Endoscopic, portographic, and hemodynamic evaluation of prolonged propranolol administration in pigs with experimental portal hypertension and esophageal varices

The effect of long-term propranolol administration on esophageal varices, portocollateral shunting, portal pressure, hepatosplanchnic hemodynamics, and liver function was studied in a pig model with experimentally induced prehepatic portal hypertension and esophageal varices. Five pigs were treated with 160 mg propranolol daily from week 5 to week 24 after portal-vein banding, and five pigs served as nontreated controls. Administration of propranolol caused an initial, significant reduction (20%) of portal venous pressure, followed by a gradual increase to levels not different from control pressures. In contrast, a marked reduction of the caliber of the coronary vein and size of the esophageal varices was noticed. Twenty weeks of propranolol treatment did not change liver blood flow or liver function. We conclude that the size of the varices rather than portal venous pressure depicts the effect of propranolol treatment and suggest that the beneficial effect of propranolol on variceal bleeding can be explained by a reduction in the wall tension of the varices, initiated and maintained by a diminution of splanchnic blood flow.     

Varizenblutung bei Patienten mit Leberzirrhose

In patients with cirrhosis, portal hypertension induces the development of portosystemic collaterals. Bleeding from these collateral vessels, however, only develops if the portosystemic pressure gradient is below 12 mmHg. Portal hypertension in cirrhosis is mediated by an increased intrahepatic resistance of the liver on the one hand and by an increase in the portal tributary blood flow on the other. Consequently, therapy can aim to reduce intrahepatic resistance or mesenteric blood flow (shunts, pharmacologic therapy) or can act locally on the source of bleeding itself (endoscopic therapy). Four aims can be defined: (1) inhibition of the development of varices, (2) prevention of the first bleeding episode when varices already exist, (3) therapy of the acute bleeding episode, and (4) prevention of recurrent bleeding.     

Long-term follow-up study of adult patients with non-cirrhotic obstruction of the portal system: comparison with cirrhotic patients.

Thirty-two patients with non-cirrhotic portal system obstruction and oesophageal varices of non-malignant etiology were recruited over 13 years. Diagnosis was based on the presence of oesophageal varices at endoscopy, minor alterations in liver function tests and liver histology, a low hepatic venous pressure gradient, and pertinent angiographic patterns. Twenty-three had portal vein thrombosis, nine had splenic vein thrombosis. Twenty-one had idiopathic portal vein obstruction, 11 had secondary obstruction. The outcome was compared with a group of 32 patients with cirrhosis and portal hypertension, matched for age, Child-Pugh class, previous history of gastrointestinal bleeding, and size of oesophageal varices. Patients with non-cirrhotic obstruction of the portal system were followed for up to 171 months (mean 94 months). During follow-up ten patients had gastrointestinal bleeding, and eight died (five of gastrointestinal bleeding). After 6 years of follow-up, the cumulative risk of gastrointestinal bleeding was 24%, the cumulative risk of death was 17%, and the cumulative risk of death from gastrointestinal bleeding was 14%. Cumulative probability of death by any cause and the probability of gastrointestinal bleeding were significantly lower in patients with non-cirrhotic obstruction of the portal system than in patients with cirrhosis comparable for liver function and portal hypertension (p = 0.04 for both). The cumulative probability of death by gastrointestinal bleeding was not significantly different. In conclusion, the prognosis for non-cirrhotic obstruction of the portal system is significantly better than for patients with cirrhosis with comparable levels of liver function impairment and severity of portal hypertension.     

The epidemiology and pathogenesis of gastrointestinal varices

Gastrointestinal varices are a consequence of portal hypertension that can occur in the setting of cirrhosis or extrahepatic portal vein obstruction. Increased intrahepatic vascular resistance, a hyperdynamic circulation, and increased flow through the portal and collateral venous system lead to persistently elevated portal pressures that result in angiogenesis and formation of collaterals between the portal and systemic circulation. Despite this physiological attempt at decompression, portal hypertension persists as collateral vessels have higher resistance than the normal liver. Variceal wall tension is the main factor that determines vessel rupture and bleeding occurs when tension in the wall exceeds the limit of elasticity of the vessel. Progressive distension leads to increasing resistance to flow and hemorrhage ensues when the limits of resistance to further dilation are surpassed. Gastroesophageal varices are present in 50% of patients with cirrhosis and progress in size at a rate of 8%-10% per year. Hemorrhage occurs at a rate of approximately 12% per year and large esophageal varices carry a higher risk of rupture. Gastric varices occur in 20% of patients with portal hypertension and bleed less frequently, but more severely. Cardiofundal varices have a complex vascular anatomy that is important to consider as it pertains to the effectiveness of strategies used for management. Ectopic varices make up 2%-5% of all variceal bleeding, occur more frequently in patients with extrahepatic portal hypertension, and their identification should prompt assessment of the intra-abdominal vasculature. Varices in the setting of splenic vein thrombosis should be considered a distinct entity owing to their disparate etiologic basis and treatment approach.     

