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Unlabelled: Recent studies have shown that liver cirrhosis (LC) behaves as an acquired hypercoagulable state with increased thrombotic risk. This is why anticoagulation therapy (AT) is now frequently used in these patients. Variceal bleeding is a severe complication of LC. It is unknown whether AT may impact the outcome of bleeding in these patients. Fifty-two patients on AT with upper gastrointestinal bleeding (UGIB) were evaluated. Portal vein thrombosis (PVT) and different cardiovascular disorders (CVDs) were the indication for AT in 14 and 38 patients, respectively. Overall, 104 patients with LC and UGIB not under AT matched for severity of LC, age, sex, source of bleeding, and Sequential Organ Failure Assessment (SOFA) score served as controls. UGIB was attributed to portal hypertension (PH) in 99 (63%) patients and peptic/vascular lesions in 57 (37%). Twenty-six (17%) patients experienced 5-day failure; SOFA, source of UGIB, and PVT, but not AT, were independent predictors of 5-day failure. In addition, independent predictors of 6-week mortality, which was observed in 26 (11%) patients, were SOFA, Charlson Comorbidity index, and use of AT for a CVD. There were no differences between patients with/without AT in needs for rescue therapies, intensive care unit admission, transfusions, and hospital stay., Conclusions: Factors that impact the outcome of UGIB in patients under AT are degree of multiorgan failure and comorbidity, but not AT itself., (© 2015 by the American Association for the Study of Liver Diseases.)

Background & Aims: Myeloproliferative neoplasms are the most common aetiological cause of splanchnic vein thrombosis (SVT). In these patients, the JAK2V617F mutation has facilitated the diagnosis of an underlying myeloproliferative neoplasm (MPN). Recently, somatic mutations of the calreticulin (CALR) gene have been identified in MPN patients lacking the JAK2 mutation. The aim of the present study was to ascertain whether CALR mutations could also play a role in the diagnosis of masked MPN in SVT., Methods: We included 209 patients with SVT (140 with PVT and 69 with Budd-Chiari syndrome) who had a complete aetiological diagnostic work-out. They were investigated for CALR mutations., Results: CALR mutations were found in 4 of the 209 patients (1.9%). They represented 5.4% of patients with an underlying MPN of whom all had already been diagnosed with a MPN using conventional criteria including bone marrow biopsy findings., Conclusions: In the screening of underlying MPNs in patients with SVT, given its high frequency in these disorders, the JAK2 mutation must be evaluated first and, if negative, CALR mutations should also be investigated. This approach would increase the diagnostic yield of masked MPNs by reducing the need for additional studies., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Idiopathic portal hypertension (IPH) is a rare cause of intrahepatic portal hypertension. Data on natural history and prognosis of IPH are limited. We sought to describe the complications and long-tem outcome of IPH by retrospectively studying 69 biopsy-proven cases of IPH. Mean duration of follow-up was 6.7 ± 4.6 years. All patients had evidence of portal hypertension (PH) at diagnosis, and 42% were symptomatic. Variceal bleeding (VB) was the most common manifestation. In those without bleeding at diagnosis, 74% had varices at first endoscopy. In those with large varices, the 1-year probability of first bleeding despite primary prophylaxis was 9%. The 1-year probability of rebleeding was 22%. Ascites and hepatic encephalopathy was documented in 26% and 7% of patients, respectively, at least once during the clinical course. The 1-year probability of developing portal vein thrombosis (PVT) was 9%, and 53% of patients receiving anticoagulation achieved recanalization. Human immunodeficiency virus (HIV) infection and VB at diagnosis were the independent predictors of PVT. Seven patients died (6 as a result of an IPH-related cause) and 2 were transplanted. Probability of liver transplantation-free survival was 82% at 10 years. Presence of a severe associated disorder and ascites as a presenting symptom were associated with poor survival., Conclusion: Variceal bleeding is a major complication of IPH. Using, in IPH patients, the same management approach for PH as in cirrhosis is safe and maintains a low incidence of first bleeding and rebleeding in IPH patients. PVT is a frequent complication, particularly in those with HIV infection. Despite several complications, overall survival of patients with IPH is considerably good., (© 2014 by the American Association for the Study of Liver Diseases.)

