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The prevention and management of bleeding and thrombosis in patients with cirrhosis poses several difficult clinical questions. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics, including current views on haemostasis in liver disease, controversy regarding the need to correct thrombocytopenia and abnormalities in the coagulation system in patients undergoing invasive procedures, and the need for thromboprophylaxis in hospitalised patients with haemostatic abnormalities. Multiple recommendations in this document are based on interventions that the panel feels are not useful, even though widely applied in clinical practice.

Background & Aims Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. Methods We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. Results Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. Conclusions These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. Lay summary Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.

It is well established that portal hypertension can occur in the absence of cirrhosis, as reported in patients with immune disorders, infections and thrombophilia. However, similar histological abnormalities primarily affecting the hepatic sinusoidal and (peri)portal vasculature have also been observed in patients without portal hypertension. Thus, the term porto-sinusoidal vascular disorder (PSVD) has recently been introduced to describe a group of vascular diseases of the liver featuring lesions encompassing the portal venules and sinusoids, irrespective of the presence/absence of portal hypertension. Liver biopsy is fundamental for PSVD diagnosis. Specific histology findings include nodular regenerative hyperplasia, obliterative portal venopathy/portal vein stenosis and incomplete septal fibrosis/cirrhosis. Since other conditions including alcohol-related and non-alcoholic fatty liver disease, or viral hepatitis, or the presence of portal vein thrombosis may occur in patients with PSVD, their relative contribution to liver damage should be carefully assessed. In addition to histology and clinical diagnostic criteria, imaging and non-invasive tests such as liver and spleen stiffness measurements could aid in the diagnostic workup. The introduction of PSVD as a novel clinical entity will facilitate collaborative studies and investigations into the underlying molecular pathomechanisms encompassed by this term.

Budd-Chiari Syndrome (BCS) and non-cirrhotic non-tumoral portal vein thrombosis (NCPVT) are two rare disorders, with several similarities that are categorized under the term splanchnic vein thrombosis. Both disorders are frequently associated with an underlying pro-thrombotic disorder. They can cause severe portal hypertension and usually affect oung patients, negatively influencing life expectancy when the diagnosis and treatment is not done at an early stage. Yet, they have specific features that require individual considerations. The current review will focus on the available knowledge on pathophysiology, diagnosis and management of both entities. BCS is defined as the obstruction of hepatic venous outflow regardless of its causative mechanism or level of obstruction. This obstruction can be traced to the small hepatic venules up to the entrance of the inferior vein cava (IVC) into the right atrium. Hepatic outflow obstruction related to cardiac disease, pericardial disease or sinusoidal obstruction syndrome have different pathophysiological and clinical implications and are excluded from this definition. BCS is classified as primary when the obstruction originates in the vein and thrombosis is the main cause, or secondary when the vein is externally compressed (abscess, tumor). The focus of this review is on primary BCS. NCPVT refers to the presence of a thrombus in the main portal vein trunk and/or the left or right intrahepatic portal vein branches that may extend to the splenic vein and/or the superior or inferior mesenteric veins. Isolated splenic or mesenteric vein thrombosis are out of the scope of this review.Copyright © 2019. Published by Elsevier B.V.

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published

Background & Aims Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria. Materials Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine. Results Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the inner mucus layer and pathological translocation of GFP-E. coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran, but only slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli. Conclusions Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. Lay summary For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis.

Background/Aims Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension. Methods Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed. Results Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels. Conclusions This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.