3 Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding

Promoting the development of oesophageal varices and ascites, portal hypertension dominates the clinical course of cirrhosis. Varices appear in patients with portal pressure gradient above 10 mmHg and enlarge in 10–20% within 1–2 years of their detection. Bleeding occurs in patients with portal pressure gradient above 12 mmHg when the wall tension causes the rupture of varices, with an incidence of about 10% per year. Indicators of bleeding risk are portal pressure gradient, variceal pressure, large varices and liver dysfunction. Mortality per bleeding episode is 30–50%. Among survivors 60% will rebleed and 30% will die in the following year. The risk of rebleeding decreases in patients with spontaneous or treatment induced reduction of portal pressure gradinent or variceal pressure. Ascites develops in almost all patients along the course of the disease. Median survival after its appearance is less than 2 years. Less than 5% of cirrhotic patients die without ascites or without a previous bleeding. Thus portal hypertension is a major determinant of survival in cirrhosis.     

Modern management of portal hypertension

The development of portal hypertension plays a major role in the pathogenesis of many of the complications of chronic liver disease. In developed countries, most patients with portal hypertension have cirrhosis, and, in this condition, portal pressure is elevated as a result of both an increase in hepatic resistance to portal perfusion and increased mesenteric blood flow. Bleeding from oesophageal varices is a major cause of mortality in patients with significant portal hypertension. This review concentrates on the recognition, prevention and acute management of this life threatening complication of cirrhosis.     

门脉高压诊断现状及其治疗新进展

门脉高压是各种原因所致肝内血管阻力增大和门静脉血流量增加的结果,是肝硬化严重并发症(静脉曲张出血和顽固性腹水)的主要死亡原因,特别是在失代偿期肝硬化患者中,进行门脉高压早期评估、治疗及管理能够有效降低严重并发症发生率和患者病死率。目前测量肝静脉压力梯度是公认的评估门脉高压程度的金标准,近年来无创诊断评估手段层出不穷,但能够应用于临床的技术较少;针对门脉高压的治疗包括药物治疗、内镜治疗、微创介入、外科手术和肝移植等。本文就目前门脉高压的诊断及治疗新进展作一综述。     

Pathogenesis of Portal Hypertension: Extrahepatic Mechanisms

Chronic liver diseases, including hepatic cirrhosis, chronic hepatitis, alcoholic liver disease, and hepatocellular carcinoma, are one of the commonest causes of death and liver transplantation in adults worldwide. They are accompanied by profound disturbances that are not limited to the intrahepatic circulation, but involve also the splanchnic and systemic vascular beds. These hemodynamic disturbances are responsible for the development of portal hypertension, the most frequent and severe of cirrhosis. This syndrome is characterized by a pathological increase of blood pressure in the portal vein and concomitant increases in splanchnic blood flow and portosystemic collateral vessel formation. Increased blood flow in splanchnic organs draining into the portal vein augments in turn the portal venous inflow. Such increased portal venous inflow perpetuates and exacerbates portal pressure elevation and determines the formation of ascites during chronic liver disease. In addition, portosystemic collateral vessels include the gastroesophageal varices, which are particularly prone to rupture causing massive gastroesophageal bleeding. Collateral vessels are also responsible for other major consequences of chronic liver disease, including portosystemic encephalopathy and sepsis. Extrahepatic mechanisms are clearly of major importance for disease progression and aggravation of the portal hypertensive syndrome. Accordingly, most of the therapies currently used in portal hypertension do not act inside the liver but they actually target the increased splanchnic blood flow. This paper reviews the consequences of the splanchnic circulatory abnormalities in portal hypertension and the complex signals capable of increasing vasodilatation, hyporesponsiveness to vasoconstrictors and angiogenesis in the splanchnic vascular bed and the portosystemic collateral circulation in this pathological setting.     

Acute variceal bleeding: pharmacological treatment and primary/secondary prophylaxis

Variceal bleeding is one of the most severe complications of portal hypertension related to liver cirrhosis. Primary prophylaxis is considered mandatory in patients with cirrhosis and high-risk oesophageal varices, and once varices have bled, every effort should be made to arrest the haemorrhage and prevent further bleeding episodes. In acute variceal bleeding, vasoactive drugs that lower portal pressure should be started even before endoscopy, and should be maintained for up to 5 days. The choice of vasoactive drug should be made according to local resources. Terlipressin, somatostatin and octreotide can be used; vasopressin plus transdermal nitroglycerin may be used if no other drug is available. In variceal bleeding, antibiotic therapy is also mandatory. In primary and secondary prophylaxis, beta-blockers are the mainstay of therapy. In secondary prophylaxis (but not in primary prophylaxis) these drugs can be combined with organic nitrates.     

