Clin Liver Dis 10 (2006) 613625

A Commonsense Approach to Esophageal Varices

Anna V. Longacre, MD, Guadalupe Garcia-Tsao, MD*
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520, USA

Variceal hemorrhage continues to be one of the most serious complications of portal hypertension and cirrhosis, and is associated with a mortality of at least 20% at 6 weeks, despite improvements in therapy over the last decade [13]. Short-term mortality is increased in those with higher model of endstage liver disease (MELD) or Child-Pugh scores, higher blood transfusion requirements, or advanced hepatocellular carcinoma [3,4]. Furthermore, variceal hemorrhage predisposes cirrhotic patients to worsening hepatic decompensation, infection, or renal insuciency, which can predict mortality [3,5]. Optimal treatment of variceal hemorrhage ideally involves a multidisciplinary approach, including an endoscopist, hepatologist, interventional radiologist, intensivist, and, in some cases, a transplant or hepatobiliary surgeon. In reality, many patients present to hospitals that do not have this diversity of specialty and technical skills, so that initial management may be determined by the available expertise at a particular location. Ultimately, some patients may require transfer to a tertiary care center where more advanced care is available. Providing primary prophylaxis against rst variceal hemorrhage, management of an acute bleeding episode, and comprehensive treatment after variceal hemorrhagedmainly prevention of rebleedingdare equally important components of care for the cirrhotic patient who has gastroesophageal varices (GEVs). Detailed references and rationale for many aspects of treatment are presented in the preceding articles; herein the authors describe a practical approach to the management of cirrhotic patients who have GEVs. This approach is based on evidence from the literature and consensus conferences among experts [68].

* Corresponding author. E-mail address: guadalupe.garcia-tsao@yale.edu (G. Garcia-Tsao). 1089-3261/06/$ - see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2006.08.016 liver.theclinics.com

614

LONGACRE & GARCIA-TSAO

Pathophysiology of portal hypertension and gastroesophageal varices In cirrhosis, portal pressure increases mostly as a result of architectural distortion of the liver from brosis and regenerative nodules, as well as a component of intrahepatic vasoconstriction that is due to decreased nitric oxide [9]. Portal hypertension results in portosystemic collaterals, with a minimum threshold hepatic venous pressure gradient (HVPG) of 10 to 12 mm Hg necessary for their formation [10]. The most relevant of these collaterals are GEVs, because these are the most likely to rupture. The risk for variceal rupture correlates with variceal wall tension, which is related to vessel diameter and pressure within the varix, which, in turn, is related to portal pressure. Clinical predictors of variceal hemorrhage include decompensated cirrhosis and endoscopic features, including the size of varices and the presence of red wale signs [11]. GEVs are present in 50% of unselected cirrhotic patients and in up to 70% of those who have decompensated cirrhosis [12]. In those who have large varices, the risk for hemorrhage is at least 30% within the rst 2 years of diagnosis [13]; thus, treatment of variceal hemorrhage starts at the stage of screening patients who have cirrhosis for esophageal varices and preventing rst variceal hemorrhage.

Screening for esophageal varices Before considering endoscopic screening and prophylaxis in patients who have cirrhosis, clinicians need to identify patients who may have cirrhosis and portal hypertension. Physical signs of liver disease and portal hypertension; routine laboratory tests, including liver tests, coagulation studies, and platelets; and abdominal imaging that is done for other purposes can suggest the presence of chronic liver disease; its etiology can be determined by history as well as by laboratory tests to assess for viral, autoimmune, or metabolic causes. In a patient who has chronic liver disease, the most sensitive ndings that are suggestive of cirrhosis are a palpable left lobe of the liver with a small, nonpercussible right lobe and a low platelet count. In patients in whom there is a clinical suspicion of cirrhosis, the possibility can be conrmed by imaging studies (liver-spleen scan, ultrasound with Doppler, CT scan), particularly when ndings that are suggestive of portal hypertension (colloid shift, splenomegaly, collaterals) are present. For those in whom cirrhosis remains in question after initial evaluation, liver biopsy should be considered to help dene its presence. Practice guidelines recommend that all patients who have cirrhosis have endoscopic screening for esophageal varices [6,7], because there is no noninvasive way to assess their presence reliably [14]. Esophageal capsule endoscopy was shown in a pilot study to be a safe and sensitive way to diagnose esophageal varices, and it may play a future role in screening for esophageal varices if additional studies support its use [15]. Cost-eectiveness analysis

A COMMONSENSE APPROACH TO ESOPHAGEAL VARICES

615

has suggested that universal screening of patients who have cirrhosis may be more costly than is empiric universal treatment with b-blockers [16]. Universal screening for esophageal varices is recommended, however, because the development of varices cannot be prevented pharmacologically [17], pharmacologic therapy is associated with side eects, and only patients who have medium or large GEVs are known to benet from prophylactic therapies [13].

