Portal hypertension: A surgical hepatologist's view of current management

Current strategies for management of acute esophageal variceal bleeding and for long-term treatment after an episode of variceal bleeding are outlined. Acute variceal bleeding is best managed by means of endoscopic therapy (sclerotherapy, band ligation, or "superglue"), whereas the role of pharmacologic agents remains controversial. In cases of failure of endoscopic therapy, a transjugular intrahepatic portosystemic shunt (TIPS) procedure, an emergency shunt, or a transection operation should be performed. Patients who experience an acute variceal bleeding episode require long-term management to prevent recurrent bleeding. Endoscopic treatment is preferred using either sclerotherapy or banding. The principal alternative is long-term pharmacologic therapy with beta-adrenergic receptor blocking agents. Major surgical procedures should be reserved for failures of endoscopic or pharmacologic therapy. The distal splenorenal shunt or the new narrow-diameter polytetrafluoroethylene portacaval shunt is preferred. All patients who are first seen with acute variceal bleeding should be considered for a liver transplant, although few will ultimately become transplant candidates. Patients with end-stage liver disease who are not transplant candidates should be identified and major high-cost therapy discontinued. Prophylactic therapy prior to variceal bleeding should be considered in selected patients. At present, only pharmacologic therapy is justified. The major problem remains identification of those patients at high risk for a first episode of variceal bleeding.     

Sclerotherapy versus ligation in hemorrhage caused by rupture of esophageal varices. Direct meta-analysis of randomized trials

OBJECTIVES: To compare the advantages of endoscopic ligation and endoscopic sclerotherapy for bleeding esophageal varices, published randomized clinical trials were critically reviewed by meta-analysis. Only ten clinical trials concerning a history of recent or active bleeding esophageal varices were included. METHODS: The methodology, population, treatment and outcomes of each relevant trial were evaluated by duplicate independent review. RESULTS: Endoscopic sclerotherapy compared to banding ligation significantly increased the rate of rebleeding (OR: 1.6; 95% IC: 1.1-2.3) without increasing early mortality compared to endoscopic banding ligation (OR: 1.3; 95% IC: 0.8-1.9). The rate of varice eradication associated with these two types of treatment was not different (OR: 0.9; 95% IC: 0.6-1.3) but was obtained more quickly with endoscopic banding ligation (3.8 +/- 1.6 versus 5.8 +/- 2.2; P < 0.05). The rate of complications was higher after sclerotherapy (OR: 2.5; 95% IC: 1.7-3.7), in those cases with a positive heterogeneity test. CONCLUSIONS: This meta-analysis shows a lower morbidity with endoscopic banding ligation in patients with variceal hemorrhage. The most important advantage of endoscopic banding ligation was the reduction of the rate of rebleeding.     

Borrowing strength from external trials in a meta-analysis

There exists a variety of situations in which a random effects meta-analysis might be undertaken using a small number of clinical trials. A problem associated with small meta-analyses is estimating the heterogeneity between trials. To overcome this problem, information from other related studies may be incorporated into the meta-analysis. A Bayesian approach to this problem is presented using data from previous meta-analyses in the same therapeutic area to formulate a prior distribution for the heterogeneity. The treatment difference parameters are given non-informative priors. Further, related trials which compare one or other of the treatments of interest with a common third treatment are included in the model to improve inference on both the heterogeneity and the treatment difference. Two approaches to estimating relative efficacy are considered, namely a general parametric approach and a method explicit to binary data. The methodology is illustrated using data from 26 clinical trials which investigate the prevention of cirrhosis using beta-blockers and sclerotherapy. Both sources of external information lead to more precise posterior distributions for all parameters, in particular that representing heterogeneity.     

