Decrease In Portal Pressure Research Articles

Development of a new Cox model for predicting long-term survival in hepatitis cirrhosis patients underwent transjugular intrahepatic portosystemic shunts.

Transjugular intrahepatic portosystemic shunt (TIPS) placement is a procedure that can effectively treat complications of portal hypertension, such as variceal bleeding and refractory ascites. However, there have been no specific studies on predicting long-term survival after TIPS placement. To establish a model to predict long-term survival in patients with hepatitis cirrhosis after TIPS. A retrospective analysis was conducted on a cohort of 224 patients who underwent TIPS implantation. Through univariate and multivariate Cox regression analyses, various factors were examined for their ability to predict survival at 6 years after TIPS. Consequently, a composite score was formulated, encompassing the indication, shunt reasonability, portal venous pressure gradient (PPG) after TIPS, percentage decrease in portal venous pressure (PVP), indocyanine green retention rate at 15 min (ICGR15) and total bilirubin (Tbil) level. Furthermore, the performance of the newly developed Cox (NDC) model was evaluated in an internal validation cohort and compared with that of a series of existing models. The indication (variceal bleeding or ascites), shunt reasonability (reasonable or unreasonable), ICGR15, postoperative PPG, percentage of PVP decrease and Tbil were found to be independent factors affecting long-term survival after TIPS placement. The NDC model incorporated these parameters and successfully identified patients at high risk, exhibiting a notably elevated mortality rate following the TIPS procedure, as observed in both the training and validation cohorts. Additionally, in terms of predicting the long-term survival rate, the performance of the NDC model was significantly better than that of the other four models [Child-Pugh, model for end-stage liver disease (MELD), MELD-sodium and the Freiburg index of post-TIPS survival]. The NDC model can accurately predict long-term survival after the TIPS procedure in patients with hepatitis cirrhosis, help identify high-risk patients and guide follow-up management after TIPS implantation.

Portosystemic shunting prevents hepatocellular carcinoma in non-alcoholic fatty liver disease mouse models.

Non-alcoholic fatty liver disease (NAFLD) is one of the leading cause of hepatocellular carcinoma (HCC). This association is supported by the translocation of bacteria products into the portal system, which acts on the liver through the gut-liver axis. We hypothesize that portosystemic shunting can disrupt this relationship, and prevent NAFLD-associated HCC. HCC carcinogenesis was tested in C57BL/6 mice fed a high-fat high-sucrose diet (HFD) and injected with diethylnitrosamine (DEN) at two weeks of age, and in double transgenic LAP-tTA and TRE-MYC (LAP-Myc) mice fed a methionine-choline-deficient diet. Portosystemic shunts were established by transposing the spleen to the sub-cutaneous tissue at eight weeks of age. Spleen transposition led to a consistent deviation of part of the portal flow and a significant decrease in portal pressure. It was associated with a decrease in the number of HCC in both models. This effect was supported by the presence of less severe liver steatosis after 40 weeks, and lower expression levels of liver fatty acid synthase. Also, shunted mice exhibited lower liver oxygen levels, a key factor in preventing HCC as confirmed by the development of less HCCs in mice with hepatic artery ligation. The present data show that portosystemic shunting prevents NAFLD-associated HCC, utilizing two independent mouse models. This effect is supported by the development of less steatosis, and a restored liver oxygen level. Portal pressure modulation and shunting deserve further exploration as potential prevention/treatment options for NAFLD and HCC.

Historical aspects of portal hypertension surgery: evolution of thinking

The paper presents the evolution of views on the surgery of portal hypertension, as well as some historical aspects of its development. The authors considered the main types of surgical interventions to be performed in this pathology. It is noted that in the middle of the 20th century, the direct portacaval anastomosis gained the widest acceptance of all the proposed types of vascular anastomoses. A number of surgeons considered it a classical method of treatment in portal hypertension. Thereafter, the indirect portacaval anastomosis proved to have the best outcomes. The advantage of portacaval anastomoses in comparison with other modifications of surgeries was substantiated by a significant decrease in portal pressure and disappearance of oesophageal varices after developing the anastomosis. Surgical treatment of patients with liver cirrhosis and portal system thrombosis reasonably requires closer attention of doctors in various fields. Such patients should be managed in specialized clinics and well-equipped medical centers.

