Reduction In Portal Pressure Research Articles

Long-Term Outcome of Splenectomy in Advanced Cirrhotic Patients with Hepatocellular Carcinoma and Thrombocytopenia

Splenectomy may be a treatment option in hepatocellular carcinoma (HCC) and cirrhosis when there is no potential donor for liver transplantation. We retrospectively investigated the long-term outcome of splenectomy on survival in advanced cirrhotic patients with HCC and thrombocytopenia. Between 1999 and 2009, 46 cirrhotic patients with thrombocytopenia (Child-Pugh class B or C) who underwent splenectomy for the simultaneous or secondary treatment of HCC at our institute were evaluated. The 1-, 3-, and 5-year survival rates were 93.5, 76.0, and 37.9%, respectively. Splenectomy resulted in a significant reduction in mean portal venous pressure from 21.2 to 16.8 mmHg and improvements in liver function tests such as total bilirubin, prothrombin time, platelet count, Child-Pugh score for 3 years, and albumin for 2 years. The mean frequency of treatment for HCC recurrence after surgery was 3.0 times (range 1-11). Seven patients out of 16 scheduled for Interferon (IFN) therapy after surgery achieved a sustained virological response (SVR). Multivariate analysis identified SVR after IFN therapy as an independent significant prognostic factor (Hazard ratio 0.18, 95%CI 0.03-0.65, P=0.006). Postoperative complications including liver failure (n=1), portal thrombosis (n=7), ascites (n=5), and bacterial infections (n=4) were observed in 14 patients (30%). Splenectomy can be a feasible supportive therapy for the continuation of anticancer therapy and completion of IFN therapy based on improvements in liver function and thrombocytopenia with minimum complications in patients with HCC and advanced cirrhosis with no potential donor.

Regression of Fibrosis and Reversal of Cirrhosis in Rats by Galectin Inhibitors in Thioacetamide-Induced Liver Disease

Galectin-3 protein is critical to the development of liver fibrosis because galectin-3 null mice have attenuated fibrosis after liver injury. Therefore, we examined the ability of novel complex carbohydrate galectin inhibitors to treat toxin-induced fibrosis and cirrhosis. Fibrosis was induced in rats by intraperitoneal injections with thioacetamide (TAA) and groups were treated with vehicle, GR-MD-02 (galactoarabino-rhamnogalaturonan) or GM-CT-01 (galactomannan). In initial experiments, 4 weeks of treatment with GR-MD-02 following completion of 8 weeks of TAA significantly reduced collagen content by almost 50% based on Sirius red staining. Rats were then exposed to more intense and longer TAA treatment, which included either GR-MD-02 or GM-CT-01 during weeks 8 through 11. TAA rats treated with vehicle developed extensive fibrosis and pathological stage 6 Ishak fibrosis, or cirrhosis. Treatment with either GR-MD-02 (90 mg/kg ip) or GM-CT-01 (180 mg/kg ip) given once weekly during weeks 8–11 led to marked reduction in fibrosis with reduction in portal and septal galectin-3 positive macrophages and reduction in portal pressure. Vehicle-treated animals had cirrhosis whereas in the treated animals the fibrosis stage was significantly reduced, with evidence of resolved or resolving cirrhosis and reduced portal inflammation and ballooning. In this model of toxin-induced liver fibrosis, treatment with two galectin protein inhibitors with different chemical compositions significantly reduced fibrosis, reversed cirrhosis, reduced galectin-3 expressing portal and septal macrophages, and reduced portal pressure. These findings suggest a potential role of these drugs in human liver fibrosis and cirrhosis.

