Pharmacological Treatment Of Portal Hypertension Research Articles

Pharmacotherapies for Portal Hypertension: Current Status and Expanding Indications.

Non-selective beta blockers remain pharmacotherapy of choice for prevention of first episode of variceal bleeding (primary prevention) and for prevention of its recurrence after initial hemostasis (secondary prophylaxis). This review will update the current and emerging pharmacological therapies for portal hypertension. Data have emerged on carvedilol in preventing hepatic decompensation and improving patient survival among patients with clinically significant portal hypertension. Because measurement of WHVP is invasive and not feasible in routine practice, non-invasive tests with liver stiffness measurement in combination with platelet count may be accurate in identifying clinically significant portal hypertension. Carvedilol is more effective in reducing portal pressure compared to nadolol or propranolol. Its use has expanded to reduce risk of hepatic decompensation among patients with CSPH, which can be identified non-invasively using liver stiffness and platelet count. Studies are needed on non-invasive biomarkers to guide and optimize pharmacological treatment of portal hypertension.

Carvedilol improves liver cirrhosis in rats by inhibiting hepatic stellate cell activation, proliferation, invasion and collagen synthesis.

Portal hypertension (PHT) is one of the most severe consequences of liver cirrhosis. Carvedilol is a first-line pharmacological treatment of PHT. However, the antifibrogenic effects of carvedilol on liver cirrhosis and the intrinsic mechanisms underlying these effects have not been thoroughly investigated. The present study aimed to investigate the antifibrogenic effects of carvedilol on liver cirrhosis in vivo and in vitro. Liver cirrhosis was induced in rats by carbon tetrachloride (CCl4) administration for 9 weeks; carvedilol was administered simultaneously in the experimental group. Blood samples were collected for serum biochemistry. Liver tissues were used for fibrosis evaluation, histological examination, immunohistochemistry and western blot analysis. The human hepatic stellate cell (HSC) line LX-2 was used for in vitro studies. The effects of carvedilol on LX-2 cell proliferation and invasion were evaluated by Cell Counting Kit-8 assay and Transwell invasion assays, respectively. The effect of carvedilol on transforming growth factor β1 (TGFβ1)-induced collagen synthesis in LX-2 cells and the molecular mechanisms were examined by western blot analysis. The results demonstrated that carvedilol improved CCl4-induced structural distortion and fibrosis in the liver. Carvedilol inhibited HSC activation, proliferation and invasion. Carvedilol inhibited HSC collagen synthesis through the TGFβ1/SMAD pathway. In conclusion, carvedilol may alleviate liver cirrhosis in rats by inhibiting HSC activation, proliferation, invasion and collagen synthesis. Carvedilol may be a potential treatment of early-stage liver cirrhosis.

Prevention of portal hypertension: from variceal development to clinical decompensation.

Pharmacological treatment of portal hypertension (PH) has been exclusively devoted to gastroesophageal varices-related events at different frameworks, including prophylactic, emergency, or preventive therapy. The goals of treatment are to avoid the first bleeding episode, stop active bleeding, and prevent bleeding recurrence, respectively. The objective of preprimary prophylaxis (PPP) is to avoid variceal development, and therefore it necessarily deals with patients with cirrhosis at earlier stages of the disease. At these earlier stages, nonselective beta-blockers (NSBBs) have been ineffective in preventing the development of varices and other complications of PH. Therefore, treatment should not rely on NSBB. It is possible that, at these earlier stages, etiological treatment of liver disease itself could prevent progression of PH. This review will focus mainly on early treatment of PH, because, if successful, it may translate into histological-hemodynamic improvements, avoiding not only variceal development, but also other PH-related complications, such as ascites and portosystemic encephalopathy. Moreover, the advent of new therapies may allow not only the prevention of the complications of PH, but also the chance of a substantial degree of regression in the cirrhotic process, with the possible prevention of hepatocellular carcinoma (HCC).