Dual angiotensin receptor and neprilysin inhibitor reduced portal pressure through peripheral vasodilatation and decreasing systemic arterial pressure in cirrhotic rats.

Portal hypertension develops along with the progression of liver cirrhosis. Natriuretic peptides have been shown to reduce portal pressure but concomitantly activate the renin-angiotensin-aldosterone system (RAAS). Angiotensin receptor-neprilysin inhibitors (ARNIs) upregulate natriuretic peptides and avoid the adverse effects of RAAS activation. ARNIs have been shown to reduce portal pressure in rats with pre-hepatic portal hypertension, which involves relatively little liver injury. This study aimed to evaluate the relevant effects of an ARNI in rats with both liver cirrhosis and portal hypertension. Male Sprague-Dawley rats received common bile duct ligation to induce liver cirrhosis and portal hypertension. Sham-operated rats served as surgical controls. All rats were randomly allocated into three groups to receive distilled water (vehicle), LCZ696 (an ARNI), or valsartan for 4 weeks. Portal hypertension and relevant derangements were assessed after treatment. Portal hypertension and hyperdynamic circulation developed in the cirrhotic rats. In the rats with cirrhosis and portal hypertension, both LCZ696 and valsartan reduced portal hypertension, mean arterial pressure, and systemic vascular resistance. The decrease in portal pressure was highly associated with the reduction in arterial pressure and systemic vascular resistance. Blood flow in hepatic, splanchnic, and portosystemic collateral systems was not altered. LCZ696 did not significantly influence liver injury or plasma cytokine levels. Liver fibrosis and splanchnic angiogenesis were not affected. ARNI treatment exerted portal pressure lowering effects via peripheral vasodilatation and decreasing systemic arterial pressure in the rats with liver cirrhosis and portal hypertension. Caution should be taken when using ARNIs in liver cirrhosis.

To TIPS or Not to TIPS in High Risk of Variceal Rebleeding and Acute-on-Chronic Liver Failure.

Variceal bleeding is a consequence of severe portal hypertension in patients with liver cirrhosis. Although the rate of bleeding has decreased over time, variceal bleeding in the presence of acute-on-chronic liver failure (ACLF) carries a high risk of treatment failure and short-term mortality. Treatment and/or removal of precipitating events (mainly bacterial infection and alcoholic hepatitis) and decrease of portal pressure may improve outcome of patients with acute decompensation or ACLF. Transjugular intrahepatic portosystemic shunts (TIPSs), especially in the preemptive situation, have been found to efficiently control bleeding, prevent rebleeding, and reduce short-term mortality. Therefore, TIPS placement should be considered as an option in the management of ACLF patients with variceal bleeding.

The Portosystemic Shunt for the Control of Variceal Bleeding in Cirrhotic Patients: Past and Present.

Based on an experience of more than 50 years in the treatment of portal hypertension (PHT), the authors review and analyze the evolution of the surgical portocaval shunt (PCS). We would like to provide an insight into the past of PCS, in order to compare it with the current state of the treatment of PHT complications. As a landmark of the past, we shall present statistics of more than 500 cases of PHT operated between 1968 and 1983. From this group, 238 patients underwent surgical portocaval shunting during a fifteen-year period. The behavior of the portal hemodynamics following PCS was studied and the postoperative decrease in portal pressure (PP), as well as the residual PP, were recorded. The portal manometric determinations were made by electronic recordings using the Hellige device and direct intraoperative recordings through the catheterization of a ramus in the portal area. The results of PCS are superposable, in terms of hemodynamic efficiency, with those of the intrahepatic shunt (TIPS—transjugular intrahepatic portosystemic shunt). The authors discuss the current place of PCS, in obvious decline in comparison with the situation 50 years ago. The current methods of controlling variceal bleeding represent obvious progress. PCS remains with very limited indications, in specific situations when the other therapeutic methods have failed or are not recommended.

Downregulation of miR-20b-5p Contributes to the Progression of Liver Fibrosis via the STAT3 Signaling Pathway In Vivo and In Vitro.

