Hemorrhage美国肝病学会食管静脉出血治疗指

AASLD PRACTICE GUIDELINES Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis Guadalupe Garcia-Tsao,1 Arun J. Sanyal,2 Norman D. Grace,3 William Carey,4 and the Practice Guidelines Committee of the American Association for the Study of Liver Diseases, the Practice Parameters Committee of the American College of Gastroenterology This guideline has been approved by the American Asso- ciation for the Study of Liver Diseases and the American College of Gastroenterology and represents the position of both associations. Preamble These recommendations provide a data-supported ap- proach to the management of patients with varices and variceal hemorrhage. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) several con- sensus conferences among experts; (3) the American Col- lege of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines1; (4) guideline policies, including the American Association for the Study of Liver Diseases’ Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterologi- cal Association’s Policy Statement on the Use of Medical Practice Guidelines2; and (5) the authors’ years of experi- ence caring for patients with cirrhosis and varices. Intended for use by healthcare providers, these recom- mendations suggest preferred approaches to the diagnos- tic, therapeutic, and preventive aspects of care. As with other practice guidelines, this guideline is not intended to replace clinical judgment but rather to provide general guidelines applicable to the majority of patients. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on rele- vant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and re- ported with each recommendation (Table 1, adapted from the American College of Cardiology and the Amer- ican Heart Association Practice Guidelines3,4). When little or no data exist from well-designed pro- spective trials, emphasis is given to results from large series and reports from recognized experts. Further controlled clin- ical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical con- siderations may justify a course of action that differs from these recommendations. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the American College of Gastroenterology. Introduction Portal hypertension is a progressive complication of cirrhosis. Therefore, the management of the patient with cirrhosis and portal hypertensive gastrointestinal bleeding depends on the phase of portal hypertension at which the patient is situated, from the patient with cirrhosis and portal hypertension who has not yet developed varices to the pa- tient with acute variceal hemorrhage for whom the objective is to control the active episode and prevent rebleeding. Practice guidelines for the diagnosis and treatment of gastroesophageal variceal hemorrhage, endorsed by the American Association for the Study of Liver Diseases (AASLD), AmericanCollege ofGastroenterology (ACG), American Gastroenterological Association (AGA), and American Society of Gastrointestinal Endoscopy (ASGE), were published in 1997.5 Since then, a number of randomized controlled trials have advanced our ap- proach to managing variceal hemorrhage. Three interna- tional consensus conferences have been held (Baveno III in 2000, Baveno IV in 2005, and an AASLD/EASL single topic conference in 2007) in which experts in the field have evaluated the changes that have occurred in our un- derstanding of the pathophysiology and management of gastroesophageal hemorrhage.6,7 In this updated practice guideline we have reviewed the randomized controlled trials and meta-analyses published in the last decade and have incorporated recommendations made by consensus. 1From the Section of Digestive Diseases, Yale University School of Medicine and VACT Healthcare System, New Haven, CT; 2Division of Gastroenterology, Vir- ginia Commonwealth University Medical Center, Richmond, VA; 3Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA; 4Department of Gastroenterology and Hepatology, The Cleveland Clinic, Cleveland, OH. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21907 Potential conflict of interest: Nothing to report. 