According to their location, gastric varices (GV) are classified as gastroesophageal varices and isolated gastric varices. This review will mainly focus on those GV located in the fundus of the stomach (isolated gastric varices 1 and gastroesophageal varices 2). The 1-year risk of GV bleeding has been reported to be around 10%-16%. Size of GV, presence of red signs, and the degree of liver dysfunction are independent predictors of bleeding. Limited data suggest that tissue adhesives, mainly cyanoacrylate (CA), may be effective and better than propranolol in preventing bleeding from GV. General management of acute GV bleeding must be similar to that of esophageal variceal bleeding, including prophylactic antibiotics, a careful replacement of volemia, and early administration of vasoactive drugs. Small sample-sized randomized controlled trials have shown that tissue adhesives are the therapy of choice for acute GV bleeding. In treatment failures, transjugular intrahepatic portosystemic shunt (TIPS) is considered the treatment of choice. After initial hemostasis, repeated sessions with CA injections along with nonselective beta-blockers are recommended as secondary prophylaxis; whether CA is superior to TIPS in this scenario is not completely clear. Balloon-occluded retrograde transvenous obliteration (BRTO) has been introduced as a new method to treat GV. BRTO is also effective and has the potential benefit of increasing portal hepatic blood flow and therefore may be an alternative for patients who may not tolerate TIPS. However, BRTO obliterates spontaneous portosystemic shunts, potentially aggravating portal hypertension and its related complications. The role of BRTO in the management of acute GV bleeding is promising but merits further evaluation., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Variceal bleeding is one of the commonest and most severe complications of liver cirrhosis. Even with the current best medical care, mortality from variceal bleeding is still around 20%. When cirrhosis is diagnosed, varices are present in about 30-40% of compensated patients and in 60% of those who present with ascites. Once varices have been diagnosed, the overall incidence of variceal bleeding is in the order of 25% at two years. Variceal size is the most useful predictor for variceal bleeding, other predictors are severity of liver dysfunction (Child-Pugh classification) and the presence of red wale marks on the variceal wall. The current consensus is that every cirrhotic patient should be endoscopically screened for varices at the time of diagnosis to detect those requiring prophylactic treatment. Non-selective beta-adrenergic blockers (NSBB) and endoscopic band ligation (EBL) have been shown effective in the prevention of first variceal bleeding. The current recommendation for treating acute variceal bleeding is to start vasoactive drug therapy early (ideally during the transferral or to arrival to hospital, even if active bleeding is only suspected) and performing EBL. Once bleeding is controlled, combination therapy with NSBB + EBL should be used to prevent rebleeding. In patients at high risk of treatment failure despite of using this approach, an early covered-TIPS within 72 h (ideally 24 h) should be considered. Data on management of gastric variceal bleeding is limited. No clear recommendation for primary prophylaxis can be done. In acute cardiofundal variceal bleeding, vasoactive agents together with cyanoacrylate (CA) injection seem to be the treatment of choice. Further CA injections and/or NSBB may be used to prevent rebleeding. TIPS or Balloon-occluded retrograde transvenous obliteration when TIPS is contraindicated may be used as a rescue therapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background & Aims: High oxidative stress plays a major role in increasing hepatic vascular resistance in cirrhosis, by facilitating liver fibrosis and by increasing hepatic vascular tone. This study is aimed at investigating whether the use of the novel isoform of recombinant human manganese superoxide dismutase (rMnSOD) could be a new therapeutic strategy to reduce oxidative stress and portal hypertension in cirrhotic rats., Methods: In CCl(4)- and BDL-cirrhotic rats treated with rMnSOD (i.p. 15 μg/kg/day) or its vehicle for 7 days, mean arterial pressure (MAP), portal pressure (PP) and portal blood flow (PBF) or small mesenteric arterial flow (SMABF) were measured. In addition, in CCl(4)-cirrhotic rats, we evaluated the hepatic vasodilatory response to acetylcholine, liver fibrosis with Sirius red staining and hepatic stellate cell activation by α-smooth muscle actin (α-SMA) protein expression., Results: rMnSOD treatment significantly reduced PP either in CCl(4)- or BDL-cirrhotic rats without significant changes in splanchnic blood flow, suggesting a reduction in hepatic vascular resistance. MAP was not modified. Reduction in PP was associated with a significant reduction in liver fibrosis, and α-SMA protein expression as well as with improved vasodilatory response to acetylcholine., Conclusions: Chronic rMnSOD administration to cirrhotic rats reduces portal pressure by reducing hepatic vascular resistance without deleterious effects on systemic hemodynamics, suggesting that it might constitute a new antioxidant to be considered as additional therapy for treating portal hypertension in cirrhosis., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: In a recent randomized international clinical trial (RCT) in high-risk cirrhotic patients with acute variceal bleeding, the early use of transjugular intrahepatic portosystemic shunt (TIPS) was associated with marked and significant reductions in both treatment failure and mortality. The aim of this study was to confirm these results in clinical practice in the same centers of the RCT study., Methods: We retrospectively reviewed patients admitted for acute variceal bleeding and high risk of treatment failure (Child C <14 or Child B plus active bleeding), treated with early-TIPS (n=45) or drugs+endoscopic therapy (ET) (n=30)., Results: Patients treated with early-TIPS had a much lower incidence of failure to control bleeding or rebleeding than patients receiving drug+ET (3 vs. 15; p <0.001). The 1-year actuarial probability of remaining free of this composite end point was 93% vs. 53% (p <0.001). The same was observed in mortality (1-year actuarial survival was 86% vs. 70% respectively; p=0.056). Actuarial curves of failure to control bleeding+rebleeding and of survival were well within the confidence intervals of those observed in the RCT., Conclusions: This study supports the early use of TIPS in patients with cirrhosis and a high-risk variceal bleeding., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. However, the influence of TIPS on patient survival and factors that predict the outcome of TIPS in BCS patients remain unknown., Methods: One hundred twenty-four consecutive BCS patients treated with TIPS in 6 European centers between July 1993 and March 2006 were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation., Results: Prior to treatment with TIPS, BCS patients had a high Model of End Stage Liver Disease and high Rotterdam BCS prognostic index (98% of patients at intermediate or high risk) indicating severity of liver dysfunction. However, 1- and 5-year OLT-free survival were 88% and 78%, respectively. In the high-risk patients, 5-year OLT-free survival was much better than that estimated by the Rotterdam BCS index (71% vs 42%, respectively). In the whole population, bilirubin, age, and international normalized ratio for prothrombin time independently predicted 1-year OLT-free survival. A prognostic score with a good discriminative capacity (area under the curve, 0.86) was developed from these variables. Seven out of 8 patients with a score >7 died or underwent transplantation vs 5 out of 114 patients with a score <7., Conclusions: Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival. Furthermore, we identified a small subgroup of BCS patients with poor prognosis despite TIPS who might benefit from early OLT.