Medical prophylaxis of haemorrhage from oesophageal varices in patients with liver cirrhosis

Haemorrhage from oesophageal varices is a life-threatening event in patients with liver cirrhosis. About 40-80% of patients surviving the first bleeding suffer a recurrence within 1 year. This high recurrence rate substantially contributes to the mortality in patients with liver cirrhosis. Therefore, various treatment regimens in both primary and secondary prophylaxis were studied. Most experience in medical primary prophylaxis was collected with beta-blockers, mainly propranolol. Treating patients with oesophageal varices with propranolol significantly reduces the incidence of first variceal bleeding. However, the effect on mortality is marginal, and primary prophylaxis is generally not recommended in these patients. Several studies support the hypothesis that medical prophylaxis with beta-blockers is more effective in reducing the rate of first oesophageal bleeding in patients with a high risk of haemorrhage, such as those with very large varices with red spots. A score to assess an individual patient's risk of variceal bleeding would be helpful, but until such a score has been validated, no general rule for this treatment decision can be given. In secondary prophylaxis, both beta-blockers and endoscopic therapy (sclerotherapy or ligation of the varices) are effective in lowering the rate of rebleeding. However, the effect on mortality was not significant in most studies. Several studies comparing the efficacy of medical prophylaxis and endoscopic treatment showed advantages of the endoscopic therapy with a greater reduction in recurrent bleeding episodes. However, medical prophylaxis with beta-blockers has the important advantage of being immediately effective, whereas endoscopic procedures provide the best protection against recurrent bleeding after complete obliteration of the varices. Therefore, in the first weeks and months of endoscopic therapy, additional treatment with beta-blockers may further reduce the risk of rebleeding. Only half of all studies on this topic reported a significant advantage with this combined therapy. Therefore, it seems reasonable to restrict this approach to patients with a high risk of rebleeding, such as patients with large sclerotherapy-derived oesophageal ulcers.     

Endoscopic sclerotherapy versus variceal ligation in the long-term management of patients with cirrhosis after variceal bleeding. A prospective randomized study

BACKGROUND/AIMS: Long-term endoscopic injection sclerotherapy of oesophageal varices prevents rebleeding in patients with cirrhosis surviving an acute variceal bleeding episode. However, this treatment is associated with a substantial complication rate. Endoscopic band ligation is a newly developed technique in an attempt to provide a safer alternative. The aim of this study was to compare the efficacy and safety of injection sclerotherapy versus variceal ligation in the management of patients with cirrhosis after variceal haemorrhage. METHODS: Seventy-seven patients with cirrhosis who proved to have oesophageal variceal bleeding were studied. After initial control of haemorrhage by sclerotherapy, 40 of the patients were randomly assigned to sclerotherapy and 37 to ligation. Both procedures were performed under midazolam sedation at intervals of 7-14 days until all varices in the distal oesophagus were eradicated or were too small to receive further treatment. RESULTS: The eradication of varices required a lower mean number of sessions with ligation (3.7 +/- 1.9) than with sclerotherapy (5.8 +/- 2.7, p = 0.002). The mean duration of follow-up was similar in both groups (15.6 months +/- 7.3 and 15 +/- 7.4, respectively). The proportion of patients remaining free from recurrent bleeding against time was significantly higher in the ligation group as compared to the sclerotherapy group (chi 2 = 3.86, p = 0.05). Only 13 patients (35%) developed complications in the ligation group as compared to 24 (60%, p = 0.05) in the sclerotherapy group. The mortality rate was similar in both groups (20% and 21%, respectively). CONCLUSIONS: Variceal ligation is better than sclerotherapy in the long-term management of patients with cirrhosis after variceal haemorrhage which was initially controlled with sclerotherapy.     

Longer treatment with vasoactive drugs to prevent early variceal rebleeding in cirrhosis

Bleeding oesophageal varices (BOV), resulting from portal hypertension, can prove fatal. Not only is it important to stop the initial bleeding, which may lead to hypovolaemic shock, but also to treat this condition in the longer term, and, consequently, the prevention of rebleeding needs to be addressed. This review highlights the current findings on the haemostatic drug, terlipressin, focusing particular attention on the potential for longer-term treatment strategies in the prevention of rebleeding. The efficacy of terlipressin in treating acute BOV, its low incidence of severe side-effects (comparable to those of somatostatin) and its favourable comparison with sclerotherapy in the prevention of early rebleeds, all indicate the potential for terlipressin administration to be extended to 5 days in the longer-term treatment of BOV. In addition, terlipressin administration, in conjunction with sclerotherapy, can significantly reduce the likelihood of rebleeding compared with sclerotherapy alone and further supports its potential use in the longer-term treatment of BOV.     