Activated hepatic stellate cells (HSCs) are primarily involved in liver fibrosis and portal hypertension (PHT). We aimed to investigate the effect of miR-20b-5p on HSCs, liver fibrosis, and PHT. MiR-20b-5p expression in HSCs and in mouse liver fibrosis was determined by qPCR. Further, the effects of miR-20b-5p mimic on HSCs migration, proliferation, and apoptosis were investigated in vitro. A dual-luciferase reporter assay was performed to confirm the direct interaction between miR-20b-5p and STAT3. In vivo, mouse liver fibrosis was established by common bile duct ligation and intervened by agomiR-20b-5p. Sirius red staining and hydroxyproline content were used to evaluate collagen deposition. The α-SMA expression in the liver was detected by IHC and Western blotting. The STAT3 signaling pathway and its downregulated cytokines as well as portal pressure and angiogenesis were explored. MiR-20b-5p was significantly downregulated during HSCs activation and in mouse liver fibrosis. The functional analyses demonstrated that miR-20b-5p inhibited cell proliferation, activation, and promoted apoptosis in HSCs in vitro. Moreover, miR-20b-5p regulated STAT3 expression by binding to the 3'UTR of its miRNA directly. Overexpression of miR-20b-5p facilitated HSC activation and proliferation by inhibiting the STAT3 signaling pathway. MiR-20b-5p overexpression suppressed the STAT3 and its downstream cytokines and ameliorated liver fibrosis in mice. The intra- and inter-hepatic angiogenesis were also effectively inhibited. The inhibition of liver fibrosis and neoangiogenesis contributed to the decrease of portal pressure. MiR-20b-5p plays an important role in the fibrosis and angiogenesis of liver fibrosis by targeting the STAT3 signaling pathway.

Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Effect of ET‐A blockade on portal pressure and hepatic arterial perfusion in patients with cirrhosis: A proof of concept study

AbstractBackground/aimEndothelin causes vasoconstriction via the endothelin‐A receptor (ET‐A) in the intrahepatic circulation in cirrhosis and its increase leads to portal hypertension. The aim of the study was to investigate the acute effect of a selective ET‐A antagonist in patients with portal hypertension and cirrhosis.MethodsProof‐of‐concept study with two different substudies: (a) local intrahepatic administration of the ET‐A antagonist BQ 123 and (b) systemic oral administration of the ET‐A antagonist Ambrisentan. Portal pressure was determined by hepatic venous pressure gradient (HVPG, both substudies) and hepatic arterial blood flow (HABF) by intra‐arterial Doppler measurements (substudy 1) before and under the ET‐A antagonist. Systemic haemodynamic parameters were measured in substudy 2.ResultsTwelve patients (Child‐Pugh [CP] B/C n = 7/5) were included in substudy 1 and 14 patients (CP A/B/C n = 4/6/4) in substudy 2. The relative decrease in HVPG was −12.5% (IQR: −40% to 0%; P = .05) in substudy 1 and −5.0% (IQR: −11.5% to 0%; P = .01) in substudy 2. Substudy 1 revealed higher decrease in HVPG in CP B patients. HABF increased significantly and patients without portal pressure decrease showed a higher increase of HABF. Substudy 2 showed a slight decrease in the mean arterial pressure without changes of other systemic haemodynamic parameters.ConclusionAdministration of a selective ET‐A antagonist decreases the portal pressure in cirrhotic patients. This decrease was higher in CP B patients and the non‐responders showed a higher increase in hepatic arterial flow. Selective ET‐A antagonists might be a future treatment option in patients with portal hypertension.

Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis

Whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of β-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis. Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting β-blockers and again after 1 to 3 months of treatment (short-term). Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under β-blockers, decompensated patients had lower portal pressure decrease (10± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with β-blockers than survivors (21±14% vs. 15 ± 16%; p <0.05) and CO under β-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p= 0.004). In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to β-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of β-blockers on CO might adversely influence survival in decompensated cirrhosis. β-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portalpressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of β-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of β-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.

H-shaped partial splenorenal shunting with the use of a reinforced graft made of porous polytetrafluoroethylene.

