INTRODUCTION — Cirrhosis affects 3.6 out of every 1000 adults in North America, and is responsible for more than one million days of work-loss and 32,000 deaths annually. A major cause of cirrhosis-related morbidity and mortality is the development of variceal hemorrhage, a direct consequence of portal hypertension [1]. Each episode of active variceal hemorrhage is associated with up to 20 percent mortality [2-5]. In addition, survivors of an episode of active bleeding have a 70 percent risk of recurrent hemorrhage within one year of the bleeding episode [6].
Variceal hemorrhage occurs in 25 to 40 percent of patients with cirrhosis [7]. While several modalities are available for primary prophylaxis of variceal bleeding, many are associated with significant adverse effects.
Accurate identification of patients at highest risk of bleeding permits stratification in an attempt to avoid potentially harmful preventive treatments in the 60 to 75 percent of patients who will never have variceal bleeding.
This topic will review the formation and progression of varices and the predictive factors and risk classification for variceal bleeding. Primary prophylaxis for variceal hemorrhage, the treatment of variceal hemorrhage, and the prevention of recurrent variceal hemorrhage in patients with cirrhosis are discussed elsewhere. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis" and "Overview of the management of patients with variceal bleeding" and "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis".)
FORMATION OF VARICES — Portal pressure is determined by the product of portal flow volume and resistance to outflow from the portal vein. Portal hypertension (defined as hydrostatic pressure >5 mmHg) results initially from obstruction to portal venous outflow. Obstruction may occur at a presinusoidal (portal vein thrombosis, portal fibrosis, or infiltrative lesions), sinusoidal (cirrhosis), or postsinusoidal (veno-occlusive disease, Budd-Chiari syndrome) level. Cirrhosis is the most common cause of portal hypertension; in these patients, elevated portal pressure results from both increased resistance to outflow through distorted hepatic sinusoids, and enhanced portal inflow due to splanchnic arteriolar vasodilation.
Varices develop in order to decompress the hypertensive portal vein and return blood to the systemic circulation. They are seen when the pressure gradient between the portal and hepatic veins rises above 12 mmHg; patients with lower values do not form varices and do not bleed. The portal-hepatic venous pressure gradient is obtained by hepatic venous catheterization, with measurement of the difference between the wedged hepatic venous pressure (which approximates the sinusoidal and portal pressures in cirrhosis) and the free hepatic venous pressure. This procedure is routinely performed in many European centers, but less commonly in the United States. Although it does not predict the size of varices, it may be useful for monitoring the success of therapy aimed at lowering portal pressures, such as beta blockers. A systematic review of 12 studies found that a reduction of the hepatic vein pressure gradient to less than or equal to 12 mmHg was associated with a significant reduction in the risk of variceal bleeding and mortality [8].
An illustrative study evaluated the relationship between the hepatic vein pressure gradient and the formation of and bleeding from varices [9]. The following observations were noted:
●All 72 patients with varices by endoscopy had a gradient above 12 mmHg
●The mean gradient in 49 patients with bleeding varices was 20.4 mmHg and none of these patients had a gradient below 12 mmHg
●The gradient did not predict the size of varices, being similar in those with large and small varices
PROGRESSION OF VARICES — The rate of development and progression of esophageal varices in patients with cirrhosis has not been extensively evaluated. One of the largest prospective studies included 206 cirrhotic patients (113 without varices and 93 with small esophageal varices at baseline) who were followed prospectively for an average of 37 months [10]. An endoscopy was performed annually. The following findings were noted:
●New varices developed in 5 percent at year 1, and 28 percent at year 3.
●Small varices progressed in size at a rate of 12 percent in year 1, and 31 percent at year 3.
●Progression was predicted by the Child-Pugh score (calculator 1 and calculator 2), the presence of red wale marks on the first examination, and an alcohol as the cause of cirrhosis.
●The two-year risk of bleeding was significantly higher in patients with small varices at enrollment compared with those without varices (12 versus 2 percent).