Salvianolic acid B lowers portal pressure in cirrhotic rats and attenuates contraction of rat hepatic stellate cells by inhibiting RhoA signaling pathway

The contraction of hepatic stellate cells (HSCs) has a critical role in the regulation of intrahepatic vascular resistance and portal hypertension. Previous studies have confirmed that salvianolic acid B (Sal B) is effective against liver fibrosis. In the present study, we evaluated the effect of Sal B on portal hypertension and on HSCs contractility. Liver cirrhosis was induced in rats by peritoneal injection of dimethylnitrosamine and the portal pressure was measured. HSCs contraction was evaluated by collagen gel contraction assay. Glycerol-urea gel electrophoresis was performed to determine the phosphorylation of myosin light chain 2 (MLC2). F-actin stress fiber polymerization was detected by fluorescein isothiocyanate-labeled phalloidin. Intracellular Ca2+ and RhoA signaling activation were also measured. Sal B effectively reduced the portal pressure in DMN-induced cirrhotic rats. It decreased the contraction by endothelin-1 (ET-1)-activated HSCs by ∼66.5% and caused the disassembly of actin stress fibers and MLC2 dephosphorylation. Although Sal B reduced ET-1-induced intracellular Ca2+ increase, blocking Ca2+ increase completely by BAPTA-AM, a Ca2+ chelator, barely affected the magnitude of contraction. Sal B decreased ET-1-induced RhoA and Rho-associated coiled coil-forming protein kinase (ROCK) II activation by 66.84% and by 76.79%, respectively, and inhibited Thr696 phosphorylation of MYPT1 by 80.09%. In vivo, Sal B lowers the portal pressure in rats with DMN-induced cirrhosis. In vitro, Sal B attenuates ET-1-induced HSCs contraction by inhibiting the activation of RhoA and ROCK II and the downstream MYPT1 phosphorylation at Thr696. We consider Sal B a potential candidate for the pharmacological treatment of portal hypertension.

Hypertension portale : avancées et perspectives

In patients with portal hypertension due to cirrhosis, the mechanisms responsible for circulatory modifications are well-known. An elevation in intrahepatic vascular resistance related to a hepatic endothelin hyperproduction and an arterial nitric oxide (NO) hyperproduction. The presence and the degree of portal hypertension might be determined by the measurement of the hepatic venous pressure gradient but non-invasive technique as FibroTest or FibroScan might be useful to estimate the presence of severe portal hypertension. Numerous substances decrease portal pressure either by reducing hepatic vascular resistance or by reducing portal tributary blood flow. The combination of both types of substances is probably the best pharmacological treatment of portal hypertension but further hemodynamic and clinical studies are needed.

Noninvasive Assessment of Liver Fibrosis and Portal Hypertension With Transient Elastography

Hepatic fibrogenesis, the "final" common result of injury to the liver, is believed to be a critical factor leading to hepatic dysfunction and may be important in the pathogenesis of portal hypertension. Thus, accurate assessment of the degree of fibrosis is important clinically. For many years, examination of hepatic histopathology has been considered to be the "gold standard" tool used to assess fibrosis. However, liver biopsy is invasive, and in many instances not favored by patients or physicians. Thus, alternative approaches to measure liver fibrosis would be extremely attractive. To the extent that transient elastography is able to measure "liver stiffness," which is proportional to the degree of liver fibrosis, this technique holds great promise.

Prevalence and Predictors of Esophageal Varices in Patients With Primary Biliary Cirrhosis

Esophageal varices and bleeding are among the most feared complications of primary biliary cirrhosis (PBC). We aimed to determine the prevalence of esophageal varices in patients with PBC, to evaluate noninvasive markers of esophageal varices in this population, and to validate the results in an independent set of patients. Data were collected on all patients with PBC seen for the first time at the University of Florida (study group) and at Case Western Reserve University hospitals (cross-validation group) during 7 consecutive years. Logistic regression analysis was used to identify independent predictors of esophageal varices. The best cut-off values were calculated based on receiver operating characteristic curves. The diagnostic accuracy of the independent predictors of esophageal varices identified in the study group were retested in the cross-validation group. Of 210 patients with PBC seen at the University of Florida, 113 had an endoscopy and 49.6% (56 of 113) were found to have esophageal varices. After excluding 22 patients with a history of variceal bleeding, data on 91 patients were analyzed. Thirty-four patients had esophageal varices (37%). Multivariate analysis revealed that a platelet count of less than 140,000 (odds ratio, 7.6; 95% confidence interval, 1.6-37) and a Mayo risk score of 4.5 or greater (odds ratio, 10.6; 95% confidence interval, 1.8-62) were independent predictors of esophageal varices. The diagnostic accuracy of these predictors was confirmed in an independent set of patients. Among patients with PBC, a platelet count of less than 140,000 and/or a Mayo risk score of 4.5 or greater appears to identify those patients more likely to benefit from a screening endoscopy.