Histotopographic distribution of placental inflammation: analysis of 22 cases

OBJECTIVES: Acute bleeding from esophageal varices is a major complication of cirrhosis. Despite the large number of published studies no predictive factors of control of bleeding have been identified. We assessed the clinical and biological factors predictive of bleeding control within the first 2 weeks after a bleeding episode in a homogeneous group of patients enrolled in a large multicenter trial, who underwent a standardized emergency sclerotherapy session. METHODS: 101 patients with cirrhosis were enrolled. All had endoscopy-proven variceal bleeding, and the interval between hematemesis or melena and emergency sclerotherapy was always less than 24 hours. A second sclerotherapy session and other methods for the prevention of rebleeding were allowed after 5 days. RESULTS: Treatment failed in 16 patients after 24 hours and in a total of 33 patients after 15 days. Three of the 17 variables included in multivariate logistic analysis were associated with failure at 24 hours: encephalopathy (P = 0.006, OR = 4.0), blood transfusion prior to sclerotherapy (P = 0.012, OR = 6.2) and previous propranolol therapy (P = 0.022, OR = 4.6). Two variables were associated with failure between 24 hours and day 15 in patients successfully controlled after 24 hours: an interval between the onset of bleeding and sclerotherapy of less than 12 hours (P = 0.010) and blood transfusion (P = 0.018). After 15 days, three variables were associated with failure in a multivariate Cox model: encephalopathy (P = 0.0025, OR = 2.3), time to sclerotherapy (P = 0.022, OR 2.3) and blood transfusion before sclerotherapy (P = 0.0005, OR = 4.0). CONCLUSION: Encephalopathy, the severity of bleeding, assessed in terms of transfusion requirements, and the time between clinically overt bleeding and sclerotherapy are the main predictive factors of failure of the control of bleeding after emergency sclerotherapy for acute bleeding from esophageal varices.     

A learning curve for laparoscopic splenectomy at an academic institution

Variceal hemorrhage continues to be a major cause of morbidity and mortality in cirrhotic patients. Transjugular intrahepatic portosystemic shunt (TIPS) is gaining wide acceptance as a treatment for several complications of portal hypertension. The aim of the current randomized study was to compare the transjugular shunt and endoscopic sclerotherapy (ES) for the prevention of variceal rebleeding (VB) in cirrhotic patients. Forty-six consecutive cirrhotic patients with variceal bleeding were randomly allocated to receive either transjugular shunt (22 patients) or ES (24 patients) 24 hours after control of bleeding. VB (50% vs. 9%) and early (first 6 weeks) VB (33% vs. 5%) were significantly more frequent in sclerotherapy patients; the actuarial probability of being free of VB was higher in the shunt group (P <.002). Eight patients (33%) of the sclerotherapy group and 3 patients (15%) of the shunt group died; the actuarial probability of survival was higher for the shunted patients (P <.05); 6 patients in the sclerotherapy group and none in the shunt group died from VB (P <.05). No difference was found in the proportion of patients with clinically evident hepatic encephalopathy (HE). These results show that the transjugular shunt is more effective than sclerotherapy in the prevention of both early and long-term VB. Moreover, a significant improvement in survival was found in the shunt group.     