In a study of 218 patients with Child class A cirrhosis due to chronic hepatitis C with 12 years of follow-up, none of the patients who achieved a sustained virological response (SVR) developed varices compared with the rates among untreated patients (32 percent) and treated patients who did not attain an SVR (39 percent) [11]. The rate of variceal development was related to hepatitis C virus (HCV) genotype 1b and to baseline MELD score. (See "Model for End-stage Liver Disease (MELD)".)
When patients with primary sclerosing cholangitis (PSC) were followed over five years, 20 percent were found to have de novo esophageal varices. A higher baseline Mayo clinical risk score and the ratio of serum aspartate aminotransferase to serum alanine aminotransferase (AST/ALT ratio) was associated with varices, while the development of varices was associated with a platelet count less than 205,000/mm3 and a bilirubin greater than 1.7 mg/dL [12].
PREDICTIVE FACTORS — Numerous clinical and physiologic factors are useful in predicting the risk of variceal hemorrhage in patients with cirrhosis. These include:
●Location of varices
●Size of varices
●Appearance of varices
●Clinical features of the patient
●Variceal pressure
Location of varices — The most common sites for development of varices are the distal esophagus, stomach, and rectum, although theoretically varices may develop at any level of the gastrointestinal (GI) tract between the esophagus and rectum. Varices develop deep within the submucosa in the mid-esophagus, but become progressively more superficial in the distal esophagus. Thus, esophageal varices at the gastroesophageal junction have the thinnest layer of supporting tissue and are most likely to rupture and bleed.
Varices in the gastric fundus also bleed frequently. Gastric varices are often classified according to their location, which correlates with their risk of hemorrhage:
●Varices in direct continuity with the esophagus along the lesser and greater curvatures of the stomach are called gastroesophageal varices (GOV) types 1 and 2, respectively.
●Isolated gastric varices in the fundus (IGV1) occur less frequently than GOVs [13].
The relationship between the site of the varices and the clinical risk of bleeding was illustrated in a prospective study of 568 consecutive patients with varices, 393 of whom were bleeding [13]. The mean transfusion requirement in patients with bleeding gastric varices was higher than in those with esophageal varices (4.8 versus 2.9 units per patient). Bleeding from isolated gastric varices in the fundus (IGV1) occurred much more frequently than either GOVs or isolated gastric varices at other loci in the stomach (IGV2) (figure 1).
Size of varices — The risk of variceal bleeding correlates independently with the diameter (size) of the varix [14]. The explanation for the relationship between variceal size and bleeding risk is derived from Laplace's law; small increases in the vessel radius result in a large increase in wall tension (which is the force tending to cause variceal rupture).
There are several ways in which esophageal variceal size is quantified; none are exact and all involve subjective evaluation. A commonly employed system of classification includes the following (picture 1) [15,16]:
●F1: Small, straight varices
●F2: Enlarged, tortuous varices that occupy less than one-third of the lumen
●F3: Large, coil-shaped varices that occupy more than one-third of the lumen
It is important to insufflate the esophagus while estimating variceal size, as failure to do so leads to overestimation. There is increasing effort to classify varices based on those that require therapy (F2 and F3) and those that do not (usually F1, except for patients with decompensated cirrhosis who may require therapy regardless of varix size) [17]. (See 'Clinical features' below.)
Appearance of varices — In addition to size, several morphologic features of varices observed at endoscopy have been correlated with an increased risk of hemorrhage [10,13,18]. These characteristics describe manifestations of a red appearance, or "red signs":
●Red wale marks are longitudinal red streaks on varices that resemble red corduroy wales (picture 2)
●Cherry red spots are discrete red cherry-colored spots that are flat and overlie varices
●Hematocystic spots are raised discrete red spots overlying varices that resemble "blood blisters"
●Diffuse erythema denotes a diffuse red color of the varix
Clinical features — Several clinical features of the patient are related to the risk of variceal hemorrhage [19]:
●The degree of liver dysfunction is an important predictor of variceal hemorrhage. The Child classification is an index of liver dysfunction based upon serum albumin concentration, bilirubin level, prothrombin time, and the presence of ascites and encephalopathy (table 1) (calculator 1 and calculator 2). A higher score in this classification scheme is associated with a higher likelihood of variceal bleeding.