922 Pathophysiology of Portal Hypertension in Cirrhosis Cirrhosis, the end stage of any chronic liver disease, can lead to portal hypertension. Portal pressure increases ini- tially as a consequence of an increased resistance to flow mostly due to an architectural distortion of the liver sec- ondary to fibrous tissue and regenerative nodules. In ad- dition to this structural resistance to blood flow, there is an active intrahepatic vasoconstriction that accounts for 20%-30% of the increased intrahepatic resistance,8 and that is mostly due to a decrease in the endogenous pro- duction of nitric oxide.9,10 Portal hypertension leads to the formation of porto-systemic collaterals. However, portal hypertension persists despite the development of these collaterals for 2 reasons: (1) an increase in portal venous inflow that results from splanchnic arteriolar va- sodilatation occurring concomitant with the formation of collaterals11; and (2) insufficient portal decompression through collaterals as these have a higher resistance than that of the normal liver.12 Therefore, an increased portal pressure gradient results from both an increase in resis- tance to portal flow (intrahepatic and collateral) and an increase in portal blood inflow. Evaluation of Portal Hypertension The preferred, albeit indirect, method for assessing portal pressure is the wedged hepatic venous pressure (WHVP) measurement, which is obtained by placing a catheter in the hepatic vein and wedging it into a small branch or, better still, by inflating a balloon and occluding a larger branch of the hepatic vein. The WHVP has been shown to correlate very closely with portal pressure both in alcoholic and non-alcoholic cirrhosis.13 The WHVP is always corrected for increases in intraabdominal pressure (e.g., ascites) by subtracting the free hepatic vein pressure (FHVP) or the intraabdominal inferior vena cava pres- sure, which act as internal zeroes. The resultant pressure is the hepatic venous pressure gradient (HVPG), which is best accomplished with the use of a balloon catheter, usu- ally taking triplicate readings and, when measured with a proper technique, is very reproducible and reliable.14 Since it is ameasure of sinusoidal pressure, theHVPGwill be elevated in intrahepatic causes of portal hypertension, such as cirrhosis, but will be normal in prehepatic causes of portal hypertension, such as portal vein thrombosis. The normal HVPG is 3-5 mmHg. The HVPG and changes in HVPG that occur over time have predictive value for the development of esophagogastric varices,15,16 the risk of variceal hemorrhage,17-19 the development of non-variceal complications of portal hypertension,17,20,21 and death.19,21-23 Single measurements are useful in the prognosis of both compensated and decompensated cir- rhosis, while repeat measurements are useful to monitor response to pharmacological therapy and progression of liver disease. Limitations to the generalized use of HVPG measurement are the lack of local expertise and poor ad- herence to guidelines that will ensure reliable and repro- ducible measurements,14 as well as its invasive nature. Natural History of Varices Gastroesophageal varices are the most relevant porto- systemic collaterals because their rupture results in variceal hemorrhage, the most common lethal complica- tion of cirrhosis. Varices and variceal hemorrhage are the complications of cirrhosis that result most directly from portal hypertension. Patients with cirrhosis and gastro- esophageal varices have an HVPG of at least 10-12 mm Hg.15,24 Gastroesophageal varices are present in approximately 50% of patients with cirrhosis. Their presence correlates with the severity of liver disease (Table 2); while only 40% of Child A patients have varices, they are present in 85% of Child C patients.25 Patients with primary biliary cir- rhosis may develop varices and variceal hemorrhage early in the course of the disease even in the absence of estab- lished cirrhosis.26 It has also been shown that 16% of patients with hepatitis C and bridging fibrosis have esoph- ageal varices.27 Patients without varices develop them at a rate of 8% per year,16,28 and the strongest predictor for development of varices in those with cirrhosis who have no varices at the time of initial endoscopic screening is an HVPG �10 mmHg.16 Patients with small varices develop large varices Table 1. Grading System for Recommendations Classification Description Class I Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful, and effective. Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure or treatment. Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb Usefulness/efficacy is less well established by evidence/opinion. Class III Conditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not useful/effective and in some cases may be harmful. Level of Evidence Description Level A Data derived from multiple randomized clinical trials or meta- analyses. Level B Data derived from a single randomized trial, or nonrandomized studies. Level C Only consensus opinion of experts, case studies, or standard- of-care. HEPATOLOGY, Vol. 46, No. 3, 2007 GARCIA-TSAO ET AL. 923 at a rate of 8% per year. Decompensated cirrhosis (Child B/C), alcoholic cirrhosis, and presence of red wale marks (defined as longitudinal dilated venules resembling whip marks on the variceal surface) at the time of baseline en- doscopy are the main factors associated with the progres- sion from small to large varices.28 Variceal hemorrhage occurs at a yearly rate of 5%- 15%, and the most important predictor of hemorrhage is the size of varices, with the highest risk of first hemorrhage (15% per year) occurring in patients with large varices.29 Other predictors of hemorrhage are decompensated cir- rhosis (Child B/C) and the endoscopic presence of red wale marks.29 Although bleeding from esophageal varices ceases spontaneously in up to 40% of patients, and de- spite improvements in therapy over the last decade, it is associated with a mortality of at least 20% at 6 weeks.30-32 Patients with an HVPG �20 mmHg (measured within 24 hours of variceal hemorrhage) have been identified as being at a higher risk for early rebleeding (recurrent bleed- ing within the first week of admission) or failure to con- trol bleeding (83% vs. 29%) and a higher 1-year mortality (64% vs. 20%) compared to those with lower pres- sure.33,34 Late rebleeding occurs in approximately 60% of untreated patients, mostly within 1-2 years of the index hemorrhage.35,36 Variceal wall tension is probably the main factor that determines variceal rupture. Vessel diameter is one of the determinants of variceal tension. At an equal pressure, a large diameter vessel will rupture while a small diameter vessel will not rupture.37 Besides vessel diameter, one of the determinants of variceal wall tension is the pressure within the varix, which is directly related to the HVPG. Therefore, a reduction inHVPG should lead to a decrease in variceal wall tension, thereby decreasing the risk of rupture. Indeed, variceal hemorrhage does not occur when the HVPG is reduced to �12 mmHg.17,20 It has also been shown that the risk of rebleeding decreases sig- nificantly with reductions in HVPG greater than 20% from baseline.18 Patients whose HVPG decreases to�12 mmHg or at least 20% from baseline levels (“HVPG re- sponders”) not only have a lower probability of develop- ing recurrent variceal hemorrhage,36 but also have a lower risk of developing ascites, spontaneous bacterial peritoni- tis, and death.21 Gastric Varices Gastric varices are less prevalent than esophageal vari- ces and are present in 5%-33% of patients with portal hypertension with a reported incidence of bleeding of about 25% in 2 years, with a higher bleeding incidence for fundal varices.38 Risk factors for gastric variceal hemorrhage include the size of fundal varices (large�medium�small, defined as �10 mm, 5-10 mm, and �5 mm, respectively), Child class (C�B�A), and endoscopic presence of variceal red spots (defined as lo- calized reddish mucosal area or spots on the mucosal sur- face of a varix).39 Gastric varices are commonly classified based on their relationship with esophageal varices as well as their location in the stomach.38 Gastroesophageal var- ices (GOV) are an extension of esophageal varices and are categorized into 2 types. The most common are Type 1 (GOV1) varices, which extend along the lesser curvature. They are considered extensions of esophageal varices and should be managed similarly. Type 2 (GOV2) gastric var- ices extend along the fundus and tend to be longer and more tortuous. Isolated gastric varices (IGV) occur in the absence of esophageal varices and are also classified into 2 types. Type 1 (IGV1) are located in the fundus and tend to be tortuous and complex, and type 2 (IVG2) are lo- cated in the body, antrum, or around the pylorus. The presence of IGV1 fundal varices requires excluding the presence of splenic vein thrombosis. Diagnosis of Varices and Variceal Hemorrhage The gold standard in the diagnosis of varices is esopha- gogastroduodenoscopy (EGD). In a consensus meeting it Table 2. Child-Pugh Classification of the Severity of Cirrhosis Points* 1 2 3 Encephalopathy None Grade 1-2 (or precipitant-induced) Grade 3-4 (chronic) Ascites None Mild/Moderate (diuretic-responsive) Tense (diuretic-refractory) Bilirubin (mg/dL) �2 2–3 �3 Albumin (g/dL) �3.5 2.3–3.5 �2.8 PT (sec prolonged) or INR �4 4–6 �6 �1.7 1.7–2.3 �2.3 *5-6 points: Child A; 7-9 points: Child B; 10-15 points: Child C. 924 GARCIA-TSAO ET AL. HEPATOLOGY, September 2007 was recommended that the size classification be as simple as possible, i.e., in 2 grades (small and large),40 either by semiquantitative morphological assessment or by quanti- tative size with a suggested cut-off diameter of 5mm, with large varices being those greater than 5mm.When varices are classified in 3 sizes—small, medium, or large—as oc- curs in most centers by a semiquantitative morphological assessment (with