Review article: the pathophysiology and pharmacological treatment of portal hypertension.

The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.

Value of the Hepatic Venous Pressure Gradient to Monitor Drug Therapy for Portal Hypertension: A Meta-Analysis

The use of the hepatic venous pressure gradient (HVPG) to assess the efficacy of the pharmacological treatment of portal hypertension in cirrhosis is controversial. Our aim was to establish whether target HVPG reduction predicts variceal bleeding in cirrhotic patients receiving variceal bleeding prophylaxis. Data sources were MEDLINE, EMBASE, Cochrane Controlled Trials Register, citation lists, and abstracts (most recent search March 2006). Cohorts of patients on drug therapy from randomized and nonrandomized studies correlating variceal bleeding and HVPG change were used. Heterogeneity was explored by metaregression analysis. Ten studies totaling 595 patients undergoing two HVPG measurements were identified. The RR of bleeding was lower in patients achieving an overall (HVPG <or=12 mmHg or decrease >or=20%) (0.27, 95% CI 0.14-0.52), complete (HVPG <or=12 mmHg) (0.48, CI 0.28-0.81), or partial (HVPG decrease >or=20%) (0.41, CI 0.20-0.81) response, with significant heterogeneity. Regression analysis identified the interval between the HVPG measurements significantly associated with the RR of bleeding. Heterogeneity was no longer significant after exclusion of an outlier trial, which showed the longest interval to HVPG remeasurement and the lowest quality score. Even considering nonvaluable patients because of bleeding as HVPG responders, the RR of bleeding was lower in overall responders than in nonresponders (0.66, CI 0.51-0.86). Overall response was associated with lower liver-related mortality (RR 0.58, CI 0.37-0.91). Current evidence supports the validity of HVPG end points to monitor drug therapy efficacy for variceal bleeding prophylaxis. HVPG monitoring also provides valuable prognostic information.

Embolisation de varices stomiales par injection percutanée de colle biologique

In patients with cirrhosis and enterostomy, although bleeding stomal varices are rare, they can been severe and difficult to be treat. We report the first two cases of bleeding stomal varices treated by cyanoacrylate embolization, in patients with cirrhosis and colostomy. In each case, after pharmacological treatment of portal hypertension (propranolol) failed, embolization of the stomal varices by transdermal injection of biological glue effectively stopped the bleeding, without recurrence or side effects, after 8 and 16 months of follow-up. The embolization of stomal varices by biological glue is a safe, easy and efficient treatment for bleeding stomal varices.

Nitroflurbiprofen, a Nitric Oxide-Releasing Cyclooxygenase Inhibitor, Improves Cirrhotic Portal Hypertension in Rats

We studied whether administration of nitroflurbiprofen (HCT-1026), a cyclooxygenase inhibitor with nitric oxide (NO)-donating properties, modulates the increased intrahepatic vascular tone in portal hypertensive cirrhotic rats. In vivo hemodynamic measurements (n = 8/condition) and evaluation of the increased intrahepatic resistance by in situ perfusion (n = 5/condition) were performed in rats with thioacetamide-induced cirrhosis that received either nitroflurbiprofen (45 mg/kg), flurbiprofen (30 mg/kg, equimolar concentration to nitroflurbiprofen), or vehicle by intraperitoneal injection 24 hours and 1 hour prior to the measurements. Additionally, we evaluated the effect of acute administration of both drugs (250 micromol/L) on the intrahepatic vascular tone in the in situ perfused cirrhotic rat liver (endothelial dysfunction and hyperresponsiveness to methoxamine) and on hepatic stellate cell contraction in vitro. Typical systemic adverse effects of nonsteroidal anti-inflammatory drugs, such as gastrointestinal ulceration, renal insufficiency, and hepatotoxicity, were actively explored. In vivo, nitroflurbiprofen and flurbiprofen equally decreased portal pressure (8 +/- 0.8 and 8.4 +/- 0.1 mm Hg, respectively, vs 11.8 +/- 0.6 mm Hg) and reduced the total intrahepatic vascular resistance. Systemic hypotension was not aggravated in the different treatment groups (P = .291). In the perfused cirrhotic liver, both drugs improved endothelial dysfunction and hyperresponsiveness. This was associated with a decreased hepatic thromboxane A(2)-production and an increased intrahepatic nitrate/nitrite level. In vitro, nitroflurbiprofen, more than flurbiprofen, decreased hepatic stellate cells contraction. Flurbiprofen-treated rats showed severe gastrointestinal ulcerations (bleeding in 3/8 rats) and nefrotoxicity, which was not observed in nitroflurbiprofen-treated cirrhotic rats. Treatment with nitroflurbiprofen, an NO-releasing cyclooxygenase inhibitor, improves portal hypertension without major adverse effects in thioacetamide-induced cirrhotic rats by attenuating intrahepatic vascular resistance, endothelial dysfunction, and hepatic hyperreactivity to vasoconstrictors.