An Atypical Appearance of Gastric Antral Vascular Ectasia (GAVE) with Complete Resolution after Liver Transplant

Purpose: Gastric antral vascular ectasia (GAVE) is a rare cause of upper gastrointestinal bleeding in end-stage liver patients being considered for liver transplant, and can be difficult to recognize. The correct diagnosis has therapeutic implications for successful treatment of bleeding. A 56-yearold male with alcoholic cirrhosis, complicated by ascites and non-bleeding gastroesophageal varices, presented for liver transplant evaluation. The most severe manifestation of his cirrhosis was chronic blood loss anemia requiring transfusion of two units of blood every two weeks. He had melenic stools and required frequent hospital admissions for anemia. A pre-transplant esophagogastroduodenoscopy revealed gastroesophageal varices without stigmata of recent bleeding, diffuse GAVE in the antrum with some areas of active oozing, and a fleshy, nodular mass in the second part of the duodenum with thick folds of oozing, friable mucosa. The most active areas of bleeding were over this mass-like lesion. A biopsy of the mass showed vascular ectasias with thombosis, consistent with nodular GAVE in the duodenum. The patient had treatment with serial argon plasma coagulation, however still remained transfusiondependent. Six months after the diagnosis of GAVE, he underwent an orthotopic liver transplantation. After the immediate post-operative period, he was no longer transfusion dependent. An esophagogastroduodenoscopy performed a year after his transplant showed complete resolution of his antral GAVE, as well as complete resolution of his nodular, duodenal GAVE. The endoscopic appearances of GAVE have been described in literature as puctate-type vascular ectasias, which are more strongly associated with cirrhosis, as well as striped, erythematous lesions arranged radially from the pylorus, more commonly termed “watermelon stomach.” Both these presentations share the same histologic findings of mucosal capillary dilations, fibrin thrombi, and fibromusclar hyperplasia. In our patient, we present an atypical, nodular presentation of GAVE in the duodenum. Our case also highlights the resolution of GAVE in patients with liver disease after liver transplantation. The recognition of GAVE is necessary for successful treatment. GAVE-induced bleeding can be treated with thermal ablation or estrogen, and can be cured with liver transplantation; however, it has not been shown to be responsive to treatments with reduction in portal pressure.

Image-guided Intervention in Management of Complications of Portal Hypertension: More than TIPS for Success

Management of clinically important sequelae of portal hypertension, such as variceal bleeding and ascites, may involve a combination of medical, endoscopic, surgical, and interventional approaches and procedures. Although clinically significant esophageal and rectal varices are typically visible endoscopically, ectopic varices may require multiplanar portal venous phase computed tomography or magnetic resonance imaging for diagnosis. A detailed understanding of individual vascular anatomy, flow dynamics, and patient-related factors such as cardiac and hepatic status is necessary for appropriate treatment selection in patients with complicated portal hypertension. The hepatic venous pressure gradient is the key indirect measurement of portal venous pressure. Transjugular intrahepatic portosystemic shunt (TIPS) placement is regarded as the archetypal intervention for treating complicated portal hypertension by reducing portal pressure. Various modifications, such as direct portocaval shunt, may be used in patients with challenging vascular anatomy. A subset of patients with obstructed hepatic venous outflow or portal venous inflow should be considered for recanalization. Splenic artery embolization may be considered for reduction of portal pressure in selected patients, particularly when hypersplenism or splenic vein occlusion is a prominent feature. Gastric and ectopic varices may bleed even when the portal pressure is low, and balloon-occluded retrograde transvenous obliteration (BRTO) in such patients may lead to equal or improved outcome compared with TIPS placement. BRTO is not limited by poor hepatic reserve or encephalopathy; however, it does not reduce portal pressure and may aggravate esophageal varices. Interventional radiology plays an important role in maintaining the patency of surgically created portosystemic shunts, and it remains at the forefront of new approaches in shunt design and placement. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.335125166/-/DC1.