Injection sclerotherapy for gastric varices using N-butyl-2-cyanoacrylate and ethanolamine oleate

BACKGROUND/AIMS: Tissue adhesive agents, such as the cyanoacrylates, have been used as an alternative to conventional sclerotherapy to treat gastric varices, but the long-term efficacy of this approach has not been determined. We evaluated the efficacy and long-term outcome of injection sclerotherapy with n-butyl-2-cyanoacrylate and ethanolamine oleate in 16 patients with gastric varices. METHODOLOGY: We evaluated the effect of injection sclerotherapy in 16 Japanese patients with gastric varices. Injection sclerotherapy was performed on an emergency basis in 6 patients, an elective basis in 5 patients, and as prophylaxis in 5 patients. RESULTS: No bleeding was observed in the 7 patients in whom gastric varices disappeared during the 51 month follow-up period. The non-bleeding rate after treatment was significantly higher in this group than in the 9 patients in whom gastric varices did not disappear (p<0.05). Acute bleeding was stopped in 5 (83.3%) of 6 patients. The single failure was a patient in whom the sclerosant could not be injected into the gastric varices. No serious complications, such as emboli in other organs, were observed. CONCLUSION: The results suggest that this therapy is a safe and useful treatment for gastric varices and that the goal of injection sclerotherapy should be the disappearance of gastric varices.     

Modern trends in the treatment of hypertension

The main problem of treatment of hypertension in this country as well as abroad is the fact that only less than one quarter of hypertensive patients are treated effectively and have thus normal blood pressure readings. More effective treatment of hypertension is thus one of the main tasks of health care systems in different countries. The objective of treatment of hypertension is to achieve a normal blood pressure. Evidence has been provided that diuretics and beta-blockers markedly reduce cerebrovascular and cardiovascular mortality, in particular in the elderly. ACE inhibitors are the drugs of choice in patients with heart failure or asymptomatic left ventricular dysfunction and in patients with diabetic nephropathy. Unsuitable for treatment of hypertension are short acting calcium channel blockers, in particular nifedipine. On the other hand, long-acting calcium channel blockers reduce the cerebrovascular mortality in elderly hypertensive patients. A number of questions still remain the subject of research: a) should diastolic pressure be reduced to values lower than 90 mm Hg; so far it is necessary only in hypertensive subjects with diabetes mellitus and in juvenile hypertensives; b) is the influence of new groups of antihypertensive drugs, in particular calcium channel blockers, similar, better or worse than that of diuretics and beta-blockers in the prevention of cardiovascular and cerebrovascular morbidity and mortality?; c) is it wise to recommend acetylsalicylic acid also to hypertensive patients without clinical signs of IHD or atherosclerotic affection of other vessels?; d) what is the value of combined antihypertensive and hypolipidaemic pharmacological treatment? Will this combination be not much more valuable in the prevention of IHD?; e) is the prognosis of hypertensive subjects with left ventricular hypertrophy better when ACE inhibitors are used as compared with other antihypertensive drugs?; f) do ACE inhibitors influence the prognosis of diabetic patients more favourably than beta-blockers?     

A prospective randomized trial comparing somatostatin and sclerotherapy in the treatment of acute variceal bleeding

Somatostatin and endoscopic sclerotherapy are widely used in the treatment of acute variceal bleeding. Although objective evidence does exist about the advantages of either treatment, data comparing both procedures are scarce. In order to compare the effectiveness and safety of somatostatin and sclerotherapy in the treatment of acute variceal bleeding, 70 consecutive cirrhotic patients suffering from esophageal variceal hemorrhage and meeting the inclusion criteria were randomly assigned to treatment with somatostatin (35 patients) or sclerotherapy (35 patients). No differences in age, sex, alcohol intake, etiology of cirrhosis and severity of liver failure were found between groups. Failure of treatment (defined as persistence of bleeding despite therapy or subsequent rebleeding within the 48-hr trial period) occurred in seven patients (20%) in the somatostatin group and in six (17.1%) in the sclerotherapy group (NS). Early rebleeding occurred in seven of 28 patients (25%) in the somatostatin group and in five of 29 (17.2%) in the sclerotherapy group (NS). Mortality within the first 6 wk was no different between both groups: 10 (28.5%) and eight (22.8%) in the somatostatin and sclerotherapy groups, respectively. Sclerotherapy, but not somatostatin, was associated with major complications in five cases (14.2%) (p = 0.026), two of which resulted in patient's death. These results suggest that somatostatin is safer, and as effective as sclerotherapy, in controlling acute variceal bleeding until an elective treatment can be established.     