Bleeding portal-hypertensive gastropathy managed successfully by partial splenic embolization

The use of partial splenic embolization to decrease portal pressure and reduce gastric bleeding from portal-hypertensive gastropathy, a complication of liver cirrhosis, is described. A 62-year-old man with hepatic cirrhosis secondary to hepatitis C and documented portal hypertension was admitted with hypersplenism and bleeding esophageal varices. Endoscopic ligation successfully controlled acute bleeding, but blood loss continued over the next 45 days. Bleeding secondary to portal-hypertensive gastropathy was diagnosed endoscopically. The patient's poor surgical status precluded a portosystemic shunt procedure, so partial splenic embolization was performed radiologically by the injection of Gelfoam squares. Splenic volume decreased 50% following partial embolization. Over 3 weeks, the hemoglobin concentration increased from 8.5 g/dL to 9.8 g/dL, and the platelet count increased from 41,000 to 90,000/microL. Repeat endoscopy found no gastric bleeding 18 days post-procedure. Partial splenic embolization is a radiologic procedure which can be performed safely in patients too ill to undergo portosystemic shunt. This report documents its successful use to manage hypersplenism and reduce portal pressure in a cirrhotic patient with portal-hypertensive gastropathy and hypersplenism.     

Does the measurement of portal flow velocity have any value in the identification of patients with cirrhosis at risk of digestive bleeding?

Abstract: Upper gastrointestinal bleeding is a leading cause of death in patients with liver cirrhosis. In most cases haemorrhage originates from oesophageal varices or from congestive gastropathy, and the evaluation of the bleeding risk is based on oesophagogastroduodenoscopic data. The aim of this prospective study was to determine whether the measurement of portal flow velocity by Duplex-Doppler, compared with endoscopic data, can help in detecting patients with cirrhosis at risk of bleeding. One hundred and seventy-three patients underwent endoscopy to ascertain the size of the varices and the severity of congestive gastropathy. For each patient maximal portal flow velocity measurements were obtained. No difference in portal flow velocity was observed between patients with or without oesophageal varices or congestive gastropathy. During a 2-year observation period, 27 patients (15.6%) had at least one episode of acute digestive bleeding. Stepwise multiple logistic regression analysis demonstrated a correlation between oesophageal varices and congestive gastropathy endoscopic grading and the incidence of bleeding; only the former was entered into the final regression equation (p>0.001). No relationship between the max portal flow velocity value and incidence of bleeding was found. This study shows that portal flow velocity is unrelated to the degree of the endoscopic abnormalities in patients with liver cirrhosis and that it has no value in the identification of patients with cirrhosis at risk of upper gastrointestinal bleeding.     

What's new in portal hypertension?

Portal hypertension is defined as increased pressure in the portal venous system. The most common cause of portal hypertension is cirrhosis. In this setting, there is an increase in intrahepatic resistance leading to an increase in portal pressure. By increasing portal blood flow, splanchnic vasodilation further aggravates portal hypertension. New pathogenic pathways are being established which might result in new therapeutic strategies. The presence of varices at endoscopy and/or other abdominal portosystemic collaterals confirms the diagnosis of portal hypertension. The role of non‐invasive and imaging tests in the diagnosis and prognosis of portal hypertension has been clarified. Non‐selective beta‐blockers decrease both the risk of variceal haemorrhage and hepatic decompensation. Terlipressin, somatostatin or octreotide, in combination with early endoscopic therapy, are recommended for the treatment of acute variceal haemorrhage. Early Transjugular intrahepatic portosystemic shunt (TIPS) is effective as salvage therapy in acute variceal bleeding in selected patients and prevents rebleeding more effectively than endoscopic and medical therapy resulting in an increased survival.     