Pharmacologic treatment of portal hypertension in the prevention of community-acquired spontaneous bacterial peritonitis

Given that beta-blockers reduce the incidence of bacterial translocation in cirrhotic rats, the aim of this study was to compare the long-term incidence of spontaneous bacterial peritonitis in cirrhotic patients submitted to pharmacologic versus endoscopic treatment to prevent variceal rebleeding. Two hundred and thirty patients with variceal hemorrhage were included in two previous randomized trials performed to compare the efficacy of medication (nadolol plus isosorbide mononitrate, n=115) versus endoscopic treatment (n=115) with sclerotherapy or ligation for the prevention of rebleeding. The mean follow-up was 23+/-1.4 months. The characteristics of the patients and the number of patients on long-term prophylaxis with norfloxacin were similar in both groups. The incidence of spontaneous bacterial peritonitis was lower in the medication group (9 versus 14.7%, P=NS). The probability of spontaneous bacterial peritonitis was also lower in the medication group (6 versus 12% at 1 year, 22 versus 36% at 5 years; P=0.08), due to a significantly lower probability of community-acquired spontaneous bacterial peritonitis in this group (1 versus 10% at 1 year, 18 versus 32% at 5 years; P=0.02). Patients with no hemodynamic response to therapy had a significantly higher probability to develop community-acquired spontaneous bacterial peritonitis during follow-up than hemodynamic responders (P<0.03). Long-term probability of developing community-acquired spontaneous bacterial peritonitis is lower in patients submitted to pharmacologic treatment for preventing variceal rebleeding than in those submitted to endoscopic treatment. Long-term pharmacologic prophylaxis of variceal rebleeding contributes to the prevention of community-acquired spontaneous bacterial peritonitis.

Diagnostic invasif de l’hypertention portale au cours des hépatopathies chroniques: Étude critique de la mesure du gradient de pression porto-cave

Portal hypertension is defined by an increased pressure gradient between the portal vein and the inferior vena cava (N < 5 mmHg). The most commonly used technique to assess the severity of portal hypertension is the catheterization of one hepatic vein with measurement of pressures in a free position and in a wedged position using preferably a balloon catheter. The hepatic venous pressure gradient is calculated by the difference between both pressures. In most cirrhotic processes, venous pressure gradient gives a good evaluation of portal hypertension however, portal vein pressure can be higher than wedged hepatic venous pressure, particularly in presence of an increased pre-sinusoidal resistance. In such cases, a direct access to portal vein might be needed to assess the severity of portal hypertension. For an accurate interpretation of the hepatic venous pressure gradient, several strict criteria must be followed; otherwise the validity of measurements might be seriously questioned. Hepatic venous pressure gradient has been used as a prognostic marker of portal hypertension, particularly for the occurrence of bleeding from gastrophageal varices which almost never occur below a threshold value of 12 mmHg. However, the prognostic value of the hepatic venous pressure gradient for survival is still a controversial matter On the other hand, the use of hepatic venous pressure gradient has been proposed to monitor the pharmacological treatment of portal hypertension and it is generally accepted that reaching a same threshold value of 12 mmHg should almost completely abolish the risk of first or recurrent variceal bleeding. A large number of studies have also reported that a 20% hepatic venous pressure gradient decrease should be considered as a significant response to therapy, the risk of the first or recurrent bleeding being significantly reduced in responders. But again there are conflicting results.