The study was aimed at improving the immediate and remote results of splenorenal bypass grafting. A total of 57 patients presenting with hepatic cirrhosis, portal hypertension, and recurrent haemorrhage from oesophageal varices underwent an H-shaped partial splenorenal shunt procedure using an externally reinforced 1.5-2.0-cm-long synthetic graft with a diameter equalling half of that of the splenic vein in an end-to-side fashion. Assessment of efficacy of shunting was based on intraoperative measurement of venous pressure in the portal system before and after shunting, the findings of Doppler ultrasonography of the linear velocity of blood flow in the portal, splenic, and left renal veins in the early postoperative period, as well as computed tomography, esophagogastroscopy, and assessment of the degree of hepatic encephalopathy in the remote postoperative period. The findings of intraoperative measurement of venous pressure in the portal vein system before and after shunting demonstrated a statistically significant decrease in (normalization of) portal pressure in all patients after bypass grafting (p≤0.05). There were no severe postoperative complications, in-hospital mortality, nor events of decompensation of hepatic insufficiency. According to the findings of Doppler ultrasonography of the linear velocity of blood flow and control computed tomography after surgery, the splenic vein, left renal vein and the conduit between them remained patent at all terms of postoperative follow up. The findings of control esophagogastroscopy revealed a statistically significant decrease in the degree of oesophageal varices at 3, 6, and 9 months after shunting (p≤0.05). There was no statistically significant difference in the change of the degree of hepatic encephalopathy at 3, 6, and 9 months after shunting (p=0.853, p=0.712, and p=0.581, respectively). At various terms after surgery, nine patients underwent deceased donor liver transplantation, with the splenorenal shunt ligated intraoperatively. This method of splenorenal shunting makes it possible to decrease the risk of bleeding from oesophageal varices and venous thromboses in vascular anastomoses, as well as complications resulting from using autovenous conduits, to decrease the risk of decomposition of hepatic insufficiency and the frequency of the development of encephalopathy in the postoperative period. Besides, this method makes it possible to easily dismantle the previously created artificial portocaval shunt in the process of liver transplantation.

Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages. Sprague-Dawley rats were fed with high fat glucose-fructose diet (HFGFD), or control diet (CD) for 8 weeks and then treated with simvastatin (sim) (10 mg·kg−1·day−1), atorvastatin (ato) (10 mg·kg−1·day−1) or vehicle during 2 weeks. Biochemical, histological and hemodynamic determinations were carried out. Sinusoidal endothelial dysfunction was assessed in individualized sorted LSEC and hepatic stellate cells (HSC) from animal groups and in whole liver samples. HFGFD rats showed full NASH features without fibrosis but with significantly increased portal pressure compared with CD rats (10.47 ± 0.37 mmHg vs 8.30 ± 0.22 mmHg; p < 0.001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b−/CD11b−) LSEC (8% vs 1%, p = 0.005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9.29 ± 0.25 mmHg, p < 0.01; ato: 8.85 ± 0.30 mmHg, p < 0.001), NASH histology reversion, along with significant recovery of LSEC differentiation and a regression of HSC activation to a more quiescent phenotype. In an early NASH model without fibrosis with PH, LSEC transition to capillarization and HSC activation are reverted by statin treatment inducing portal pressure decrease and NASH features improvement.

Intestinal permeability in the pathogenesis of liver damage: From non-alcoholic fatty liver disease to liver transplantation.

The intimate connection and the strict mutual cooperation between the gut and the liver realizes a functional entity called gut-liver axis. The integrity of intestinal barrier is crucial for the maintenance of liver homeostasis. In this mutual relationship, the liver acts as a second firewall towards potentially harmful substances translocated from the gut, and is, in turn, is implicated in the regulation of the barrier. Increasing evidence has highlighted the relevance of increased intestinal permeability and consequent bacterial translocation in the development of liver damage. In particular, in patients with non-alcoholic fatty liver disease recent hypotheses are considering intestinal permeability impairment, diet and gut dysbiosis as the primary pathogenic trigger. In advanced liver disease, intestinal permeability is enhanced by portal hypertension. The clinical consequence is an increased bacterial translocation that further worsens liver damage. Furthermore, this pathogenic mechanism is implicated in most of liver cirrhosis complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma. After liver transplantation, the decrease in portal pressure should determine beneficial effects on the gut-liver axis, although are incompletely understood data on the modifications of the intestinal permeability and gut microbiota composition are still lacking. How the modulation of the intestinal permeability could prevent the initiation and progression of liver disease is still an uncovered area, which deserves further attention.

Vascular Targets for the Treatment of Portal Hypertension.

