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Pathogenesis of variceal bleeding in patients with cirrhosis

Pathogenesis of variceal bleeding in patients with cirrhosis
Literature review current through: May 2024.
This topic last updated: Jun 21, 2023.

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 bleeding, a direct consequence of portal hypertension [1]. Each episode of variceal bleeding is associated with up to 20 percent mortality [2,3]. In addition, survivors of an episode of active bleeding have a 70 percent risk of recurrent hemorrhage within one year of the bleeding episode [4,5].

The rationale for screening for esophageal varices is to identify patients at risk for bleeding from esophageal varices and to prevent bleeding and improve survival in such patients. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis".)

This topic will review the pathogenesis of variceal bleeding including the formation and progression of varices. The treatment of variceal bleeding and the prevention of recurrent variceal bleeding in patients with cirrhosis are discussed elsewhere. (See "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 develop variceal bleeding. The portal-hepatic venous pressure gradient (ie, the hepatic venous pressure gradient or HVPG) 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. However, such testing is not commonly performed because it is invasive and requires specialized equipment and clinical expertise. In most centers, noninvasive assessments such as platelet count and liver stiffness measurement by transient elastography are used to evaluate for portal hypertension. The indications for screening for esophageal varices are discussed separately. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis", section on 'Screening for esophageal varices'.)

The use of 12 mmHg as the threshold for defining clinically significant portal hypertension is supported by observational data. 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 [6]. (See "Portal hypertension in adults".)

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 [7]. 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 higher in patients with small varices at enrollment compared with those without varices (12 versus 2 percent).

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 [8].

PREDICTIVE FACTORS — Numerous clinical and physiologic factors are useful in predicting the risk of variceal bleeding 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 [9].

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 [9]. 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 [10]. 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).

Varices are typically categorized as large or small. During upper endoscopy, it is important to insufflate the esophagus while estimating variceal size, as failure to do so leads to overestimation of varix size. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis", section on 'Endoscopic evaluation'.)

Appearance of varices — In addition to size, several morphologic features of varices observed at endoscopy have been correlated with an increased risk of bleeding [7,9,11]. 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 1)

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 bleeding [12]:

The severity of liver disease is an important predictor of variceal bleeding. The Child classification is an index of liver disease 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 [4].

Risk factors for early rebleeding also include age >60 years, renal failure, and ascites [12,13]. 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 therapy for hepatitis C virus infection [1,14,15].

Variceal pressure — Variceal pressure may be measured accurately and relatively noninvasively with a pressure-sensitive endoscopic gauge, though this is not routinely done [16]. 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 [17]. 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 bleeding in an individual patient [18]. 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.  

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 [19]. Such varices were rare in those with a platelet count greater than 150,000 (negative predictive value of 99 percent). 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 [20].

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 topic (see "Patient education: Esophageal varices (Beyond the Basics)")

SUMMARY

Background – Variceal bleeding is a gastrointestinal emergency that is one of the major causes of death in patients with cirrhosis. Accurate identification of patients at high risk of bleeding permits targeted use of preventive measures. (See 'Introduction' above.)

Portal hemodynamics – Varices develop in order to decompress the hypertensive portal vein and return blood to the systemic circulation. A normal pressure gradient between the portal and hepatic veins (ie, the hepatic venous pressure gradient or HVPG) is 1 to 5 mmHg. Esophageal varices develop when HVPG is at least 10 mmHg, whereas the risk of bleeding from esophageal varices is associated with HVPG ≥12 mmHg. (See 'Formation of varices' above.)

Factors associated with increased risk of variceal bleeding – Numerous clinical and physiologic factors are useful in predicting the risk of variceal bleeding in patients with cirrhosis. These include the location, size, and appearance of varices, their pressure, and severity of liver disease. (See 'Predictive factors' above.)

These factors can be considered together to help predict the risk of hemorrhage in an individual patient. (See 'Risk classification' above.)

  1. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362:823.
  2. Reverter E, Tandon P, Augustin S, et al. A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology 2014; 146:412.
  3. Tapper EB, Friderici J, Borman ZA, et al. A Multicenter Evaluation of Adherence to 4 Major Elements of the Baveno Guidelines and Outcomes for Patients With Acute Variceal Hemorrhage. J Clin Gastroenterol 2018; 52:172.
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  5. Garcia-Tsao G, Bosch J. Varices and Variceal Hemorrhage in Cirrhosis: A New View of an Old Problem. Clin Gastroenterol Hepatol 2015; 13:2109.
  6. D'Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131:1611.
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  8. Treeprasertsuk S, Kowdley KV, Luketic VA, et al. The predictors of the presence of varices in patients with primary sclerosing cholangitis. Hepatology 2010; 51:1302.
  9. Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992; 16:1343.
  10. Simonetto DA, Liu M, Kamath PS. Portal Hypertension and Related Complications: Diagnosis and Management. Mayo Clin Proc 2019; 94:714.
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  14. Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010; 51:2069.
  15. Singal AG, Volk ML, Jensen D, et al. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010; 8:280.
  16. Bosch J, Bordas JM, Rigau J, et al. Noninvasive measurement of the pressure of esophageal varices using an endoscopic gauge: comparison with measurements by variceal puncture in patients undergoing endoscopic sclerotherapy. Hepatology 1986; 6:667.
  17. Nevens F, Bustami R, Scheys I, et al. Variceal pressure is a factor predicting the risk of a first variceal bleeding: a prospective cohort study in cirrhotic patients. Hepatology 1998; 27:15.
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