Approach to the patient with esophageal varices Prevention of rst variceal hemorrhage (Fig. 1) Individuals who have medium or large esophageal varices (O5 mm in diameter) benet from prophylaxis to prevent a rst variceal hemorrhage [13]. In those who have small esophageal varices, there is less data to support the use of prophylaxis, although a recent study showed that growth of small varices can be prevented [18]. Prophylaxis can be considered in patients who have small varices that are at an increased risk for variceal hemorrhage because of the presence of red wale signs or advanced liver disease [8]. In patients who do not have esophageal varices, recent data do not support the use of nonselective b-blockers to prevent the formation of esophageal varices [17], although they suggest that individuals who have at least 10% reduction in HVPG will have delayed development of esophageal varices [17]. Portal hypertension usually is a progressive condition, such that the rate of forming esophageal varices in a cirrhotic patient is approximately 7% per year, and higher in those who have decompensated cirrhosis [19]. Therefore, screening endoscopy should be repeated every 1 to 2 years in individuals who have small varices, every 2 to 3 years in those who have no
Diagnosis of Cirrhosis Endoscopy
No Varices Follow-up EGD in 2-3 yrs* Small Varices Follow-up EGD in 1-2 yrs* Medium/Large Varices

*Every year in decompensated cirrhosis

Beta-blocker# therapy
No Contraindications Contraindications or Beta-blocker intolerance

Step-wise increase until maximally tolerated dose Continue beta-blocker (life-long)

Endoscopic Variceal Band Ligation

#

non-selective beta-blocker (propranolol, nadolol)

Fig. 1. Prophylaxis of rst variceal hemorrhage. EGD, endoscopy.

616

LONGACRE & GARCIA-TSAO

varices, and yearly in patients who have decompensated cirrhosis to monitor the formation and progression of varices [7]. In patients who have cirrhosis and large esophageal varices, nonselective b-adrenergic blockers, such as propranolol or nadolol, reduce the risk for an initial bleed from approximately 30% to 14% within 2 years [13]. b-Blockers reduce portal pressure by means of reducing cardiac output (b-1 eect) and, more importantly, by allowing a-adrenergic-induced splanchnic vasoconstriction (b-2 eect), thereby reducing portal blood ow. A decrease in HVPG to less than 12 mm Hg essentially eliminates the risk for hemorrhage and improves survival [20], whereas reductions of more than 10% from baseline signicantly decrease the risk for bleeding [21]. Because HVPG measurement is not widely available and because a reduction in heart rate does not correlate with reduction in HVPG [22], the dose of nonselective b-blockers (propranolol, nadolol) is adjusted to maximal tolerability, maintaining a resting pulse of approximately 55 beats per minute. Use of additional pharmacologic agents, such as nitrates, may decrease portal pressure further. Combination therapy has not been shown to decrease the risk for initial hemorrhage signicantly and it may result in more side eects; therefore, it is not recommended [2325]. Endoscopic variceal ligation (EVL) has been compared with nonselective b-blockers in preventing rst variceal hemorrhage in several studies. A recent meta-analysis demonstrated a benet for EVL in preventing rst variceal hemorrhage [26]; however, there was no dierence in mortality between the b-blockers and EVL in this analysis and most of the included studies were small with short duration of follow-up. In fact, the largest study with the longest follow-up showed no dierences in the development of rst variceal hemorrhage between the two therapies [27]. In practice, EVL is usually oered only to patients who have contraindications to b-blockers or for those who cannot tolerate a therapeutic dose of b-blockade. Approximately 15% of patients have contraindications to the use of b-blockers, and an additional 10% to 15% is unable to tolerate a therapeutic dose and requires treatment withdrawal. Whether combined EVL and b-blockers will decrease the risk for rst variceal hemorrhage further remains to be determined; however, an initial study in which combination therapy was compared with EVL did not result in a dierence in outcome [28]. There is no role for endoscopic sclerotherapy, shunt surgery, or transjugular intrahepatic portosystemic shunt (TIPS) in the primary prophylaxis of variceal hemorrhage (Box 1). Treatment of acute variceal hemorrhage Because acute variceal hemorrhage remains one of the most life-threatening complications of portal hypertension, recognizing a patient who may be experiencing a variceal hemorrhage is the rst critical step in providing the appropriate care (Fig. 2). Variceal hemorrhage classically presents with hematemesis or melena, and can be the rst manifestation of cirrhosis in