Surgical management of portal hypertension

The surgical management of portal hypertension depends on the location of the obstruction. Suprahepatic obstruction is usually optimally treated by a surgical portacaval shunt. In extrahepatic obstruction the treatment should be sclerotherapy. For intrahepatic obstruction in emergency situations, sclerotherapy is the first choice, with portacaval systemic shunts or transjugular intrahepatic portal systemic stent shunt the second option. Liver transplantation in other situations should, if possible, be considered ahead of a portal diversion.     

Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding

BACKGROUND: Patients who have bleeding from esophageal varices are at high risk for rebleeding and death. We compared the efficacy and safety of endoscopic sclerotherapy with the efficacy and safety of nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. METHODS: Eighty-six hospitalized patients with cirrhosis and bleeding from esophageal varices diagnosed by endoscopy were randomly assigned to treatment with repeated sclerotherapy (43 patients) or nadolol plus isosorbide-5-mononitrate (43 patients). The primary outcomes were rebleeding, death, and complications. The hepatic venous pressure gradient was measured at base line and after three months. RESULTS: Base-line data were similar in the two groups, and the median follow-up was 18 months in both. Eleven patients in the medication group and 23 in the sclerotherapy group had rebleeding. The actuarial probability of remaining free of rebleeding was higher in the medication group for all episodes related to portal hypertension (P = 0.001) and variceal rebleeding (P = 0.002). Four patients in the medication group and nine in the sclerotherapy group died (P = 0.07 for the difference in the actuarial probability of survival). Seven patients in the medication group and 16 in the sclerotherapy group had treatment-related complications (P = 0.03). Thirty-one patients in the medication group underwent two hemodynamic studies; 1 of the 13 patients with more than a 20 percent decrease in the hepatic venous pressure gradient had rebleeding, as compared with 8 of the 18 with smaller decreases in the pressure gradient (P = 0.04) for the actuarial probability of rebleeding at two years). CONCLUSIONS: As compared with sclerotherapy, nadolol plus isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices.     

Legal aspects of medication administration

BACKGROUND: Sclerotherapy is associated with complications which involve adjacent structures like the pleura. The effect of sclerotherapy on function of the vagus nerve, which lies in close proximity to the thoracic esophagus, is not clear. AIM: To study gastric acid secretion as a marker of vagal function in portal hypertensive patients who have undergone sclerotherapy. METHODS: Portal hypertensive patients who had undergone at least three sessions of sclerotherapy were evaluated by mapping gastric acid-secreting mucosa by the Congo red test and by estimating gastric acid secretion using the modified sham feeding test. Patients with portal hypertension who had never been subjected to endoscopic sclerotherapy were recruited as controls. RESULTS: On Congo red test, complete or substantial reduction in acid-secreting mucosa was observed in eight patients in comparison to none of the controls. Significantly lower acid secretion on modified sham feeding test was observed in these eight patients. CONCLUSION: A lower gastric acid secretion, probably secondary to vagal dysfunction, is seen in patients who have undergone multiple sessions of sclerotherapy; vagus nerve involvement may be secondary to periesophageal inflammation.     

Oxidation of cysteine S-conjugates by rabbit liver microsomes and cDNA-expressed flavin-containing mono-oxygenases: studies with S-(1,2-dichlorovinyl)-L-cysteine, S-(1,2,2-trichlorovinyl)-L-cysteine, S-allyl-L-cysteine, and S-benzyl-L-cysteine