VSL#3® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis

In patients with decompensated cirrhosis, bacterial translocation can contribute to splanchnic vasodilatation, decreased effective circulating volume, and portal hypertension. The primary objective of this randomized, double blind placebo controlled trial was to evaluate the effect of the probiotic VSL#3(®) on the hepatic venous pressure gradient (HVPG). Seventeen patients with decompensated cirrhosis and an HVPG of ≥ 10 mmHg were randomized to receive 2 months of VSL#3(®) or an identical placebo. HVPG, endotoxin, interleukin (IL)-6, IL-8, IL-10, renin, aldosterone, nitric oxide and stool microbiota were measured at baseline and study end. Two of the 17 patients were taken off the trial before completion (one for alcohol abuse and the second for SBP - both in placebo arm). Data were analysed on the remaining 15 patients. The median model for end-stage liver disease score was 12, and 80% of patients had Child Pugh B disease. The treatment arm had a greater decrease in HVPG from baseline to study end than the placebo arm (median change from baseline -11.6% vs +2.8%), although this reduction was not statistically significant in either group. There was a significant reduction in the plasma aldosterone level in the VSL#3(®) group, but no significant changes in the other measured parameters, including the stool microflora analysis. Within the limitations of our sample size, VSL#3(®) therapy does not appear to have a significant impact on portal pressure reduction in patients with decompensated cirrhosis.

Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis

Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O2(-) levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.

Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells

The function of the endothelial isoform of nitric oxide synthase (eNOS) and production of nitric oxide (NO) is altered in a number of disease states. Pharmacological approaches to enhancing NO synthesis and thus perhaps endothelial function could have substantial benefits in patients. We analyzed the effect of cicletanine, a synthetic pyridine with potent vasodilatory characteristics, on eNOS function and NO production in normal (liver) and injured rat sinusoidal endothelial cells, and we studied the effect of cicletanine-induced NO on stellate cell contraction and portal pressure in an in vivo model of liver injury. Sinusoidal endothelial cells were isolated from normal and injured rat livers. After exposure to cicletanine, eNOS phosphorylation, NO synthesis, and the signaling pathway regulating eNOS activation were measured. Cicletanine led to an increase in eNOS (Ser¹¹⁷⁷) phosphorylation, cytochrome c reductase activity, L-arginine conversion to L-citrulline, as well as NO production. The mechanism of the effect of cicletanine appeared to be via the protein kinase B (Akt) and MAP kinase/Erk signaling pathways. Additionally, cicletanine improved NO synthesis in injured sinusoidal endothelial cells. NO production induced by cicletanine in sinusoidal endothelial cells increased protein kinase G (PKG) activity as well as relaxation of stellate cells. Finally, administration of cicletanine to mice with portal hypertension induced by bile duct ligation led to reduction of portal pressure. The data indicate that cicletanine might improve eNOS activity in injured sinusoidal endothelial cells and likely activates hepatic stellate cell NO/PKG signaling. It raises the possibility that cicletanine could improve intrahepatic vascular function in portal hypertensive patients.

Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial

Probiotics, by altering gut flora, may favourably alter portal haemodynamics in patients with cirrhosis. To investigate the effect of probiotics on portal pressure in patients with cirrhosis. Randomized double-blind placebo-controlled trial conducted in G.B. Pant Hospital, New Delhi. A total of 94 cirrhotic patients having large oesophageal varices without history of variceal bleeding were randomized to three treatment groups and given 2 months' treatment with propranolol plus placebo, propranolol plus antibiotics (norfloxacin 400 mg BD) or propranolol plus probiotic (VSL#3, 900 billion/day) randomly assigned in 1:1:1 ratio. Outcome measures were change in Hepatic venous pressure gradient (HVPG): Response rate (Percentage of patients having a decrease from baseline of ≥20% or to ≤12 mm Hg) and changes from baseline; biochemical markers of inflammation: changes from baseline. Adjunctive probiotics increased the response rate compared with propranolol alone (58% vs. 31%, P = 0.046), similar to adjunctive antibiotics (54%). The mean fall in HVPG was greater with either adjunctive probiotics (3.7 mm Hg vs. 2.1 mm Hg, P = 0.061) or adjunctive antibiotics (3.4 mm Hg) than with propranolol alone. Both adjunctive therapies were associated with greater decreases in TNF-α levels (in both peripheral and hepatic venous blood) that resulted from propranolol-only treatment. No clinically relevant between-group differences were observed in the type or frequency of adverse events. Adjunctive probiotic (VSL#3) improved the response rate to propranolol therapy and was safe and well tolerated in patients with cirrhosis. Adjunctive probiotic therapy merits further study for reduction in portal pressure.