A COMMONSENSE APPROACH TO ESOPHAGEAL VARICES

617

Box 1. Primary prophylaxis of variceal hemorrhage in patients who have medium or large esophageal varices Recommended interventions Nonselective Beta blockers (propranolol, nadolol) EVL in patients who are not candidates for b-blockers Interventions that should not be used Nitrates alone Combination b-blockers/nitrates Endoscopic sclerotherapy Shunt surgery/TIPS patients who previously are not known to have liver disease. Bleeding from esophageal varices can stop spontaneously in up to 40% of patients, yet control of the hemorrhage and prevention of recurrence is achieved best with prompt endoscopic and pharmacologic management. Patients who have suspected acute variceal hemorrhage should be admitted to an ICU setting for resuscitation and management. Initial resuscitation involves basic measures, including assessing the patients airway, obtaining peripheral venous access, and preparing to transfuse blood products as needed. Blood volume resuscitation should be undertaken promptly, but with caution, with the goals of maintaining hemodynamic stability and a hemoglobin of around 8 g/dL. The transfusion of fresh frozen plasma and platelets can be considered to correct coagulopathy and in patients who have signicant thrombocytopenia during acute hemorrhage. Even in the absence of other medical comorbidities, volume expansion should be performed
Variceal Hemorrhage Suspected Cautious blood volume restitution Antibiotic prophylaxis Vasoactive drugs + Ligation* Consider intubation *Sclerotx if ligation not possible

Initial Management

Acute Hemorrhage Controlled? NO Balloon Tamponade YES

Early rebleeding? YES NO

Rescue TIPS/Shunt surgery Further bleeding

2nd Endoscopy

Prophylaxis against recurrent hemorrhage

Fig. 2. Management of acute variceal hemorrhage.

618

LONGACRE & GARCIA-TSAO

with care to prevent overexpansion of the plasma volume, which can increase portal pressure and precipitate recurrent variceal bleeding. Generally, the use of saline resuscitation should be avoided, because this can worsen or precipitate the formation of ascites or other extravascular uid accumulation. Given the volume of blood loss that can be associated with acute variceal hemorrhage, aspiration of blood can occur. Therefore, elective or more emergent intubation may be required for airway protection before endoscopy, particularly in patients who have concomitant hepatic encephalopathy. Cirrhotic patients are at high risk for bacterial infection during acute variceal hemorrhage, independent of the presence of ascites and the associated risk for spontaneous bacterial peritonitis [29]. The use of short-term prophylactic antibiotics decreases the risk for bacterial infections, reduces the risk for early rebleeding, and increases survival [2931]. The recommendation is for an oral poorly absorbable uoroquinolone, such as noroxacin. An intravenous uoroquinolone can be administered until medications can be administered by mouth [31] for a recommended duration of 7 days, although the duration may be less if the patient is discharged from the hospital. Recent preliminary data suggest that intravenous ceftriaxone is more eective than is oral noroxacin in preventing bacterial infections in cirrhotic patients who have gastrointestinal hemorrhage [32]. Given the associated risk for renal insuciency, use of aminoglycosides should be avoided [33]. A combination of pharmacologic and endoscopic therapy seems to be the most promising approach in treating acute variceal hemorrhage [34]. When variceal hemorrhage is suspected, treatment with a safe vasoconstrictor, such as terlipressin, somatostatin or somatostatin analogues (octreotide, vapreotide), should be initiated, even before diagnostic or therapeutic endoscopy. These drugs temporarily lower portal pressure by causing splanchnic vasoconstriction, and, thus, decrease acute variceal bleeding, enable better visualization of the esophageal lumen during endoscopy, and decrease the risk for early rebleeding [35]. Of these, only octreotide is available in the United States. Octreotide, 50-mg bolus followed by 50 mg/h infusion, is used commonly with a low risk for associated side eects. Octreotide infusion can be maintained for 5 days after a patients presentation, spanning the period during which the risk for early rebleeding is highest. Use of somatostatin consists of a 100-mg bolus followed by infusion of 50 mg/h. Vapreotide is given as a 50-mg bolus followed by infusion of 50 mg/h. The use of vasopressin, 0.2 to 0.4 U/min, is limited by side eects, and should be used only in conjunction with intravenous nitroglycerin, starting dosage of 40 mg/min, adjusted to maintain a systolic blood pressure of greater than 90 mm Hg. Given the risks for generalized tissue ischemia that is associated with vasopressin and nitroglycerin, continuous infusion extending beyond 24 hours is not recommended, and use of this medication combination has fallen out of favor. Terlipressin, a longer-acting vasopressin analog, is eective in controlling acute variceal hemorrhage, is safe in terms of its side eect prole, and has been associated with a decreased mortality, but is not available in the United States.