Background/aims: Tetrahydrobiopterin is an essential cofactor for NOS enzymes to synthesize NO. It has been suggested that reduced intrahepatic tetrahydrobiopterin decreases intrahepatic NO and contributes to increase hepatic vascular resistance and portal pressure in cirrhosis. The main aim of the study was to evaluate the effect of tetrahydrobiopterin supplementation in portal pressure in CCl4 cirrhotic rats., Methods: Cirrhotic rats received vehicle or tetrahydrobiopterin (10mg/kg/day i.p.) for 3 days. Hepatic and systemic hemodynamics and hepatic tetrahydrobiopterin, NOS activity and cGMP levels were measured. In addition, hepatic and systemic hemodynamics were evaluated in normal rats in which tetrahydrobiopterin deficiency was induced by administrating 2,4-diamino-6-hydroxy-pyrimidine (DAHP) for 8h., Results: In cirrhotic rats, tetrahydrobiopterin administration increased liver NOS activity and cGMP levels and markedly and significantly reduced portal pressure. Amelioration of portal hypertension was associated with a normalization of arterial pressure. In normal rats DAHP decreased hepatic tetrahydrobiopterin and NOS activity and increased hepatic vascular tone. These effects of DAHP administration were corrected by tetrahydrobiopterin supplementation., Conclusions: The present study shows that tetrahydrobiopterin markedly reduces portal hypertension and improves systemic hemodynamics in cirrhotic rats. These data support the concept that tetrahydrobiopterin supplementation may represent a new therapeutic strategy for portal hypertension.