615 EARLY USE OF TIPS DECREASES REBLEEDING AND IMPROVES THE SURVIVAL IN CIRRHOTIC PATIENTS OF EVL ULCER BLEEDING: A PROSPECTIVE STUDY

S 21 ANNUAL CONFERENCE —2013 C rrh o is & C o m p ica tio n s EARLY USE OF TIPS DECREASES REBLEEDING AND IMPROVES THE SURVIVAL IN CIRRHOTIC PATIENTS OF EVL ULCER BLEEDING: A PROSPECTIVE STUDY Ashok Choudhury, Hitendra Garg, Amar Mukund, Manoj Kumar, R. Kumar, Shiv K. Sarin Institute of Liver and Biliary Sciences, New Delhi, India Background: Endoscopic variceal ligation (EVL) is the recommended method to manage esophageal variceal bleeding with lower variceal ulceration and rebleeding rates compared to sclerotherapy. A proportion of patients develops EVL induced ulcers and present with massive bleeding. In these cases, endotherapy is difficult and often unsuccessful and definitive methods, such as TIPS need to be evaluated. Aim: Determine the effectiveness of reduction in portal pressure by polytetrafluoroethylene-covered transjugular stenting (TIPS) for band-induced esophageal ulcer bleeding. Method: Following admission within 24 hours, consecutive patients with cirrhosis and EVL induced bleeding ulcers were prospectively treated using standard therapy (endoscopy and vasoactive drugs; Group 1, n=17) or standard therapy plus TIPS (Group 2, n=22). Primary endpoint was survival at 6 wks. Secondary end-points were early and late rebleeding. Results: Total 488 cirrhotic patients who underwent EVL from 2010-11, 36 (7%) (Median age 42 (range 32-72), 90% males) developed bleeding EVL ulcer. These patients were enrolled and offered either of the two treatments. Baseline parameters including age, presence of ascites, HE, HRS, platelets, PT (INR), HVPG, Child and MELD score were similar in both the groups. After follow-up of 6 wks, 10 patients (62%) in group 1 and 5 (25%) in group 2 died (P<0.05). The incidence of failure to control bleed/early rebleed was seen in 9 patients (56%) in group1 and in 1(5%) in group 2 (P <0.05). Similarly, the incidence of late rebleeding was seen in 5 patients (45.4%) in group 1 while in 1(5%) in group2 (P <0.05). The median time to death was 2.5 (0.5-12) days and 13 (2-21) days in the two groups (P <0.05). Conclusion: Around 7% patients develop life threatening EVL induced ulcer bleeding. Portal pressure reduction with the TIPS is significantly superior in the control of bleeding, preventing rebleeding and reduction in mortality. Corresponding author. Hitendra Garg. E-mail: drhitendragarg@yahoo.com

Early use of Tips Decreases Rebleeding and Improves the Survival in Cirrhotic Patients of EVL Ulcer Bleeding: A Prospective Study

Background: Endoscopic variceal ligation (EVL) is the recommended method to manage esophageal variceal bleeding with lower variceal ulceration and rebleeding rates compared to sclerotherapy. A proportion of patients develops EVL induced ulcers and present with massive bleeding. In these cases, endotherapy is difficult and often unsuccessful and definitive methods, such as TIPS need to be evaluated. Aim: Determine the effectiveness of reduction in portal pressure by polytetrafluoroethylene-covered transjugular stenting (TIPS) for band-induced esophageal ulcer bleeding. Method: Following admission within 24 hours, consecutive patients with cirrhosis and EVL induced bleeding ulcers were prospectively treated using standard therapy (endoscopy and vasoactive drugs; Group 1, n=17) or standard therapy plus TIPS (Group 2, n=22). Primary end-point was survival at 6 wks. Secondary end-points were early and late rebleeding. Results: Total 488 cirrhotic patients who underwent EVL from 2010-11, 36 (7%) (Median age 42 (range 32-72), 90% males) developed bleeding EVL ulcer. These patients were enrolled and offered either of the two treatments. Baseline parameters including age, presence of ascites, HE, HRS, platelets, PT (INR), HVPG, Child and MELD score were similar in both the groups. After follow-up of 6 wks, 10 patients (62%) in group 1 and 5 (25%) in group 2 died (P<0.05). The incidence of failure to control bleed/early rebleed was seen in 9 patients (56%) in group1 and in 1(5%) in group 2 (P <0.05). Similarly, the incidence of late rebleeding was seen in 5 patients (45.4%) in group 1 while in 1(5%) in group2 (P <0.05). The median time to death was 2.5 (0.5-12) days and 13 (2-21) days in the two groups (P <0.05). Conclusion: Around 7% patients develop life threatening EVL induced ulcer bleeding. Portal pressure reduction with the TIPS is significantly superior in the control of bleeding, preventing rebleeding and reduction in mortality.