Appraisal of DSRS with SPGD for esophagogastric varices: a retrospective comparative study according to the underlying liver diseases

BACKGROUND/AIMS: The differences in long-term results of distal splenorenal shunt with splenopancreatic and gastric disconnection (DSRS with SPGD) for portal hypertension of different etiologies including non-cirrhotic portal hypertension have yet to be reported. The data are important to determine the indications and contraindications for this procedure. METHODOLOGY: Records of 54 patients of esophagogastric varices who survived 3 years or longer after DSRS with SPGD operation were reviewed. Patients were divided into three groups based on underlying liver disease; posthepatitic cirrhosis (HC) group, alcoholic cirrhosis (AC) group, and idiopathic portal hypertension (IPH) group. RESULTS: The only serious long-term complication of DSRS with SPGD was portal thrombosis in two patients in the IPH group. Postoperative bleeding occurred in two cases of each group; one in IPH group was the only variceal bleeding and others were bleeding from portal hypertensive gastropathy. Hepatocellular carcinoma (HCC) was developed in 28.6% patients in both the HC group and AC group. In all the cases, treatment for HCC was accomplished without aggravation of the varices. The cumulative survival rate was similar in the three groups, and no patient died of gastrointestinal bleeding. CONCLUSIONS: A favorable outcome was achieved by DSRS with SPGD operation both in the patients with cirrhosis or IPH. Underlying liver disease is not a factor when considering DSRS with SPGD for portal hypertension.     

Development of Gastroesophageal Varices and Risk of Variceal Bleeding in Patients With Cirrhosis

Abstract: We studied the relationships between portal pressure measured using the portal venous pressure gradient, the development of gastroesophageal varices, and the risk of variceal bleeding in 56 patients with cirrhosis. Portal pressure was higher in patients with varices than in those without (P>0.01), and 11 mmHg was the lowest portal pressure measured in the patients with varices. The size of the varices was not associated with the portal pressure. There was no difference in the value of portal pressure measurements for the patients with variceal bleeding and those without and there was no linear-relationship between the degree of portal hypertension and the rate of variceal bleeding. 12 mmHg was the lowest portal pressure measured in the patients with variceal bleeding. The size of the varices was related to the rate of variceal bleeding (P>0.05). We conclude that (a) a portal pressure of 11 mmHg is necessary for the formation of varices, (b) 12 mmHg of portal pressure is necessary for variceal bleeding to occur but the degree of portal hypertension has no predictive value for the risk of variceal bleeding, and (c) the size of the varices does not depend on the degree of portal hypertension but is associated with the risk of variceal bleeding.     

Long-term effects of oral propranolol on splanchnic and systemic haemodynamics in patients with cirrhosis and oesophageal varices

Splanchnic and systemic haemodynamics were measured in 24 patients with cirrhosis and oesophageal varices and no previous bleeding. The patients were randomized either to long-term treatment with propranolol (14 patients) or no active treatment (controls, 10 patients). Catheterization was performed again 1 year after randomization. After 1 year of treatment the hepatic venous pressure gradient had decreased in both the propranolol and control group (-16% versus -24% (NS), respectively). Hepatic blood flow decreased substantially in both groups but significantly more in the propranolol group (-39% versus -17% (p less than 0.05), respectively). Azygos blood flow was significantly reduced after 1 year in the propranolol group (-47%, n = 5 (p less than 0.05)), and no obvious effect was observed in the control group (-2%, n = 4). The cardiac index decreased significantly in the propranolol group but not in the control group (-20% versus -1% (p less than 0.05), respectively). Our results demonstrate that the splanchnic hyperdynamic condition observed in cirrhosis is in some of the patients partly reversible without pharmacologic treatment. No additional effect of propranolol was observed on portal pressure after 1 year of treatment with propranolol, whereas a decrease in azygos blood flow was observed only in the propranolol group. The beneficial effect of propranolol on the risk of bleeding from oesophageal varices may, therefore, mostly be due to a selective decrease in collateral blood flow and thereby variceal blood flow.     

Hepatic venous pressure gradient measurement: Time to learn!

Portal hypertension is a clinical syndrome defined by a pathological increase in portal pressure. The development of cirrhosis of the liver is characterized by clinical manifestations related to portal hypertension like esophageal varices, ascites, bleeding, and encephalopathy. Direct measurement of portal pressure is invasive, inconvenient, and clinically impractical. Currently, the most commonly used parameter is the Hepatic Venous Pressure Gradient (HVPG), i.e., the difference between the wedged (WHVP) and the free hepatic venous pressures. HVPG represents the gradient between pressures in the portal vein and the intra-abdominal portion of inferior vena cava. When blood flow in a hepatic vein is stopped by a wedged catheter, the proximal static column of blood transmits the pressure from the preceding communicated vascular territory (hepatic sinusoids) to the catheter. Thus, WHVP reflects hepatic sinusoidal pressure and not the portal pressure itself. In the normal liver, due to pressure equilibration through interconnected sinusoids, wedged pressure is slightly lower than portal pressure, though this difference is clinically insignificant. In liver cirrhosis, the static column created by balloon inflation cannot be decompressed at the sinusoidal level due to disruption of the normal intersinusoidal communications; therefore, WHVP gives an accurate estimation of portal pressure in cirrhosis. The normal HVPG value is between 1 to 5 mmHg. Pressure higher than this defines the presence of portal hypertension, regardless of clinical evidence. HVPG >/= 10 mmHg (termed clinically significant portal hypertension) is predictive of the development of complications of cirrhosis, including death. HVPG above 12 mmHg is the threshold pressure for variceal rupture. The main advantages of HVPG are its simplicity, reproducibility, and safety. This review summarizes the technique of the HVPG measurement.     