Noncirrhotic, nontumoral portal vein thrombosis (PVT) is the second most-frequent cause of portal hypertension in the world. General thrombophilic factors can be identified in approximately 60% of patients. PVT may manifest as an acute process. However, the acute episode more frequently is asymptomatic or paucisymptomatic and portal vein thrombosis is misdiagnosed until the development of complications secondary to portal hypertension, such as variceal bleeding or portal biliopathy. Although no randomized controlled trials have been performed, after the diagnosis of acute PVT early initiation of anticoagulation (within 30 days of the onset of symptoms) is recommended to achieve recanalization. In patients with portal cavernoma, anticoagulation is aimed to prevent the progression and recurrence of thrombosis. Because of the lack of data in this specific population, variceal bleeding is managed as in cirrhotic patients. Ursodeoxycholic acid has been proposed empirically for the treatment of patients with symptomatic portal biliopathy. Choledocholithiasis might be present, complicating a bile duct stenosis. Accordingly, an endoscopic retrograde cholangiopancreatography with sphincterotomy, extraction with balloon catheter, and stent placement is indicated. Mortality among patients with PVT is low (5-year mortality rate of 5 to 10%) and is mainly related to associated diseases rather than to complications of portal hypertension.

Portal hypertension is a major cause of morbidity and mortality in liver cirrhosis. This article provides a background on the most important aspects of the evaluation of portal hypertension in patients with chronic liver diseases, with special attention to the measurement of portal pressure by hepatic vein catheterization. The rationale, technique, applications, costs, and limitations of measurements of the hepatic venous pressure gradient are thoroughly reviewed. Emerging, noninvasive methodologies for the evaluation of the patient with portal hypertension are also discussed.

In cirrhosis, intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension. Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH4) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis. Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl4 cirrhosis. Thereafter, rats were treated with tetrahydrobiopterin, and eNOS activity, NO bioavailability, assessed with a functional assay, and the vasodilator response to acetylcholine (endothelial function) were evaluated. Livers with cirrhosis showed reduced BH4 levels and decreased GTP-cyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine. Tetrahydrobiopterin supplementation increased BH4 hepatic levels and eNOS activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis. In conclusion, the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the eNOS cofactor, tetrahydrobiopterin. Tetrahydrobiopterin supplementation improved the endothelial dysfunction of cirrhotic livers.