A COMMONSENSE APPROACH TO ESOPHAGEAL VARICES

619

Emergency endoscopy should be performed after initial stabilization of the patient. Endoscopic therapy is eective in controlling active hemorrhage as well as preventing early rebleeding, and it should be considered the gold standard in the management of acute bleeding. A signicant percentage of cirrhotic patients that presents with gastrointestinal hemorrhage are bleeding from sites other than varices (eg, gastritis, Mallory Weiss tears, peptic ulcer disease); thus, identifying the bleeding source is the rst critical step of management. Although the choice of endoscopic therapy can depend on the available expertise, EVL is the preferred endoscopic approach in controlling active hemorrhage from esophageal varices. It has been shown to produce fewer complications, lower rates of rebleeding, and lower mortality [36,37]. Endoscopic sclerotherapy is also eective in controlling active hemorrhage, and can be used in clinical situations in which ligation is technically dicult, particularly when active hemorrhage limits the eld of vision during endoscopy. While initial resuscitation and pharmacologic and endoscopic therapies are being performed, assessment of the patients underlying liver disease should also be undertaken. For individuals in whom variceal hemorrhage is their rst presentation of liver disease, a full evaluation is required, including investigations regarding the etiology of cirrhosis, comprehensive laboratory tests, and imaging. The severity of liver disease should be assessed in all patients, and risk factors for bleeding should be sought, including hepatocellular carcinoma, active alcohol use, or medical noncompliance for those receiving primary prophylaxis for variceal hemorrhage. Despite receiving optimal care, 10% to 20% patients who have variceal hemorrhage will have hemorrhage that is uncontrolled by standard pharmacologic and endoscopic measures or present with early rebleeding within 24 to 72 hours. Early rebleeding should prompt a repeat attempt at endoscopic therapy. If a second endoscopic attempt is not eective in controlling hemorrhage, TIPS should be considered as the next step in management [38]. TIPS functions as a side-to-side porto-caval shunt, which eectively decreases portal pressure and results in the cessation of bleeding. The placement of TIPS can lead to other complications, including worsening hepatic function or encephalopathy, particularly in those who have severe liver dysfunction, yet it remains the only choice for rapidly decreasing portal pressure aside from surgical shunting procedures. The role of balloon tamponade is limited as a temporary or bridge measure to control variceal bleeding when endoscopic and pharmacologic therapies fail. Balloon tamponade can stabilize a patient to enable transfer to an advanced facility, or when therapy is otherwise delayed. Although eective in decreasing acute bleeding, deation of the balloon can lead to rebleeding. Furthermore, balloon tamponade also can result in complications that range from esophageal ulcerations to pressure necrosis of the esophageal wall that can be lethal, and, thus, its use is limited and strictly temporary.