Cruveilhier-Baumgarten syndrome: An efficient spontaneous portosystemic collateral preventing oesophageal varices bleeding

The protective role of large spontaeous portosystemic shunts in oesophageal varices bleeding due to portal hypertension in liver cirrhosis is still debated. A series of 20 consecutive patients with haemodynamically efficient collaterals involving the para-umbilical-epigastric venous route (evaluated by Echo-Doppler flowmetry) is reported. All patients presented absent or mild oesophageal varices at endoscopy. During a mean follow-up period of 23.5 months, no patient developed large varices or experienced variceal bleeding. Hepatic encephalopathy was present in 35% of patients. Haemodynamically efficient spontaneous portosystemic shunts may protect cirrhotic patients from the risk of oesophageal varices forming and bleeding. The diversion of large amounts of blood from portal to systemic circulation correlates with the higher trend of hepatic encephalopathy in these patients.     

Endoscopic management of acute esophageal variceal bleeding

Esophageal varices develop in the setting of portal hypertension, most commonly caused by cirrhosis. Esophagogastroduodenoscopy is considered the gold standard for both diagnosis and treatment of acute variceal bleeding. In this review, we highlight the management of both acute and refractory bleeding from esophageal varices, with an emphasis on endoscopic therapies, including injection sclerotherapy, band ligation, and esophageal stent placement.     

Endoscopic measurement of gastric mucosal blood flow with special reference to the effect of sclerotherapy in patients with liver cirrhosis

Gastric mucosal blood flow plays an important role as a background factor in the pathogenesis of acute gastric mucosal lesion. In this study, endoscopic measurement of regional gastric mucosal blood flow was performed on 41 patients with esophageal varices due to liver cirrhosis to ascertain the possible relations of this parameter to liver function, portal pressure, and acute gastric mucosal lesion. The effect of sclerotherapy and of esophageal transection on gastric mucosal blood flow were also investigated. Regional gastric mucosal blood flow in either the antrum or the corpus was significantly decreased in these patients, compared with normal controls. There was also a significant difference in gastric mucosal blood flow between two subgroups of patients, one with gastric mucosal lesions and the other without these lesions. Sclerosing therapy for esophageal varices tended to affect this parameter. Gastric mucosal blood flow had no significant correlation with portal pressure.     

Somatostatin plus isosorbide 5-mononitrate versus somatostatin in the control of acute gastro-oesophageal variceal bleeding: a double blind, randomised, placebo controlled clinical trial

BACKGROUND: Variceal bleeding is a severe complication of portal hypertension. Somatostatin reduces portal pressure by decreasing splanchnic blood flow, and nitrates by diminishing intrahepatic resistance. Experimental studies have shown that the combination of somatostatin and nitrates has an additive effect in decreasing portal pressure. AIM: To compare the therapeutic efficacy of either intravenous infusion of somatostatin plus oral isosorbide 5-mononitrate or somatostatin alone in gastro-oesophageal variceal bleeding associated with liver cirrhosis. METHODS: A unicentre, double blind, placebo controlled, clinical trial was conducted. Sixty patients bleeding from oesophageal or gastric varices were randomised to receive intravenous infusion of somatostatin (250 microg/hour) plus oral isosorbide 5-mononitrate (40 mg/12 hours) (group I) or somatostatin infusion plus placebo (group II) for 72 hours. RESULTS: The two groups of patients had similar clinical, endoscopic, and haematological characteristics. Control of bleeding was achieved in 18 out of 30 patients (60%) in group I and 26 out of 30 patients (87%) in group II (p<0.05). There was no significant difference in mean transfusion requirements between the two groups: 2.6 (2.2) v 1.8 (1.6) respectively; means (SD). Mortality and side effects were similar in the two groups, but development of ascites was higher in group I (30%) than in group II (7%) (p<0.05). CONCLUSION: In cirrhotic patients with acute gastro-oesophageal variceal bleeding, addition of isosorbide 5-mononitrate to somatostatin does not improve therapeutic efficacy, induces more adverse effects, and should not be used.