Gastroenterology, Department of Clinical Research, University of Berne, SwitzerlandSee Article, pages 1391–1399Body epithelial surfaces, such as the airways, the skin, the mouth,and the lower gastrointestinal tract provide residence to a num-ber of microbes that by far exceeds the number of cells of humanbeings. These microbial populations not only contribute to theprocess of development of their host and maintain tissue homeo-stasis, but also play a critical role in governing important physi-ological processes like for instance the absorption of vitaminsand nutrients from the intestinal lumen [1]. Under normal condi-tions, the barrier function of the intestinal mucosa prevents bac-teria from translocating through the gut epithelium into theportal and systemic circulation. The permeability of the intestinalwall is maintained thanks to three main mechanisms. First, intra-luminal bacteria are prevented from growing excessively by theperistaltic activity of the muscular layers and by the action ofantimicrobial peptides and defensins. Second, tight junctions,an intact epithelial layer, and mucus represent the main physicalbarriers to the passage of bacteria. Finally, cellular components ofthe gut-associated lymphoid tissue (dendritic cells, macrophages,lymphocytes) provide the third line of defence by eliminating anybacteria that is able to penetrate through the epithelial barrier[2–4].The impact of the intestinal bacterial flora on host physiologyis not limited to the digestive tube. For example, interactionsbetween the immune system and gut bacteria can significantlyaffect the energetic balance of the host by altering the absorptionof sugars, by modifying the degree of insulin resistance or bymodulating inflammatory signalling [5,6]. Emerging evidenceshows that systemic pathological conditions, such as obesity,may be influenced by the microbiota in the gut [7]. Lifestylechanges characterized by an increased caloric intake, high fatdiets, and sedentary habits may result in an altered compositionof the intestinal flora called dysbiosis that ends in an imbalancebetween tolerogenic and inflammatory members of the microbi-ota. In addition, recent data demonstrate that gut-flora-formedtrimethylamine (TMA) from dietary choline acts as a proathero-genic compound after its conversion into TMA N-oxide in theliver, suggesting a direct link between intestinal microflora andrisk of cardiovascular disease [8].The current increasing incidence of non-alcoholic fatty liverdisease (NAFLD) in the general population is a consequence ofthe growing burden of the metabolic syndrome [9]. Importantly,while simple steatosis seems to be very well tolerated and tohave only mild consequences, a significant proportion of patientswith NAFLD develop non-alcoholic steatohepatitis, a conditionthat may result in hepatic fibrosis [10], cirrhosis, and hepatocel-lular carcinoma [11]. Although the circumstances that may leadto liver fibrosis have been broadly related to insulin resistanceand pro-inflammatory conditions, the precise mechanisms andthe cofactors that aggravate fibrogenesis remain largelyunknown. The hypothesis that components from the intestinalmicroflora may contribute to the regulation of pro-fibrogenicand inflammatory processes in the liver has been investigatedin recent years [12] and it has become clear that this area willneed extensive investigation in the near future. In both animalmodels [13] and humans [14], an increased systemic concentra-tion of bacterial lipopolysaccharide (LPS), a component of the cellwall from Gram negative bacteria, has been demonstrated inobese subjects compared to lean controls as well as in patientswith NAFLD (for a comprehensive review see reference [6]).These data suggest that intestinal bacteria may play a role inthe development of obesity and metabolic syndrome.Commensal and pathogenic microbes share similar molecularstructures, such as lipopolysaccharide, lipoproteins, flagellins,and peptidoglycans. The recognition of specific signature mole-cules termed pathogen-associated molecular patterns (PAMPs)by toll-like receptors (TLRs) is the basis of the innate immunesystem, which represents the first line defense against invadingpathogens [15]. TLR4 is the main receptor for LPS while otherTLRs recognize microorganism-derived ligands like flagellins ornucleic acids. Metabolic systems are closely integrated withdownstream signals of TLR. When pathogens are sensed by theinnate immune system, insulin signalling, and inflammatorypathways are modulated as a consequence of the interactionbetween signals that control immunologic and metabolic pro-cesses [16,17]. Obesity and insulin resistance are associated withan increased expression of pro-inflammatory and profibrogeniccytokines [10]: this observation opens the question on whetherJournal of Hepatology 2011 vol. 55

Background/Aims : Hepatic stellate cells (HSC) are involved in the pathogenesis of liver fibrosis; although ET-1 is increased in cirrhosis, its pathophysiological role in fibrogenesis and portal hypertension remains controversial. The aim of this study was to investigate splanchnic hemodynamics and to correlate them with changes in ET-1 expression and HSC activation in bile duct ligated (BDL) rats. Methods/Results : Expression of the ET-1 gene was increased early as measured by quantitative reverse transcriptase-polymerase chain reaction (6-fold 3 days after BDL) whereas ET-1 peptide measured by RIA increased significantly only in the late phase (30-fold at 28 days). There was a linear correlation between portal pressure and the amount of ET-1 in the portal vein ( r =0.66; P =0.003), as well as between ET-1 and the volume fraction of myofibroblasts ( r =0.80, P −7 ) as assessed by morphometry and immunohistochemical staining using α-smooth muscle actin. Conclusions : During chronic liver injury activation of HSCs and of preproET-1 mRNA is accentuated in the early phase after BDL. The late increase in ET-1 peptide may indicate that this peptide is only secondarily involved in HSC activation. The correlation between ET-1 in portal vein and portal pressure suggests that ET-1 may play an important role in the development of portal hypertension.