Portal hypertension is the main driver for severe complications in patients with liver cirrhosis. With improved understanding of molecular pathways that promote hepatic vascular remodeling, vasoconstriction, and sinusoidal capillarization potential vascular targets for the treatment of portal hypertension have been identified. Inhibition of vascular endothelial and platelet-derived growth factors-driven angiogenesis has been shown to reduce portal pressure and decrease hepatic inflammation. Angiopoietin/Tie signaling represents additional promising vascular targets in liver disease. The eNOS-NO-sGC-cGMP pathway modulates sinusoidal vasoconstriction and capillarization. Nuclear farnesoid X receptor (FXR) agonists decrease intrahepatic vascular resistance by inhibition of fibrogenesis and sinusoidal remodeling. Statins ameliorate endothelial dysfunction, decrease portal pressure, and reduce fibrogenesis. Anticoagulation with low-molecular heparin or anti-Xa inhibitors improved portal hypertension by deactivation of hepatic stellate cells and potentially via reduction of sinusoidal microthrombosis. This review summarizes important vascular targets for treatment of portal hypertension that have shown promising results in experimental studies.

Future Pharmacological Therapies of Portal Hypertension.

To provide an overview of recent pharmacological treatments for portal hypertension evaluated in early clinical trials, with particular emphasis on the pathophysiological basis of their use. In patients with compensated cirrhosis, even small decreases in portal pressure (as small as 1 mmHg) are associated with a lower probability of decompensation. In patients with decompensated cirrhosis, portal pressure "response" to non-selective beta-blocker (NSBB) therapy is associated with a lower mortality. When present, significant portal hypertension persists even after elimination of the etiology of cirrhosis and this justifies the continued development of new drugs that target portal hypertension. Over several decades we have gained great depth in the understanding of portal hypertension, its mechanisms and complications. NSBBs, which act by reducing portal venous inflow (an extrahepatic target), are effective in reducing portal pressure and have been the mainstay of therapy for portal hypertension in the last 35 years -being effective in preventing decompensation and variceal hemorrhage. However, because not all patients will have a sufficient response to NSBB and some may be intolerant to NSBB, alternative drugs or drugs that will augment the effect of NSBB on portal pressure are being tested in pre-clinical and early-clinical trials. Many of these drugs target more than one of the intrahepatic or extrahepatic mechanisms implicated in the pathogenesis of portal hypertension in cirrhosis. Out of these proposed therapies, statins have emerged as the most promising new pharmacological therapy for the treatment of portal hypertension.

Safety and Efficacy of a Novel Shunt Surgery Combined with Foam Sclerotherapy of Varices for Prehepatic Portal Hypertension: A Pilot Study

OBJECTIVES:This pilot study investigated the safety and efficacy of a novel shunt surgery combined with foam sclerotherapy of varices in patients with prehepatic portal hypertension.METHODS:Twenty-seven patients who were diagnosed with prehepatic portal hypertension and underwent shunt surgeries were divided into three groups by surgery type: shunt surgery alone (Group A), shunt surgery and devascularization (Group B), and shunt surgery combined with foam sclerotherapy (Group C). Between-group differences in operation time, intraoperative blood loss, portal pressure decrease, postoperative complications, rebleeding rates, encephalopathy, mortality rates and remission of gastroesophageal varices were compared.RESULTS:Groups A, B and C had similar operation times, intraoperative bleeding, and portal pressure decrease. The remission rates of varices differed significantly (p<0.001): one patient in Group A and 6 patients in Group B had partial response, and all 9 patients in Group C had remission (2 complete, 7 partial). Two Group A patients and one Group B patient developed recurrent gastrointestinal bleeding postoperatively within 12 months. No postoperative recurrence or bleeding was observed in Group C, and no sclerotherapy-related complications were observed.CONCLUSIONS:Shunt surgery combined with foam sclerotherapy obliterates varices more effectively than shunt surgery alone does, decreasing the risk of postoperative rebleeding from residual gastroesophageal varices. This novel surgery is safe and effective with good short-term outcomes.

Role of band ligation for secondary prophylaxis of variceal bleeding.