small varices generally defined as mini- mally elevated veins above the esophageal mucosal sur- face, medium varices defined as tortuous veins occupying less than one-third of the esophageal lumen, and large varices defined as those occupying more than one-third of the esophageal lumen), recommendations for medium- sized varices are the same as for large varices,29 because this is how they were grouped in prophylactic trials. As shown below, nonselective �-blockers prevent bleeding in more than half of patients with medium or large varices. Therefore, it is recommended that patients with cirrhosis undergo endoscopic screening for varices at the time of diagnosis.41,42 Since the point prevalence of medium/large varices is approximately 15%-25%,25 the majority of subjects undergoing screening EGD either do not have varices or have varices that do not require pro- phylactic therapy. There is, therefore, considerable inter- est in developing models to predict the presence of high- risk varices by non-endoscopic methods. Several studies have evaluated possible noninvasive markers of esopha- geal varices in patients with cirrhosis, such as the platelet count, Fibrotest, spleen size, portal vein diameter, and transient elastography.43,44 However, the predictive accu- racy of such noninvasive markers is still unsatisfactory, and until large prospective studies of noninvasive markers are performed, endoscopic screening is still the main means of assessing for the presence of esophageal varices.43 Cost-effective analyses usingMarkov models have sug- gested either empiric �-blocker therapy for all patients with cirrhosis45 or screening endoscopy for patients with compensated cirrhosis, and universal �-blocker therapy without screening EGD for patients with decompensated cirrhosis.46 Neither of these strategies considers a recent trial showing that �-blockers do not prevent the develop- ment of varices and are associated with significant side effects,16 nor do they consider endoscopic variceal ligation as an alternative prophylactic therapy. Until prospective studies validate these approaches, screening EGD is still the recommended approach. The frequency of surveillance endoscopies in patients with no or small varices depends on their natural history. EGD should be performed once the diagnosis of cirrhosis is established.6,41 In patients with compensated cirrhosis who have no varices on screening endoscopy, the EGD should be repeated in 2-3 years.6 In those who have small varices, the EGD should be repeated in 1-2 years.6 In the presence of decompensated cirrhosis, EGD should be re- peated at yearly intervals.41,42 EGD is expensive and usually requires sedation. It can be avoided in patients with cirrhosis who are already on nonselective �-blockers for other reasons (e.g., arterial hypertension. In those on a selective �-blocker (metopro- lol, atenolol) for other reasons, switching to a nonselective �-blocker (propranolol, nadolol) would be necessary. A procedure that may replace EGD is esophageal capsule endoscopy. Two recent pilot studies show that capsule endoscopy is a safe and well-tolerated way to diagnose esophageal varices,47,48 although its sensitivity remains to be established. Thus, capsule endoscopymay play a future role in screening for esophageal varices if additional larger studies support its use. EGD also remains the main method for diagnosing variceal hemorrhage.7,41 The diagnosis of variceal hemor- rhage is made when diagnostic endoscopy shows one of the following: active bleeding from a varix, a “white nip- ple” overlying a varix, clots overlying a varix, or varices with no other potential source of bleeding.40 Recommendations 1. Screening esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal and gastric varices is recommended when the diagnosis of cirrhosis is made (Class IIa, Level C). 2. On EGD, esophageal varices should be graded as small or large (>5 mm) with the latter classification encompassing medium-sized varices when 3 grades are used (small, medium, large). The presence or absence of red signs (red wale marks or red spots) on varices should be noted (Class IIa, Level C). Management Recommendations Rationale for the management of varices Current therapies for the management of varices/ variceal hemorrhage and their effect on portal venous in- flow, portal resistance, and portal pressure are summarized in Table 3. Pharmacological therapy consists Table 3. Effect on Portal Flow, Resistance and Pressure with the Different Therapies for Varices/Variceal Hemorrhage Treatment Portal flow Portal resistance Portal pressure Vasoconstrictors (e.g., �-blockers) 22 1 2 Venodilators (e.g., nitrates) 2 2* 2 Endoscopic therapy – – – TIP