620

LONGACRE & GARCIA-TSAO

Prevention of recurrent variceal hemorrhage For individuals who have survived a variceal hemorrhage, therapies to prevent recurrent bleeding should be started promptly, before discharge from the hospital (Fig. 3). The risk for recurrent variceal hemorrhage is high (w60%) in the rst year [39]. Pharmacologic and endoscopic therapies decrease the risk for rebleeding. The lowest rebleeding rates (w10%) have been observed in patients in whom the HVPG is reduced pharmacologically to less than 12 mm Hg or greater than 20% from baseline [39]. Because HVPG is not widely available, patients should be treated with the next best therapy; that seems to be the combination of variceal ligation plus nonselective b-blockers with which rebleeding rates are approximately 15% to 23% at 16 months [40,41]. Because the data on combination therapy are not strong, patients also can be treated with ligation alone or with pharmacologic therapy alone (b-blockers plus nitrates) [39,41]. EVL should be repeated until esophageal varices are obliterated which usually requires two to four endoscopic sessions. EVL is usually performed every 2 weeks until obliteration, although recent data suggest that performing EVL every 2 months may increase eradication and decrease variceal recurrence [42]. After obliteration, surveillance endoscopy to evaluate for recurrence of varices should be performed every 6 months, with repeat EVL if they have recurred. As with the use of b-blockers for primary prevention of variceal hemorrhage, b-blockers should be titrated to maximum tolerability, usually starting at a low dosage (eg, nadolol, 40 mg/d). If the choice is to use pharmacologic therapy alone, then nitrates should be used as well. Nitrates

Control of Acute Variceal Hemorrhage

Beta-blockers + nitrates or Variceal ligation (EVL) or Beta-blockers + EVL*

* Probably better

Recurrent Hemorrhage NO Surveillance endoscopy and/or life-long pharmacological Rx YES Patient on beta-blockers + EVL? NO Initiate combination Rx YES TIPS/Shunt Surgery

Further bleeding

Fig. 3. Prophylaxis of recurrent variceal hemorrhage. Rx, therapy.

A COMMONSENSE APPROACH TO ESOPHAGEAL VARICES

621

can be added sequentially, starting at a low dosage (eg, isosorbide mononitrate, 10 mg twice daily, with escalation to 20 mg twice daily if tolerated). Failure to prevent recurrent variceal hemorrhage while an individual is receiving beta-blockers plus EVL should prompt the consideration of TIPS or shunt surgery. TIPS and distal splenorenal shunts have similar rates of rebleeding, encephalopathy, and mortality in patients who have Childs A or B cirrhosis [43]; the primary complication of TIPS is TIPS revision. Use of polytetrauoroethylene-covered stent-grafts have improved primary and secondary TIPS patency rates and decreased the rates of stent occlusion and stenosis [44], such that TIPS usually is the preferred therapy. Patients who have advanced cirrhosis or who are under consideration for TIPS or shunt surgery also should be evaluated for liver transplantation. Approach to the patient with fundal gastric varices Gastric varices, less prevalent than esophageal varices, are present in approximately 20% of patients with cirrhosis. Gastric varices are classied commonly based on their relationship with esophageal varices as well as their location in the stomach [45]. GEVs are an extension of esophageal varices and are categorized into two types. Type 1 (GEV1) is the more common type of gastric varices and it extends along the lesser curvature. Because they are considered similar to esophageal varices, the approach to their management should be the same as for esophageal varices. Type 2 (GEV2) extends along the fundus and tends to be longer and more tortuous. Isolated gastric varices (IGVs) occur in the absence of esophageal varices and also are classied into two types. Type 1 (IGV1) is located in the fundus and tends to be tortuous and complex, and type 2 (IVG2) is located in the body, antrum, or around the pylorus. GEV2 and IGV1 make up fundal varices, for which there are limited data on which to base treatment recommendations. At this point, no consensus exists as to the optimal management of gastric varices, specically for GEV2 and IGV1, except when IGV1 are secondary to splenic vein thrombosis, in which case therapy consists of splenectomy. There have been no studies that examine primary prophylaxis of variceal hemorrhage from fundal varices using b-blockers or endoscopic therapies. Until randomized controlled trials are performed to guide management, primary prophylaxis with b-blockers has been considered a sensible approach, particularly in large fundal varices. Bleeding from gastric varices should be suspected when active bleeding or a clot is visualized in the fundus, or when large gastric varices are present in the absence of esophageal varices or another endoscopically evident source of hemorrhage. The supportive care of a patient who has gastric variceal hemorrhage parallels that of the cirrhotic patient who has esophageal hemorrhage. Compared with endoscopic sclerotherapy or band ligation, endoscopic variceal obturation with tissue adhesive (eg, N-butyl-cyanoacrylate, isobutyl-2-cyanoacrylate, thrombin) is more eective for acute gastric