Background/Aims: In vivo studies have shown that arterial vasodilation induced by synthetic openers of ATP-sensitive K + (K ATP ) channels is decreased in rats with cirrhosis. Since vasodilation induced by these substances is mediated by membrane potential hyperpolarization in arterial smooth muscle cells, membrane potential hyperpolarization in response to K ATP channel openers may be altered in cirrhotic smooth muscle cells. The aim of the present study was to investigate the effects of K ATP channel modulators (i.e. openers and blockers of these channels) on the membrane potential in smooth muscle cells in isolated aortae from cirrhotic and normal rats. The influence of endothelin-1 production by endothelial cells on smooth muscle cells membrane potential responses to K ATP channel modulators was also studied. Methods: Cells were impaled in situ (in intact and endothelium-denuded aortae) with a microelectrode that was used to measure membrane potentials. K ATP channel openers were diazoxide or cromakalim; blockers were glibenclamide or tolbutamide. Bosentan (a mixed endothelin receptor antagonist) and exogenous endothelin-1 were also used. Preproendothelin-1 mRNA was assayed in aortae by RNase protection assay. Aortic wall endothelin-1 concentration was measured by double antibody radioimmunoassay technique. Results: As expected, in smooth muscle cells in intact normal aortae, K ATP channel openers induced membrane potential hyperpolarization and K ATP channel blockers membrane potential depolarization. In smooth muscle cells in intact cirrhotic aortae, K ATP channel openers and blockers did not significantly change the membrane potential. Endothelium removal or exposure of intact aortae to bosentan restored normal membrane potential responses to K ATP channel modulators in cirrhotic smooth muscle cells and did not alter the effects of these substances in normal smooth muscle cells. In endothelium-denuded aortae, exposure to exogenous endothelin-1 suppressed membrane potential responses to K ATP channel modulators. In intact aortae, the abundance of preproendothelin-1 mRNA and endothelin-1 did not significantly differ between normal and cirrhotic rats. Conclusions: K ATP channel opener-induced membrane hyperpolarization and K ATP channel blocker-elicited membrane depolarization are blunted in smooth muscle cells in intact cirrhotic aortae. This blunting is due to the activation of the endothelin-1 pathway in the aortic wall, downstream to the endothelial production of endothelin-1.

Endothelin-1 plays an important role in the regulation of portal hypertension; endothelin antagonists have been extensively studied in portal hypertensive animals. We aimed to evaluate the efficacy of highly selective endothelin antagonists in partial portal vein ligated (PPVL) rats.Four groups of 7 male Sprague-Dawley rats were administered orally ABT-627 (ET(A)-selective), A-192621 (ET(B)-selective), or A-182086 (non-selective), with the fourth group serving as control. On the 3rd day after beginning treatment animals underwent PPVL. On the 11th day hemodynamics were studied and portal vein ET-1 was measured.In the control group portal pressure was 13.4+/-SD 0.2 mmHg; this increased to 14.9+/-1.8 (p0.05) in the ET(B) blocked group. In contrast, ET(A) blockade improved portal hypertension (11.7+/-1.1, p0.05), while the treatment with the non-selective antagonist had no effect (12.3+/-0.7 n.s.). Mean arterial pressure was not significantly affected by any treatment. Portal vein ET-1 was increased in all groups compared to controls; this increase was limited to the pre-stenotic area (79+/-43 vs 194+/-76 in the pre- and post-stenotic portal vein; p0.0025).Oral administration of an ET(A) antagonist ameliorated portal hypertension; we suggest that long-term therapy of portal hypertension with selective ET(A) antagonists may be more beneficial than mixed antagonists.

The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.