●History of a previous variceal bleed predicts a high likelihood of a subsequent bleeding episode. As an example, while only one-third of all patients with cirrhosis experience variceal hemorrhage, more than 70 percent experience further episodes of variceal bleeding after an index bleed. These bleeding episodes may be considered as "early" or "late" with respect to their temporal relationship to the index bleed; one-third of patients with an index bleed will rebleed within six weeks, and one-third will rebleed after six weeks [6].
Risk factors for early rebleeding also include age >60 years, renal failure, and ascites [16,19]. The risk of early rebleeding is greatest immediately after cessation of active hemorrhage (50 percent of such episodes occur within 48 hours) and subsides over time.
There is evidence that treatment of the underlying cause of the liver disease may reduce the severity of the portal hypertension and subsequent variceal hemorrhage. This is most often seen in patients who start alcohol abstinence and in those who have achieved a sustained virological response after hepatitis C therapy [1,11,20].
Variceal pressure — Variceal pressure may be measured accurately and relatively noninvasively with a pressure-sensitive endoscopic gauge, though this is not routinely done [21]. The variceal pressure may be an important predictor for variceal hemorrhage. In one study, for example, 87 patients with cirrhosis and large esophageal varices who had never had variceal bleeding were followed for 12 months [22]. Variceal hemorrhage developed in 28 patients (32 percent). Variables predictive of a first bleed included: the level of variceal pressure; risk classification using the Child class, variceal size, and endoscopic appearance of the varices (see below); and the interval between diagnosis of varices and the start of the study. Specifically, the incidence of variceal bleeding with different levels of variceal pressure was as follows:
●≤13 mmHg - 0/25 (0 percent)
●>13 and ≤14 mmHg - 1/11 (9 percent)
●>14 and ≤15 mmHg - 2/12 (17 percent)
●>15 and ≤16 mmHg - 7/14 (50 percent)
●>16 mmHg - 18/25 (72 percent)
Adding variceal pressure (categorized as > or ≤15.2 mmHg) to the risk classification discussed below significantly improved the predictive value of this classification.
RISK CLASSIFICATION — The Child class (calculator 1 and calculator 2), variceal size, and presence of red wale markings can be used to calculate a prognostic index that numerically quantifies the risk of variceal hemorrhage in an individual patient (table 2) [15]. The calculated risk is greatest in the first one to two years from the time of identification of these risk factors. As an example, a patient with Child class C cirrhosis and tense ascites who has large varices with red signs has an approximately 76 percent likelihood of developing variceal hemorrhage within one year. Such a patient is clearly a candidate for prophylactic therapy to prevent bleeding. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis".)
One study evaluated variables that predicted the presence of high-risk varices (ie, medium to large varices) in 1000 patients with hepatitis C virus (HCV) who had advanced fibrosis but compensated liver function [23]. Such varices were rare in those with a platelet count greater than 150,000 (negative predictive value of 99 percent). Whether these data can be generalized to other forms of liver disease is unclear. A second study showed that a calibrated Model for End-stage Liver Disease (MELD) score was able to predict mortality after acute variceal bleeding in cohorts of patients from Spain and Canada [2]. A MELD score >19 was associated with 20 percent mortality rate, while a MELD score <11 was associated with <5 percent mortality rate. MELD scores have also been shown to predict gastric variceal bleeding [24].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cirrhosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials: "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)
●Beyond the Basics topics (see "Patient education: Esophageal varices (Beyond the Basics)")
SUMMARY
●Variceal hemorrhage occurs in 25 to 40 percent of patients with cirrhosis. Accurate identification of patients at highest risk of bleeding permits targeted use of preventive measures. (See 'Introduction' above.)
●Numerous clinical and physiologic factors are useful in predicting the risk of variceal hemorrhage in patients with cirrhosis. These include the location, size, and appearance of varices, their pressure, and clinical features of the patient. (See 'Predictive factors' above.)
●These factors can be considered together to help predict the risk of hemorrhage in an individual patient (table 2). (See 'Risk classification' above.)
