Key points

Background

Cirrhosis is a common and burdensome condition. It is responsible for approximately 1 million days of work lost and 32,000 annual deaths in the United States, and thus has a substantial effect on productivity and survival. The high mortality in cirrhosis is attributable, in part, to the development of varices and subsequent hemorrhage. Despite substantial advances in medical management of variceal bleeding, each episode of active variceal bleeding is fatal in 30% of cases.

Development of varices is a direct consequence of portal hypertension and reflects abnormal changes in both portal resistance and flow. Portal hypertension is commonly measured using the hepatic venous pressure gradient (HVPG), which is the difference between wedged and free hepatic venous pressure. Varices generally develop when the hepatic venous pressure gradient (HVPG) exceeds 5 to 10 mm Hg as a compensatory mechanism to decompress the portal system; variceal bleeding occurs when the HVPG exceeds 12 mm Hg. Esophageal varices are present in approximately 40% of patients with cirrhosis and as many as 60% of patients with cirrhosis and ascites. In patients without varices, new varices develop at the rate of 5% to 8% per year. In patients with small varices at the time of initial endoscopic screening, progression to large varices occurs at a rate of 10% to 15% per year. One of the largest prospective studies that followed the natural history of variceal progression enrolled 206 patients with cirrhosis. Of these, 113 patients did not have varices at baseline and 93 patients had small varices. After an average follow-up of 37 months, 28% of patients (without varices) developed varices, whereas 31% of patients (with small varices) experienced progression in variceal size. The strongest predictors of progression were the Child-Pugh score at baseline, presence of stigmata of bleeding (red wale markings), baseline platelet count, and alcohol-related liver disease. The risk of variceal bleeding was significantly higher in the patients who had small varices at baseline compared with those who did not have varices (12% vs 2% at 2 years). A more recent study using data from the HALT-C trial found a similar rate of de novo varices development and progression (26.2% and 35.3%, respectively) during a median follow-up of 48 months. Hispanic race and lower baseline albumin level were both strongly associated with the risk of varices development.

Several clinical and physiologic factors are associated with the risk of first variceal hemorrhage. These include variceal location, size, appearance of the varices, underlying HVPG, and the degree of hepatic dysfunction. Of these, HVPG is the most important and a potentially modifiable risk factor. HVPG serves as an accurate surrogate marker of variceal development, as well as the risk of variceal bleeding. In a systematic review of prospective studies, a reduction in the HVPG to 12 mm Hg or lower, or a reduction of 20% or more from baseline significantly reduced the risk of first variceal bleeding (pooled odds ratio 0.21, 95% confidence interval [CI] 0.05–0.80). Therapies aimed at reducing the HVPG below this threshold can affect the progression of varices and reduce the risk of first variceal bleeding.

Background

Cirrhosis is a common and burdensome condition. It is responsible for approximately 1 million days of work lost and 32,000 annual deaths in the United States, and thus has a substantial effect on productivity and survival. The high mortality in cirrhosis is attributable, in part, to the development of varices and subsequent hemorrhage. Despite substantial advances in medical management of variceal bleeding, each episode of active variceal bleeding is fatal in 30% of cases.

Development of varices is a direct consequence of portal hypertension and reflects abnormal changes in both portal resistance and flow. Portal hypertension is commonly measured using the hepatic venous pressure gradient (HVPG), which is the difference between wedged and free hepatic venous pressure. Varices generally develop when the hepatic venous pressure gradient (HVPG) exceeds 5 to 10 mm Hg as a compensatory mechanism to decompress the portal system; variceal bleeding occurs when the HVPG exceeds 12 mm Hg. Esophageal varices are present in approximately 40% of patients with cirrhosis and as many as 60% of patients with cirrhosis and ascites. In patients without varices, new varices develop at the rate of 5% to 8% per year. In patients with small varices at the time of initial endoscopic screening, progression to large varices occurs at a rate of 10% to 15% per year. One of the largest prospective studies that followed the natural history of variceal progression enrolled 206 patients with cirrhosis. Of these, 113 patients did not have varices at baseline and 93 patients had small varices. After an average follow-up of 37 months, 28% of patients (without varices) developed varices, whereas 31% of patients (with small varices) experienced progression in variceal size. The strongest predictors of progression were the Child-Pugh score at baseline, presence of stigmata of bleeding (red wale markings), baseline platelet count, and alcohol-related liver disease. The risk of variceal bleeding was significantly higher in the patients who had small varices at baseline compared with those who did not have varices (12% vs 2% at 2 years). A more recent study using data from the HALT-C trial found a similar rate of de novo varices development and progression (26.2% and 35.3%, respectively) during a median follow-up of 48 months. Hispanic race and lower baseline albumin level were both strongly associated with the risk of varices development.

