety of non-selective ß-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. ß-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, ß-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

Interventions for preventing and managing advanced liver disease in cystic fibrosis.

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

A prospective study of the effect of terlipressin on portal vein pressure and clinical outcomes after hepatectomy: A pilot study.

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

Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial.

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

Use of fenestration to revise shunt dysfunction after transjugular intrahepatic portosystemic shunt.

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

Current and future pharmacological therapies for managing cirrhosis and its complications.

Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis, and may impede hepatic fibrogenesis and decompensation. Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management, nutritional optimisation and patient education.

Vascular Remodeling of Visceral Arteries Following Interruption of the Splenic Artery During Liver Transplantation.

Splenic artery (SA) ligation can be performed during liver transplantation (LT) to avoid portal hyperperfusion, which is involved in the pathogenesis of both small-for-size and SA syndrome. The SA can also be used as an inflow for arterial reconstruction. Exceptionally, SA interruption or agenesis has been associated with positive remodeling of collateral arteries supplying the spleen via the left gastric artery (LGA), short gastric vessels, and the gastroepiploic arcade (GEA), with subsequent severe upper gastrointestinal (GI) bleeding. To determine incidence, magnitude, predictors, and clinical implications of vascular remodeling after SA interruption during LT, we identified 465 patients transplanted in the period 2007-2017 who had the SA ligated or interrupted at LT. Among them, 88 had a computed tomography angiography suitable for evaluation of vascular remodeling after LT. The presence of prominent gastric arterial collaterals and the increase in LGA and GEA diameter were evaluated on 2-dimensional axial images and multiplanar reconstructions. Of the 88 patients, 28 (31.8%), 32 (36.4%), and 22 (25.0%) developed gastric collateralization graded as mild, moderate, or severe. Of the patients for whom comparison with pre-LT imaging was possible (n = 54), 51 (94.4%) presented a median 37% and 55% increase in LGA and GEA diameter, respectively. Severe gastric collateralization was associated with lower body mass index (odds ratio, 0.84; 95% confidence interval [CI], 0.71-0.98; P = 0.03), whereas a GEA caliper measurement increase was positively correlated with Model for End-Stage Liver Disease score (r2 = 0.12; 95% CI, 0.65-4.15; P = 0.008). Out of 465 patients, 2 (0.43%) had severe episodes of arterial upper GI bleeding, possibly exacerbated by vascular remodeling. In conclusion, vascular remodeling after SA interruption during LT is frequent and can aggravate GI bleeding during follow-up.

Original Study: Transjugular Intrahepatic Portosystemic Shunt as a Bridge to Abdominal Surgery in Cirrhotic Patients.

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

Performance of ultrasound for detection of transjugular intrahepatic portosystemic shunt dysfunction: a meta-analysis.

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

Clinical Efficacy of Transjugular Intrahepatic Portosystemic Shunt Created with Expanded Polytetrafluoroethylene-Covered Stent-Grafts: 8-mm Versus 10-mm.

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

Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats.

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

Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.

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

Is Portal Venous Pressure Modulation Still Indicated for All Recipients in Living Donor Liver Transplantation?

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