Staged Transcatheter Treatment of Portal Hypoplasia and Congenital Portosystemic Shunts in Children

Congenital portosystemic shunts (CPSS) with portal venous hypoplasia cause hyperammonemia. Acute shunt closure results in portal hypertension. A transcatheter method of staged shunt reduction to afford growth of portal vessels followed by shunt closure is reported. Pressure measurements and angiography in the CPSS or superior mesenteric artery (SMA) during temporary occlusion of the shunt were performed. If vessels were diminutive and the pressure was above 18 mmHg, a staged approach was performed, which included implantation of a tailored reducing stent to reduce shunt diameter by ~50 %. Recatheterization was performed approximately 3 months later. If the portal pressure was below 18 mmHg and vessels had developed, the shunt was closed with a device. Six patients (5 boys, 1 girl) with a median age of 3.3 (range 0.5-13) years had CPSS portal venous hypoplasia and hyperammonemia. Five patients underwent staged closure. One patient tolerated acute closure. One patient required surgical shunt banding because a reducing stent could not be positioned. At median follow-up of 3.8 (range 2.2-8.4) years, a total of 21 procedures (20 transcatheter, 1 surgical) were performed. In all patients, the shunt was closed with a significant reduction in portal pressure (27.7 ± 11.3 to 10.8 ± 1.8 mmHg; p = 0.016), significant growth of the portal vessels (0.8 ± 0.5 to 4.0 ± 2.4 mm; p = 0.037), and normalization of ammonia levels (202.1 ± 53.6 to 65.7 ± 9.6 μmol/L; p = 0.002) with no complications. Staged CPSS closure is effective in causing portal vessel growth and treating hyperammonemia.

Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats

Resveratrol, a polyphenol found in a variety of fruits, exerts a wide range of beneficial effects on the endothelium, regulates multiple vasoactive substances and decreases oxidative stress, factors involved in the pathophysiology of portal hypertension. Our study aimed at evaluating the effects of resveratrol on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl₄ cirrhotic rats. Resveratrol (10 and 20 mg/kg/day) or its vehicle was administered to cirrhotic rats for two weeks and hepatic and systemic hemodynamics were measured. Moreover, we evaluated endothelial function by dose-relaxation curves to acetylcholine, hepatic NO bioavailability and TXA2 production. We also evaluated liver fibrosis by Sirius Red staining of liver sections, collagen-1, NFκB, TGFβ mRNA expression, and desmin and α-smooth muscle actin (α-SMA) protein expression, as a surrogate of hepatic stellate cell activation. Resveratrol administration significantly decreased portal pressure compared to vehicle (12.1 ± 0.9 vs. 14.3 ± 2.2 mmHg; p <0.05) without significant changes in systemic hemodynamics. Reduction in portal pressure was associated with an improved vasodilatory response to acetylcholine, with decreased TXA2 production, increased endothelial NO, and with a significant reduction in liver fibrosis. The decrease in hepatic fibrosis was associated with a reduced collagen-1, TGFβ, NFκB mRNA expression and desmin and α-SMA protein expression. Resveratrol administration reduces portal pressure, hepatic stellate cell activation and liver fibrosis, and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting it may be a useful dietary supplement in the treatment of portal hypertension in patients with cirrhosis.