Several clinical and physiologic factors are associated with the risk of first variceal hemorrhage. These include variceal location, size, appearance of the varices, underlying HVPG, and the degree of hepatic dysfunction. Of these, HVPG is the most important and a potentially modifiable risk factor. HVPG serves as an accurate surrogate marker of variceal development, as well as the risk of variceal bleeding. In a systematic review of prospective studies, a reduction in the HVPG to 12 mm Hg or lower, or a reduction of 20% or more from baseline significantly reduced the risk of first variceal bleeding (pooled odds ratio 0.21, 95% confidence interval [CI] 0.05–0.80). Therapies aimed at reducing the HVPG below this threshold can affect the progression of varices and reduce the risk of first variceal bleeding.

Primary prophylaxis

Prophylaxis is derived from the Greek word prophulaktikos , meaning “prevention.” Primary prophylaxis entails prevention of the first episode of variceal bleeding after diagnosis of varices. However, this concept can be expanded to (1) prevention of formation of varices (preprimary prophylaxis), (2) prevention of progression of variceal size (early-primary prophylaxis), and (3) prevention of the first episode of bleeding (primary prophylaxis).

Screening for varices

Although the point prevalence of varices in patients with cirrhosis is relatively high, most patients with cirrhosis may not have varices. As a result, guidelines recommend screening for the presence of varices in patients with cirrhosis and initiating treatment targeted at primary prophylaxis for patients identified to have high-risk varices.

Esophagogastroduodenoscopy (EGD) is considered the gold standard for the diagnosis of varices. However, EGD is relatively expensive and requires specialized expertise to perform. Moreover, as mentioned previously, most patients undergoing EGD either do not have varices or have varices that do not require prophylactic treatment (see later in this article), thus substantially increasing the cost associated with screening with EGD. The alternative strategies to universal screening with EGD are empiric beta-blocker therapy (ie, without prior screening) or screening with less expensive and less invasive diagnostic tools.

A randomized controlled trial (RCT) showed that empiric, nonselective beta-blockers are ineffective in preventing varices in patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events. However, only a small proportion of patients included in this trial had Child class B cirrhosis (10%) and none had Child class C cirrhosis. Therefore, it is unclear if the strategy of empiric beta-blockers would be effective in patients with a high probability of underlying varices, such as those with decompensated cirrhosis. Nonetheless, in light of these data, beta-blockers cannot be recommended empirically in patients without documented varices.

Given its noninvasive nature and relative ease of administration, video capsule endoscopy (VCE) may play a role in screening for varices. However, a multicenter trial designed to assess the diagnostic performance of VCE in comparison with EGD found that EGD was superior to VCE in identifying patients with varices. Overall, EGD identified esophageal varices in 180 (62.5%) of 292 patients. VCE identified esophageal varices in 152 of these patients (difference 15.6%; 95% CI 11.4–19.8 in favor of EGD). VCE had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 84%, 88%, 92%, and 77%, respectively, for identifying patients with esophageal varices compared with the gold standard of EGD. In differentiating between medium/large varices requiring treatment and absent/small varices requiring surveillance, the sensitivity, specificity, PPV, and NPV for VCE were 78%, 96%, 87%, and 92%, respectively. In another study, 120 patients with both cirrhotic and noncirrhotic portal hypertension underwent VCE followed by EGD at the time of screening. The sensitivity, specificity, NPV, and PPV of VCE for diagnosis of varices was 77%, 86%, 69%, and 90%, respectively. The interobserver concordance was generally poor (diagnosis of varices 79.4%; grading of varices 66.4%; indication for prophylaxis 89.7%) in this study.