The evidence that endoscopic band ligation (EBL) has greater efficacy and fewer side effects than endoscopic injection sclerotherapy has renewed interest in endoscopic treatments for portal hypertension. The introduction of multishot band devices, which allow the placement of 5-10 bands at a time, has made the technique much easier to perform, avoiding the use of overtubes and their related complications. EBL sessions are usually repeated at 2 week intervals until varices are obliterated, which is achieved in about 90% of patients after 2-4 sessions. Variceal recurrence is frequent, with 20-75% of patients requiring repeated EBL sessions. According to current evidence, nonselective beta-blockers are the preferred treatment option for prevention of a first variceal bleed, whereas EBL should be reserved for patients with contraindications or intolerance to beta-blockers. Nonselective beta-blockers, probably in association with the vasodilator isosorbide mononitrate, and EBL are good treatment options to prevent recurrent variceal rebleeding. The efficacy of EBL might be increased by combining it with beta-blocker therapy. Patients who are intolerant, have contraindications or bled while receiving primary prophylaxis with beta-blockers must be treated with EBL. In the latter situation, EBL should be added to rather than replace beta-blocker therapy. EBL, in combination with vasoactive drugs, is the recommended form of therapy for acute esophageal variceal bleeding; however, endoscopic injection sclerotherapy can be used in the acute setting if EBL is technically difficult.

Unlabelled: Concanavalin-A (Con-A)-induced hepatitis is an experimental model of human autoimmune hepatitis characterized by leukocyte activation and infiltration of the liver. The aim of the present study was to evaluate the role of P-selectin on leukocyte-endothelial interactions within the hepatic microvasculature in response to Con-A., Methods: The study was performed in P-selectin-deficient mice and wild-type mice pretreated with anti-P-selectin blocking monoclonal antibody (mAb) or vehicle. After 2 h of Con-A (20 mg/kg i.v.) or PBS administration, leukocyte rolling and adhesion and the index of sinusoidal perfusion were evaluated using the intravital microscopy technique in the liver. Apoptosis was determined by flow cytometry analysis of caspase-3 activity assayed on freshly isolated hepatocytes., Results: Con-A induced a significant increase in leukocyte rolling, mainly located at the central venule (2.1+/-0.4 vs 0.6+/-0.2 cells/min in wild-type mice treated with vehicle) and less marked, but still significant, in portal venules. This was associated with a significant increase in leukocyte adhesion. In P-selectin-deficient mice treated with Con-A, leukocyte rolling in portal and central venules was markedly reduced. However, leukocyte adhesion was only partially attenuated. A few sinusoids were perfused in wild-type mice treated with Con-A (26%). The percentage of perfused sinusoids was significantly higher in P-selectin-deficient mice (45%; P<0.05 vs wild-type). Similar effects were noted after the simultaneous injection of Con-A and anti-P-selecting mAb in wild-type mice. After Con-A treatment, apoptosis was markedly reduced in isolated hepatocytes of P-selectin-deficent mice (37+/-7% vs 75+/-5% in wild type)., Conclusion: The results of this intravital microscopy study clearly demonstrate that P-selectin is involved in the initial leukocyte rolling that leads to the development of Con-A-induced liver injury.

Patients suspected of having portal hypertension (either by clinical history, physical examination, or previous diagnosis) should undergo ultrasonography and upper gastrointestinal endoscopy. Ultrasonography, preferably using the duplex technique, can disclose the patency of the portal venous system, the presence of signs of portal hypertension (splenomegaly, portocollateral vessels, repermeabilization of the umbilical vein, and so forth) and provide additional information about liver, biliary, or pancreatic diseases that may be the cause of portal hypertension. Endoscopy can assess the presence and size of gastroesophageal varices, the appearance of the variceal wall, and the presence and severity of portal hypertensive gastropathy. Patients showing a patent portal vein should have hepatic vein catheterization to evaluate the presence of presinusoidal, sinusoidal, or postsinusoidal portal hypertension. Patients in whom presinusoidal portal hypertension is suspected (those having esophageal varices with an HVPG below 10 mm Hg) should have liver biopsy and percutaneous transhepatic measurement of portal pressure. In sinusoidal portal hypertension, the results of endoscopy and HVPG measurement are decisive for the therapeutic management of the patients. The authors' results indicate that, before starting prophylactic therapy with beta-blockers, all patients should undergo at least an hepatic vein catheterization to assess HVPG; it would be preferable to have a variceal pressure measurement also. These measurements must be repeated 3 to 4 weeks after the final dose of therapy has been reached to assess the risk of variceal bleeding or rebleeding.