AIMTo summarize and critically examine the role of band ligation in secondary prophylaxis of variceal bleeding in patients with cirrhosis.METHODSA literature review was performed using the MEDLINE and PubMed databases. The search terms consisted of the words “endoscopic band ligation” OR “variceal band ligation” OR “ligation” AND “secondary prophylaxis” OR “secondary prevention” AND “variceal bleeding” OR “variceal hemorrhage” AND “liver cirrhosis”. The data collected from relevant meta-analyses and from the most recent randomized studies that were not included in these meta-analyses were used to evaluate the role of endoscopic band ligation in an effort to demonstrate the most recent advances in the treatment of esophageal varices.RESULTSThis study included 11 meta-analyses published from 2002 to 2017 and 10 randomized trials published from 2010 to 2017 that evaluated the efficacy of band ligation in the secondary prophylaxis of variceal bleeding. Overall, the results proved that band ligation was superior to endoscopic sclerotherapy. Moreover, the use of β-blockers in combination with band ligation increased the treatment effectiveness, supporting the current recommendations for secondary prophylaxis of variceal bleeding. The use of transjugular intrahepatic portosystemic shunt was superior to combination therapy regarding rebleeding prophylaxis, with no difference in the survival rates; however, the results concerning the hepatic encephalopathy incidence were conflicting. Recent advances in the management of secondary prophylaxis of variceal bleeding have targeted a decrease in portal pressure based on the pathophysiological mechanisms of portal hypertension.CONCLUSIONThis review suggests that future research should be conducted to enhance current interventions and/or to develop innovative treatment options with improved clinical endpoints.

The Role of Cannabinoids in the Setting of Cirrhosis.

Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation. The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids. CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation. CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function. Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects. The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.

PORTAL PRESSURE DECREASE AFTER ESOPHAGOGASTRIC DEVASCULARIZATION AND SPLENECTOMY IN SCHISTOSOMIASIS: LONG-TERM VARICES BEHAVIOR, REBLEEDING RATE, AND ROLE OF ENDOSCOPIC TREATMENT

Schistosomiasis is an endemic health problem affecting about four million people. The hepatosplenic form of the disease is characterized by periportal hepatic fibrosis, pre-sinusoidal portal hypertension and splenomegaly. Liver function is preserved, being varices bleeding the main complication of the disease. The surgical treatment used in the majority of centers for the prevention of rebleeding is esophagogastric devascularization and splenectomy. Most authors reported better results with the association of surgical and postoperative endoscopic treatment. The aim of this study was to compare the intra operative portal pressure decrease and esophageal varices behavior and rebleeding rates in patients submitted to surgical and postoperative endoscopic treatment after long-term follow-up. A retrospective study of 36 patients with schistosomiasis with, at least, one previous bleeding from esophageal varices rupture submitted to esophagogastric devascularization and splenectomy, added to endoscopic varices postoperative treatment was performed. Patients were stratified according to the intra operative portal pressure decrease in two groups: reduction below and above 30%. Long-term varices presence, size and bleeding recurrence were evaluated. Regarding varices behavior, no significant influence was observed in both groups of portal pressure fall. Regarding bleeding recurrence, despite three times more frequent in the group with lower portal pressure fall, no significant difference was observed. All patients were submitted to postoperative endoscopic treatment. Esophageal varices banding, rather than portal pressure decrease, seems to be the main responsible factor for good results after combination of two therapies (surgery and endoscopy) for patients with portal hypertension due to schistosomiasis; further studies are necessary to confirm this hypothesis.

Transjugular Intrahepatic Portosystemic Shunting (TIPS Procedure) and its Influence on Portosystemic Hemodynamics in Patients with Portal Hypertension

Aim. To study the peculiarities of portosystemic hemodynamics in patients with cirrhotic portal hypertension before and after TIPS procedure and to identify its influence on the development of typical complications of portal hypertension including bleeding from gastric and esophageal varices, ascites and hepatorenal syndrome. Material and Methods. The TIPS procedure was performed in 136 patients with complicated cirrhotic portal hypertension. Surgical anatomy of liver vascular system and porto-hepatic hemodynamics have been studied using CT-splenoportography, Doppler ultrasonography of portal vein system and CT- angiography portal and hepatic veins. The surgical results were evaluated on various dates postoperatively with the period rate of 3–6 months. Results. Portal vein’s and hepatic veins’ angioarchitecture in a context of TIPS procedure was studied. Algorithm of intrahepatic portosystemic canal creation with the direction determined by surgeon is developed. It gives the opportunity to reach the optimal parameters of shunt’s hemodynamics. It is established decrease of portal pressure and portosystemic venous pressure gradient after surgical intervention. Consideration of anatomic features while forming the intrahepatic portosystemic shunt makes it possible to achieve stable portal decompression even in the environment of significant cirrhotic process. Conclusion. TIPS procedure enables to effectively decrease portal vein system pressure, normalize portosystemic hemodynamics indicators and significantly promote prevention of complications induced by portal hypertension.