622

LONGACRE & GARCIA-TSAO

variceal bleeding, with better control of initial hemorrhage as well as lower rates of rebleeding [46,47]. Therefore, the use of these agents is preferred; however, they are not approved for use in the United States and are not widely available. The use of 2-octyl cyanoacrylate, an agent that is approved for skin closure in the United States, was described as eective in achieving initial hemostasis and preventing rebleeding from fundal varices in an initial uncontrolled pilot study [48]. Side eects of endoscopic variceal obturation usually are mild, including abdominal pain and fever; however, embolic phenomena also can occur, particularly when larger volumes of adhesive are injected, because of the presence of portosystemic shunting. In Asia, additional techniques have been described. These include a balloon-occluded retrograde transvenous obliteration by way of spontaneous gastrorenal shunts; however, this techniques is not widely used [49,50]. In contrast to esophageal variceal hemorrhage, in which TIPS is pursued only after two attempts at endoscopic therapy have failed, the threshold to place TIPS for gastric variceal hemorrhage is lower and can be recommended after a single failed attempt at endoscopic treatment. Surgical shunting procedures also can be considered. Because b-blockers and varix obliteration are the mainstays of preventing recurrent esophageal hemorrhage, a similar approach for gastric varices is warranted, despite a paucity of data. For patients who have bled from fundal varices, the use of b-blockers or obturation with N-butyl-cyanoacrylate or other tissue adhesive can be oered, and TIPS should be considered if a patient has had more than one episode of bleeding. Management of fundal variceal bleeding is summarized in Fig. 4. Despite improvements in care, variceal hemorrhage continues to carry signicant mortality risk, which makes clinician recognition and action important at all stages of management. By screening all patients who have
Variceal Hemorrhage Suspected Cautious blood volume restitution Antibiotic prophylaxis Vasoactive drugs Consider intubation

Initial Management

Variceal obturation possible? NO YES

Bleeding controlled? NO TIPS Surgical Shunt* *Child A patients Not possible or rebleed YES Variceal obliteration + beta-blockers

Fig. 4. Management of acute fundal variceal bleeding.

A COMMONSENSE APPROACH TO ESOPHAGEAL VARICES

623

cirrhosis, applying prophylaxis appropriately, actively managing acute variceal hemorrhage, and aggressively preventing recurrence with combined endoscopic and pharmacologic treatments, we have the best opportunity to improve survival in this patient group.

References
[1] El-Serag HB, Everhart JE. Improved survival after variceal bleeding over an 11-year period in the Department of Veterans Aairs. Am J Gastroenterol 2000;95:356673. [2] Carbonell N, Pauwels A, Serfaty L, et al. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004;40:6529. [3] DAmico G, DeFranchis R, Cooperative Study Group. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003;38: 599612. [4] Amitrano L, Guardascione MA, Bennato R, et al. MELD score and hepatocellular carcinoma identify patients at dierent risk of short-term mortality among cirrhotics bleeding from esophageal varices. J Hepatol 2005;42(6):8205. [5] Cardenas A, Gines P, Uriz J, et al. Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis. Hepatology 2001;34:6716. [6] Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:86880. [7] de Franchis R. Updating consensus in portal hypertension: report of the Baveno III consensus workshop on denitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:84652. [8] de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005;43:16776. [9] Wiest R, Groszmann RJ. Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Semin Liver Dis 1999;19:41126. [10] Garcia-Tsao G, Groszmann RJ, Fisher RL, et al. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:41924. [11] The North Italian Endoscopic Club for the Study and treatment of Esophageal Varices. Prediction of the rst variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988;319:9839. [12] Madhotra R, Mulcahy HE, Willner I, et al. Prediction of esophageal varices in patients with cirrhosis. J Clin Gastroenterol 2002;34(1):815. [13] DAmico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999;19(4):475505. [14] DAmico G, Morabito A. Noninvasive markers of esophageal varices: another round, not the last. Hepatology 2004;39(1):304. [15] De Franchis R, Eisen GM, Haifa R, et al. Esophageal capsule endoscopy (Pillcam Eso) is comparable to traditional endoscopy for screening/surveillance for esophageal varices [abstract]. Hepatology 2005;42(4):210A. [16] Spiegel BM, Targownik L, Dulai GS, et al. Endoscopic screening for esophageal varices in cirrhosis: is it ever cost eective? Hepatology 2003;37(2):36677. [17] Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent esophageal varices in patients with cirrhosis. N Engl J Med 2005;353:225461. [18] Merkel C, Marin R, Angeli P, et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004;127(2): 47684.