Chylous Ascites Controlled with Octreotide

Purpose: Introduction: Chylous ascites is characterized by the accumulation of lymphatic fluid in the peritoneal cavity. The most common causes of chylous ascites in developed countries are abdominal malignancy, lymphatic abnormalities, and cirrhosis; but tuberculosis and filariasis accounts for the majority of cases in developing countries. We report a rare case of chylous ascites caused by alcoholic liver cirrhosis controlled by octreotide. Case Report: A 57-year-old man with a history of chronic alcoholism was seen for gradual worsening of abdominal and bilateral leg swelling. Physical examination revealed abdominal distension, shifting dullness and bilateral lower extremity edema. Paracentesis was performed with the removal of 8 liters of milky fluid. Analysis of the fluid showed serum-ascites albumin gradient (SAAG) of >1.1 and elevated triglyceride level (157 mg/dl). Cytological and microbiological examination was negative for malignancy and tuberculosis, respectively. A computed tomography scan of the chest and abdomen showed cirrhosis and no malignancy was found. Patient was diagnosed with chylous ascites secondary to alcoholic liver cirrhosis. Despite medical management with low salt diet, furosemide and spironolactone; patient required a second paracentesis after 7 days with the removal of 4 liters of milky fluid. Analysis of the fluid again revealed SAAG of >1.1 and elevated triglyceride level (229 mg/dl). Octreotide was started at 100 microgram subcutaneous three times a day. Patient's ascites was controlled and the patient required only one repeat paracentesis over 6 months of follow-up. Discussion: Reported incidence of chylous ascites in cirrhotic patient is 0.5 to 1%. Mechanism of formation of chylous ascites in cirrhosis is poorly understood but can be explained by leakage of lymph due to rupture of dilated serosal lymphatic channels secondary to excessive lymph flow (around 18-20 liters/day). Diagnosis of chylous ascites can be confirmed by high triglyceride level of > 110 mg/dl in the ascitic fluid or elevated ascites-plasma triglyceride ratio of > 2:1. Reduction of Lymph formation and reduction of portal pressure should be the aim of management. Octreotide works by reducing portal pressure by inhibiting glucagon and other intestinal peptides mediated splanchnic vasodilatation. Long term use of octreotide can reduce the formation of chylous ascites and it can even stop formation of ascites by helping repair of ruptured lymphatics.

Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents

Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice. S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension.

Lessons from liver transplantation

Lessons from liver transplantation

PMO-127 Biological effects of oral nanoporous carbon in bile duct ligated rats

IntroductionGut-derived bacterial products and associated dysregulated inflammatory response play a central role in the pathogenesis of cirrhosis. Therapeutic options to target these factors are currently limited to long-term antibiotics. Nanoporous...

PMO-123 Gene transfer of dimethylarginine dimethylaminohydrolase-1 reduces portal pressure in a rodent model of cirrhosis

IntroductionPortal hypertensive bleeding is a grave complication of cirrhosis. Asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor, is elevated in cirrhosis, relates to degree of portal hypertension, and is prognostic in...

Anti‐fibrotic activity and enhanced interleukin‐6 production by hepatic stellate cells in response to imatinib mesylate

To examine imatinib mesylate's effects on stellate cell responses in vivo and in vitro. The hepatic stellate cell (HSC) is a key target of anti-fibrotic therapies. Imatinib mesylate is a small molecule receptor tyrosine kinase inhibitor indicated for treatment of chronic myelogenous leukaemia and GI stromal tumours. Because imatinib inhibits β-PDGFR signalling, which stimulates HSC proliferation, we assessed its activity in culture and in vivo, and examined downstream targets in a human stellate cell line (LX-2) using cDNA microarray. Imatinib inhibited proliferation of LX-2 cells (0.5-10 mM) but not primary human stellate cells, with no effect on viability, associated with attenuated β-PDGFR phosphorylation. Mitochondrial activity and superoxide anion production were decreased in response to imatinib. cDNA microarray uncovered up-regulation of 29 genes in response to imatinib, including interleukin-6 (IL-6) mRNA, which was correlated with progressive IL-6 secretion. Imatinib also decreased gene expression of collagen α(1) (I), alpha smooth muscle actin, β-PDGFR, transforming growth factor β receptor type 1, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2. In vivo, imatinib administered to rats beginning 4 weeks after starting thioacetamide (TAA) led to reduced collagen content, with significant reductions in portal pressure and down-regulation of fibrogenic genes in whole liver. Importantly, hepatic IL-6 mRNA levels were significantly increased in TAA-treated animals receiving imatinib. These findings reinforce the anti-fibrotic activity of imatinib and uncover an unexpected link between inhibition of HSC activation by imatinib and enhanced secretion of IL-6, a regenerative cytokine.