Several studies have evaluated the predictive accuracy of multidetector computerized tomography (CT) esophagography to detect and grade esophageal varices. This procedure requires esophageal insufflation via a transnasal catheter and thus is minimally invasive. The study by Kim and colleagues included 90 patients with cirrhosis (65 men, mean age 54.8 years); 30 patients had endoscopic evidence of large esophageal varices. There was close correlation and substantial agreement between endoscopic and CT esophagographic grades (κ = 0.831). CT esophagography performed well in differentiating between low- and high-risk varices with the area under the receiver operating characteristic curve (AUROC) of 0.93 to 0.95. Perri and colleagues prospectively evaluated 102 patients who underwent both CT and endoscopic screening for gastroesophageal varices. The multidetector CT scan with intravenous contrast was highly sensitive in identifying large esophageal varices (sensitivity = 90% compared with EGD). However, the specificity was limited (specificity = 50%). Patients preferred CT scan over EGD in both studies.

The use of the platelet count/spleen diameter ratio has also been proposed as a noninvasive tool to predict the presence of varices. This ratio is calculated by dividing the platelet count (number/mm ³ ) by the maximum spleen diameter (in mm) as estimated by abdominal ultrasound. In using a cutoff value of 909, Giannini and colleagues found that the PPV and NPV of platelet count/spleen diameter ratio for the presence of varices were 96% and 100%, respectively, the AUROC was 0.98. However, restricting the analysis to patients with compensated cirrhosis (the population in which this index may have the highest clinical utility), the PPV dropped to 74%. In an independent multicenter cohort study, the PPV and NPV of the platelet count/spleen diameter ratio were 76.6% and 87.0%, respectively. Neither study demonstrated this index to be a reliable predictor of varices.

In summary

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  Several noninvasive and minimally invasive means of identifying patients with varices have been tested in the recent years. However, the predictive accuracy of these markers is still unsatisfactory.

  
  
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  Until large prospective studies are conducted, EGD screening remains the principal means of assessing for the presence of varices.

  
  
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  More studies are needed to ascertain whether the simplicity and improved patient tolerance of VCE or CT esophagography over EGD can increase the rate of adherence to screening programs. For the time being, these modalities may be used in selected patients who are unwilling or unable to undergo EGD.

Pre-primary prophylaxis

Currently, the most effective strategy in preventing development of varices is effective management of the underlying liver disease. For example, in a prospective study by Bruno and colleagues, only one of the patients with chronic hepatitis C cirrhosis who achieved a sustained virological response (SVR) developed varices during a 12-year follow-up period. In contrast, 32% of untreated patients and 39% of patients who were treated but did not achieve SVR developed varices.

Thus, the most effective strategy in preventing development of varices in patients with cirrhosis is effective management of the underlying liver disease

Primary prophylaxis in patients with small varices

There has been one meta-analysis evaluating the role of nonselective beta-blockers in the prevention of a first variceal bleed in patients with small varices. Since the publication of this meta-analysis, 2 additional trials have evaluated this same question. Combining these data, the incidence of first variceal bleeding was 2.5% in the treatment group compared with 7.4% in the control group over 2-year follow-up (a statistically nonsignificant difference).

Two of these studies investigated the efficacy of beta-blockers in preventing the enlargement of small varices with contradictory results. In the first study, 2-year proportion of patients with large varices was higher in the propranolol group compared with the placebo group (31% vs 14%). However, more patients in the propranolol group had varices at baseline compared with the placebo group (52% vs 30%). Moreover, one-third of the patients in this study were lost to follow-up. In the second larger randomized trial, patients with small varices treated with nadolol had a significantly slower progression to larger varices (11% at 3 years) than patients who received placebo (37% at 3 years). In this study, patients received beta-blockers within 3 (±2.5) months of varices diagnosis.

Collectively, these data suggest that the risk of variceal bleeding is low in patients with small varices, and that beta-blockers do not reduce this risk further, at least in the intermediate term. Beta-blockers may slow the progression of varices, but this effect needs to be confirmed in future studies. Patients with small varices and no high-risk features should undergo routine surveillance to monitor for development of variceal enlargement and high-risk features. Of note, none of these aforementioned studies presented data stratified on the basis of the severity of underlying liver disease or presence versus absence of high-risk endoscopic features to inform decisions based on these factors.

Given the available data, the American Association for Study of Liver Diseases (AASLD) and the Baveno V guidelines provide the following recommendations for patients who have small varices.

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  In patients with cirrhosis and small varices that have not bled and have no criteria for increased risk of bleeding, beta-blockers can be used, although their long-term benefit has not been established

  
  
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  In patients with cirrhosis and small varices that have not bled but have criteria for increased risk of bleeding (child class B or C or presence of red wale markings on varices), beta-blockers should be used for the prevention of first variceal hemorrhage.