Incidental esophageal varices

Incidental esophageal varices

Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis

In cirrhotic patients under pharmacologic treatment for portal hypertension, a reduction in hepatic venous pressure gradient (HVPG) of ≥20% of baseline or to ≤12 mm Hg markedly reduces the risk of variceal rebleeding. This study was aimed at evaluating whether these hemodynamic targets also prevent other complications of portal hypertension and improve long-term survival. One hundred five cirrhotic patients included in prospective trials for the prevention of variceal rebleeding were studied. Seventy-three of the patients had 2 separate HVPG measurements, at baseline and under pharmacologic therapy with propranolol ± isosorbide mononitrate. Patients were followed for up to 8 years. Survival and risk of developing portal hypertension-related complications were compared between responders and nonresponders. Twenty-eight patients showed a reduction of HVPG ≥20% of baseline or to ≤12 mm Hg (responders), and 45 patients were nonresponders. Nonresponders had a significantly greater risk of developing variceal rebleeding ( P = .013), ascites ( P = .025), spontaneous bacterial peritonitis ( P = .003), hepatorenal syndrome ( P = .026), and hepatic encephalopathy ( P = .024) than responders. Eight-year cumulative probability of survival was significantly lower in nonresponders than in responders (52% vs. 95%, respectively, P = .003). At multivariate analysis, being a nonresponder was independently associated with the risk of developing rebleeding, ascites, spontaneous bacterial peritonitis, and lower survival. In conclusion, in cirrhotic patients receiving pharmacologic treatment for prevention of variceal rebleeding, a decrease in HVPG ≥20% or to ≤12 mm Hg is associated with a marked reduction in the long-term risk of developing complications of portal hypertension and with improved survival. (H epatology 2003;37:902-908.)

The HVPG-response to pharmacological treatment of portal hypertension predicts prognosis and the risk of developing complications of cirrhosis

A reduction in HVPG >20% of baseline or to 20% or to 20% or to < 12 mmHg during longterm pharmacological treatment is associated with a marked reduction in the risk of developing complications of portal hypertension and with improved survival.

Pharmacologic treatment of portal hypertension: past, present, and future

Pharmacologic treatment of portal hypertension: past, present, and future

Pharmacologic treatment of portal hypertension contributes to preventcommunity-acquired spontaneous bacterial peritonitis (SBP)

Pharmacologic treatment of portal hypertension contributes to preventcommunity-acquired spontaneous bacterial peritonitis (SBP)

Mixed endothelin receptor antagonist, SB209670, decreases portal pressure in biliary cirrhotic rats in vivo by reducing portal venous system resistance

Background/Aims: This study aimed to evaluate the hemodynamic effects of endothelin-1 or mixed endothelin receptor antagonist, SB209670 in cirrhotic rats, and to elucidate the role of endothelin in cirrhotic portal hypertension. Methods: Secondary biliary cirrhosis was induced by bile duct ligation. Hemodynamics were studied using the radioactive microsphere technique. Results: Plasma and hepatic endothelin levels in cirrhotic rats were significantly higher than those in normal rats (plasma, 9.0±1.3 vs. 2.6±0.5 pg/ml, p<0.001; liver, 74.8±13.3 vs. 12.6±2.5 pg/g wet tissue, p<0.001). Intraportal administration of endothelin-1 (3 nmol/kg) progressively raised portal pressure without an initial transient reduction, which was observed in systemic arterial pressure, in both cirrhotic and normal rats. SB209670 (5.4 μmol/kg) reduced portal pressure in cirrhotic rats (−19±5%, p<0.01) without modifying systemic arterial pressure and renal blood flow, but not in normal rats. This reduction was associated with reduced portal venous system resistance (vehicle, 2.5±0.2 vs. SB209670, 1.7±0.1 mmHg·min·100 g bw/ml, p<0.01), but not with change in portal venous inflow and collateral blood flow. Conclusions: Mixed endothelin antagonist, SB209670, decreased portal pressure by reducing portal venous system resistance without modifying systemic arterial pressure and renal blood flow in cirrhotic rats. This result, together with the findings that plasma and hepatic endothelin levels were elevated in cirrhotic rats and that exogenous endothelin-1 increased portal pressure, provides further support for a role of endothelin in portal hypertension and suggests a potential use of mixed endothelin antagonist in the pharmacological treatment of portal hypertension.

Doppler evaluation of the effects of pharmacological treatment of portal hypertension

The splanchnic pharmacodynamic effects of the drugs used for the treatment of hemorrhagic complications of portal hypertension were poorly clarified until some years ago. The introduction of Doppler ultrasound provided a powerful tool to investigate such hemodynamic effects and brought new insights in this field. The present article reviews the pharmacodynamics of the substances used in the treatment of portal hypertension, with particular regard to the effects assessable by duplex Doppler ultrasonography.