Microvascular impairment observed during reperfusion following ischemia (IR) is a major determinant of the development of liver injury. Previous studies have shown that hyper-responsiveness to endothelin-1 (ET-1) contributes to microvascular dysfunction following a primarily inflammatory stress induced by endotoxin. The present study investigates whether a similar hypercontractile response to ET-1 occurs in the hepatic portal system of IR rats. Pentobarbital-anesthetized Sprague-Dawley rats underwent liver ischemia of the left and medial lobes for 60 min (IR: n = 8) or a sham operation (n = 8). Six hours after reperfusion, the liver was isolated and perfused through the portal vein. Baseline portal pressure (Pp), portal flow (Qp), and sinusoidal diameter (Ds) were measured before and 3 and 10 min after adding ET-1 (1 nM). In baseline, IR livers had a significantly greater Pp, portal resistance, and Ds than sham. ET-1 significantly increased Pp and portal resistance and significantly decreased Qp and Ds in IR and sham rats. However, these effects were significantly greater in IR. The results of the present study demonstrate that IR increases the porto-hepatic contractile response to ET-1, which may further sensitize the portal circulation to elevated ET-1 and may be a prominent contributor to the development of microvascular impairment following IR.

Background: Sclerotherapy has been widely recommended as initial treatment for prevention of variceal rebleeding. The present study was aimed at comparing the efficacy of endoscopic sclerotherapy and long-term administration of propranolol in the prevention of rebleeding and long-term survival in patients who had bled from varices., Methods: One hundred sixteen consecutive cirrhotic patients admitted because of variceal bleeding were randomly allocated to either continuous administration of propranolol to reduce the resting heart rate by 25% (58 patients) or weekly intravariceal sclerotherapy sessions using 5% ethanolamide oleate until varices disappeared (58 patients). Results were analyzed on an intention-to-treat basis., Results: Rebleeding occurred in 37 patients of the propranolol group and in 26 patients of the sclerotherapy group (RR = 1.45; 95% CI, 1.03-2.03). The actuarial probability of rebleeding was lower in the sclerotherapy group (P = 0.02). No differences were found in rebleeding index, hospitalization requirements, survival, and causes of death. Complications were significantly more frequent and severe in the sclerotherapy group., Conclusions: Despite the higher efficacy of sclerotherapy decreasing the probability of rebleeding when compared with propranolol, no beneficial effects were observed on other parameters also reflecting the efficacy of therapy. Moreover, complications of sclerotherapy were more frequent and severe than those of propranolol, which probably shall restrict the use of long-term elective sclerotherapy.

Twenty five patients with acute liver failure were measured for hepatic venous pressure gradient as an index of portal pressure during the course of a transjugular liver biopsy. Hepatic venous pressure gradient ranged from 4 to 24.5 mm Hg with a mean of 12.8 (5.3) mm Hg (normal values less than 5 mm Hg). All patients but one had increased portal pressure gradient. Portal hypertension correlated with the degree of architectural distortion of the liver, as suggested by a direct correlation between hepatic venous pressure gradient and the area of reticulin collapse, evaluated by means of a morphometric analysis on Sirius red stained liver slides (r = 0.43, p less than 0.05). Hepatic venous pressure gradient was significantly higher in patients with ascites (15.1 (5) mm Hg, n = 15) or renal failure (14.4 (5.3) mm Hg, n = 16) than in those without (9.3 (3.4) mm Hg and 10.1 (4) mm Hg, respectively; p less than 0.05). Portal hypertension was associated with systemic vasodilation and a hyperkinetic circulatory state, with decreased arterial pressure, and peripheral resistance and increased cardiac output.