624

LONGACRE & GARCIA-TSAO

[19] Merli M, Nicolini G, Angeloni S, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003;38(3):26672. [20] Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a rst variceal hemorrhage. Gastroenterology 1990;99(5):5902. [21] Aracil C, Lopez-Balaguer JM, Monfort D, et al. Hemodynamic response to beta-blockers and prediction of clinical ecacy in the primary prophylaxis of variceal bleeding in patients with cirrhosis [abstract]. Hepatology 2003;38:296A. [22] Garcia-Tsao G, Grace ND, Groszmann RJ, et al. Short-term eects of propranolol on portal venous pressure. Hepatology 1986;6(1):1016. [23] Merkel C, Marin R, Enzo E, et al. Randomised trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Lancet 1996;348: 167781. [24] Spanish Variceal Bleeding Group. Propranolol placebo vs propranolol isosorbide-5mononitrate in the prevention of the rst variceal bleeding. A multicenter double-blind randomized trial [abstract]. J Hepatol 1999;30(Suppl 1):50. [25] DAmico G, Pasta L, Politi F, et al. Isosorbide mononitrate with nadolol compared to nadolol alone for prevention of the rst bleeding in cirrhosis. A double-blind placebocontrolled randomized trial. Gastroenterology International 2002;15:4050. [26] Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21: 34761. [27] Schepke M, Kleber G, Nurnberg D, et al. Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2004;40(1):6572. [28] Sarin SK, Wadhawan M, Agarwal SR, et al. Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding. Am J Gastroenterol 2005;100:797804. [29] Bernard B, Grange JD, Khac EN, et al. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999;29:165561. [30] Hou MC, Lin HC, Liu TT, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004;39(3):74653. [31] Blaise M, Pateron D, Trinchet JC, et al. Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1994;20(1):348. [32] Planas R, Fernandez J, del Arbol LR, et al. Randomized, multicenter controlled trial comparing oral noroxacin vs intravenous ceftriaxone in the prevention of bacterial infection in cirrhotics with severe liver failure and gastrointestinal bleeding. Gastroenterology 2005; 128(4):A6878. [33] Hampel H, Bynum GD, Zamora E, et al. Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroenterol 2001;96(7):220610. [34] Banares R, Albillos A, Rincon D, et al. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology 2002;35(3): 60915. [35] Cales P, Masliah C, Bernard B, et al. Early administration of vapreotide for variceal bleeding in patients with cirrhosis. N Engl J Med 2001;344:238. [36] Lo GH, Lai KH, Cheng JS, et al. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997;25:11014. [37] Avgerinos A, Armonis A, Stefanidis G, et al. Sustained rise of portal pressure after sclerotherapy, but not band ligation, in acute variceal bleeding in cirrhosis. Hepatology 2004; 39(6):162330. [38] Chau TN, Patch D, Chan YW, et al. Salvage transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding. Gastroenterology 1998;114:9817.

A COMMONSENSE APPROACH TO ESOPHAGEAL VARICES

625

[39] Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet 2003;361:9524. [40] Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus nadolol and sulcrafate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32(3):4615. [41] de la Pena J, Brullet E, Sanchez-Hernandez E, et al. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 2005; 41(3):5728. [42] Yoshida H, Mamada Y, Taniai N, et al. A randomized control trial of bimonthly versus biweekly endoscopic variceal ligation of esophageal varices. Am J Gastroenterol 2005;100: 20059. [43] Henderson M, Boyer TD, Kutner MH, et al. DSRS vs. TIPS for refractory variceal bleeding: a prospective randomized controlled trial [abstract]. Hepatology 2004;40(4):725A. [44] Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinical outcome using polytetrauoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126(2):46975. [45] Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classication and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992; 16:13439. [46] Sarin SK, Jain AK, Jain M, et al. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002;97:10105. [47] Lo GH, Lai KH, Cheng JS, et al. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001; 33:10604. [48] Rengstor DS, Binmoeller KF. A pilot study of 2-octyl cyanoacrylate injection for treatment of gastric fundal varices in humans. Gastrointest Endosc 2004;59(4):5538. [49] Yoshida H, Onda M, Tajiri T, et al. New techniques: combined endoscopic injection sclerotherapy and ligation for acute bleeding from gastric varices. Hepatogastroenterology 2002; 49:9324. [50] Motsumoto A, Hamamoto N, Nomura T, et al. Balloon-occluded retrograde transvenous obliteration of high-risk gastric fundal varices. Am J Gastroenterol 1999;94:6439.