582 METAL METABOLISM IMPAIRMENT IN PATIENTS WITH HEPATIC ENCEPHALOPATHY

in the pathogenesis of cirrhosis. Therapeutic options to target these factors are currently limited to long-term antibiotics. Nanoporous carbons are non-absorbable, synthetic materials which are safe with porosity manipulated for adsorption of middle and high molecular weight molecules and surface chemistry modified to alter adsorption capacity for biological molecules such as cytokines and endotoxin. The aims of this study were to determine whether oral administration of these carbons would prevent the complications of cirrhosis. Methods: 131 male Sprague-Dawley rats underwent bile ductligation or sham biliary surgery. Animals were pair fed with or without oral carbon therapy two weeks from surgery until completion of the experiment at 4–5 weeks. Intraperitoneal lipopolysaccharide (LPS) was administered to 4 subgroups 3.5 hours prior to completion of study. The following groups were studied: Sham (n=16), Sham + carbon (n =15), Sham + LPS (n =11), Sham+LPS+carbon (n =10), BDL (n =27), BDL + carbon (n =26), BDL+LPS (n =10), BDL+LPS+carbon (n =16). Portal haemodynamics were performed on 93 rats and Kupffer cell population and ROS production were performed by flow cytometry in a subgroup of animals. Biochemistry and portal venous cytokines were measured. Results: A significant reduction in portal pressure was observed in BDL+LPS (mean 18.1mmHg (0.88) untreated, 10.2mmHg (1.07) with carbon, p = 0.0007) and BDL (mean 12.6mmHg (0.43) untreated, 11.0mmHg (0.28) with carbon, p = 0.004) groups following carbon treatment. A significant reduction in ALT was observed in the carbon treated BDL+LPS (p =0.01) and BDL groups (p = 0.04). Carbon treatment in BDL rats was associated with a significant reduction in LPS-induced ROS production by the Kupffer cells. A trend towards reduction in portal venous IL-4 and IL-10 were observed in carbontreated BDL rats. A significant increase in final body mass was observed in the BDL carbon-treated group (p =0.03). Conclusions: The data from this study suggests that nanoporous carbon is a novel approach to reducing gut translocation which prevents Kupffer cell activation thereby preventing portal hypertension.

Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis: a randomized controlled trial.

The efficacy of portal pressure reduction by beta-blockers and the utility of serial hepatic venous pressure gradient (HVPG) measurements for the management of small (≤5mm) esophageal varices in patients of cirrhosis are not clear. The study had the following aims: to study (1) the effect of propranolol on the growth of small varices and (2) whether single or serial HVPG measurements result in a better outcome compared to no measurement in patients with small varices. Consecutive cirrhosis patients with small varices, without any history of variceal bleed, were randomized to receive propranolol or placebo and to undergo no HVPG, only baseline HVPG, or serial HVPG measurements. A total of 150 cirrhotics (cirrhosis predominantly viral or alcohol induced) were included (77 in the beta-blocker and 73 in the placebo group). Baseline characteristics were similar. The actuarial 2-year risk of growth of varices (primary endpoint) was 11 and 16% in the propranolol and placebo group, respectively (P=0.786). Variceal bleeding and mortality were also comparable in the two groups. Similarly, the outcome was not influenced by HVPG measurements (whether serial, only baseline, or no HVPG). A bilirubin level of ≥1.5mg/dl was found to be an independent predictor of variceal progression. In cirrhotics with small esophageal varices, nonselective beta-blockers are unable to prevent the growth of varices, variceal bleed, or mortality. HVPG monitoring of these patients did not change the outcome; however, the role of HVPG-guided therapy modification needs to be studied.