This study was aimed at investigating the effects of propranolol on esophageal variceal pressure in patients with portal hypertension. Variceal pressure was measured at endoscopy using a miniature pressure-sensitive gauge in 20 patients with portal hypertension. Measurements were obtained under baseline conditions and 20 min after double-blind administration of propranolol (0.15 mg/kg; n = 10) or an identical amount of placebo (normal saline, 0.3 ml/kg; n = 10). Under baseline conditions, variceal pressure was similar in propranolol and placebo groups (14.1 +/- 5 mm Hg vs. 14.9 +/- 6.6 mm Hg, respectively; not significant). Placebo had no significant effect on variceal pressure (baseline = 14.9 +/- 6.6 mm Hg; placebo = 15.5 +/- 6.6 mm Hg; not significant), and values after placebo administration were closely correlated with baseline values (r = 0.98; y = 1.1 + 0.97 x; p less than 0.0001). In contrast, propranolol caused a significant decrease in the pressure of esophageal varices (from 14.1 +/- 5 mm Hg to 11.3 +/- 4.4 mm Hg; p less than 0.0002). No significant changes in the size of esophageal varices were observed after propranolol or placebo administration. This study shows (a) the endoscopic pressure-gauge technique has a low variability and may be used to assess acute drug-induced changes in variceal pressure; and (b) propranolol causes significant decreases in variceal pressure in patients with portal hypertension and esophageal varices.

This study investigated whether oral doses of isosorbide-5-mononitrate, a preferential venous dilator that decreases portal pressure, could enhance the effects of propranolol on portal hypertension. Taking part in the study were 28 patients with cirrhosis and portal hypertension. Twenty patients (group 1) had hemodynamic measurements in baseline conditions after beta-blockade by intravenous administration of propranolol and after receiving oral doses of isosorbide-5-mononitrate. The remaining eight patients (group 2) were given oral isosorbide-5-mononitrate while receiving chronic propranolol therapy. In group 1, propranolol significantly reduced portal pressure (estimated as the gradient between wedged and free hepatic venous pressures) from 21.5 +/- 3.9 to 18.6 +/- 4.2 mm Hg (-13.7%, p less than 0.001), azygos blood flow (-38%, p less than 0.001), hepatic blood flow (-12.8%, p less than 0.05), cardiac output (-24.5%, p less than 0.001) and heart rate (-18.4%, p less than 0.001) without significant changes in mean arterial pressure. Addition of oral isosorbide-5-mononitrate caused a further and marked fall in portal pressure (to 15.7 +/- 3.1 mm Hg, p less than 0.001), without additional changes in azygos blood flow but with significant additional reductions in hepatic blood flow (-15.5%, p less than 0.05), cardiac output (-11.5%, p less than 0.001) and mean arterial pressure (-22%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Portal hypertension is a frequent syndrome characterized by a chronic increase in portal venous pressure and by the formation of portal-systemic collaterals. Its main consequence is massive bleeding from ruptured esophageal and gastric varices. Bleeding is promoted by increased portal and variceal pressure, and is favored by dilatation of the varices. The evaluation of the portal hypertensive patient should include the assessment of portal vein patency by ultrasonography, endoscopic evaluation of the presence, size, and extent of esophageal varices, and hemodynamic studies with measurements of portal pressure and of portal-collateral blood flow. The preferred techniques are hepatic vein catheterization and measurement of azygos blood flow. Endoscopic measurements of variceal pressure and estimations of portal blood velocity by the Doppler technique have recently been introduced, but are still research procedures. Acute variceal hemorrhage should be treated under intensive care. Specific therapy to arrest variceal bleeding includes balloon tamponade, vasopressin, somatostatin, sclerotherapy, and emergency surgery. Treatment of portal hypertension is aimed at preventing variceal hemorrhage and bleeding-related deaths. Pharmacologic prophylaxis is based on the use of drugs that cause a sustained reduction in portal pressure; most studies have used propranolol. Surgery and endoscopic sclerotherapy can also be used to prevent rebleeding.