Complement plays important roles in host immune defences, and recent studies suggest that adipose tissue is an important site of production for some complement proteins. Starvation has been associated with low complement levels, but studied populations have usually had concomitant opportunistic infections or other conditions which might affect complement levels. To determine the impact of body weight and changes in body weight on serum complement, we investigated levels of complement proteins in otherwise healthy patients with a wide range of body weights, including patients with anorexia nervosa before and after treatment, obese dieters before and after weight loss, and normal weight controls. We found that complement proteins of the alternative pathway (C3, B, and D), alternative pathway haemolytic activity (AP50) and the inhibitors H and I were low in starving anorectics and normalized with weight gain. C3a levels were comparable in anorectics at low weight and after weight gain, indicating that low serum complement levels were attributable to hypoproduction and not complement cascade activation with consumption. Further, levels of C3, B, AP50, H and I, but not D, were higher than controls in obese patients and decreased toward normal after weight loss. Overall, percentage of ideal body weight, changes in body weight, and serum transferrin were each highly correlated with serum levels of complement proteins. We conclude that levels of alternative pathway complement components are determined in part by factors that influence body weight and by weight changes, possibly due to changes in production in adipose tissue or at other sites.     

Hemolysis of normal human erythrocytes by autologous serum complement

Unsensitized normal human erythrocytes (E) were shown to be lysed when incubated with autologous serum in the presence of zymosan (Zy). The hemolysis proceeded slowly with a relatively constant rate for at least 24 h at 37 degrees C. It was shown that the hemolytic reaction is antibody independent and mediated by complement activation through the alternative pathway and that hemolysis is not due to the decay or inactivation of complement regulators present on the E membrane. The mechanism of the phenomenon was studied by use of several kinds of sera genetically deficient in C3, C5, C7 or C9. The reaction was found to be divided into two stages: in the first step, neither E, C5, C7 nor C9 but Zy, serum factors containing C3 and metal ions are necessary, and in the second step, neither C3 nor metal ions but E, C5, C7 and C9 are necessary. Thus, E seem to be lysed by reactive lysis induced by C5 convertase formed on Zy through alternative complement pathway activation.     

Compressive sclerotherapy monitored by ultrasound]

Echosclerotherapy and sonographic control of aimed sclerotherapy resp. is a major advance in the treatment of chronic venous insufficiency. It facilitates not only aimed administration of highly active substances but ensures above all prevention of serious complications. Functional examination of the venous system helps to locate relatively accurately the sites of pathological reflux which are in the first place responsible for the development of the whole symptomatology and it prevents the administration of excessive amounts of sclerotizing substances into intact portions of the venous system. Similarly as Baccaglini et al. (1995) the authors achieved by compressive sclerotherapy with monitoring by ultrasound occlusion of up to 90% important reflux sites such as the saphenofemoral and saphenopopliteal orifice which are to a great extent responsible for serious clinical symptoms.     

Longterm outcome after injection sclerotherapy for oesophageal varices in children with extrahepatic portal hypertension

A consecutive series of 36 children with bleeding from oesophageal varices secondary to extrahepatic portal hypertension was successfully treated by endoscopic injection sclerotherapy and followed up over a mean period of 8.7 years after variceal obliteration. There were no deaths from portal hypertension or its treatment and morbidity related to oesophageal sclerotherapy was minimal. Endoscopic injection sclerotherapy alone proved safe and effective in controlling variceal bleeding from portal hypertension in over 80% of the children. Recurrent variceal bleeding developed in 10 (31%) patients but half of these were effectively treated by further sclerotherapy. Gastric variceal bleeding unresponsive to sclerotherapy necessitated successful portosystemic shunt surgery in four (13%) patients. Two children required splenectomy for painful splenomegaly. In most children injection sclerotherapy is the best treatment for the primary management of bleeding oesophageal varices, reserving portosystemic shunting or other surgical procedures for those with bleeding from gastrointestinal varices.     

Painless treatment of hydrocele: EMLA cream anaesthesia and fibrin adhesive sclerotherapy

Sclerotherapy for hydroceles was performed in 18 patients. Cutaneous anaesthesia was induced with an anaesthetic cream (lidocaine and prilocaine, EMLA cream) and a fibrin sealant (Tissucol) was injected into the sac after fluid aspiration. Patients experienced no pain during needle insertion and sclerosant procedure; 2 recurrences were observed during follow-up. EMLA cream anaesthesia and fibrin adhesive sclerotherapy represent a useful alternative to surgical treatment of hydroceles.