Medical management of bleeding varices: Primary and secondary prophylaxis

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Chapter 75A Medical management of bleeding varices

Primary and secondary prophylaxis

Overview

Variceal bleeding is the most serious complication of cirrhosis, with an up to 50% mortality rate within 30 days of presentation. However, as management has improved, so have patient outcomes (Carbonell et al, 2004; El-Serag & Everhart, 2000; Jamal et al, 2008a; Stokkeland et al, 2006). Specifically, the 30-day mortality rate has decreased from 30% to 43% in earlier eras to only 15% to 21% currently. These lower mortality rates may be attributed to the combined effects of aggressive clinical treatment protocols and the development of more effective therapies such as endoscopic band ligation; intravenous vasoactive medications, such as octreotide and terlipressin; and antibiotic prophylaxis. For example, Carbonell and colleagues (2004) reported that nearly all patients currently admitted for variceal bleeding receive antibiotic prophylaxis (94%) and endoscopic therapy (90%) within 24 hours compared with only 2% and 6%, respectively, 20 years ago. In addition, evidence suggests that prophylactic therapy is reducing the overall rate of bleeding; currently 15% fewer patients are hospitalized than a decade ago (Jamal et al, 2008b). This finding underscores the clinical utility of the early diagnosis of esophageal varices through aggressive screening strategies, careful surveillance for small varices, and prophylatic therapy with either β-blockers or endoscopic band ligation before or after variceal bleeding occurs.

Diagnosis of Esophageal Varices

Screening for esophageal varices is an important component in the long-term management of patients with portal hypertension because effective therapy may be applied once varices are identified. The gold standard test is upper endoscopy (de Franchis, 2005; Garcia-Tsao, 2007, 2008), during which the variceal size and presence of red wale markings should be noted. Varices are classified in three sizes: small varices show minimal elevation of veins above the mucosa; medium describes varices with tortuous veins that occupy less than one third of the lumen; and large varices occupy more than one third of the lumen. However, as recognized by all experienced endoscopists, the interobserver agreement in size estimation of esophageal varices varies (Bendtsen et al, 1990).

The diagnosis of esophageal varices should be considered in any patient with cirrhosis. (Garcia-Tsao et al, 2007; Garcia-Pagan et al, 2008). Because the risk of variceal progression and bleeding depend on both the severity of the underlying liver disease and appearance of the varices at endoscopy, patients with decompensated liver disease and high-risk endoscopic features (large varices, red wale markings) require more aggressive screening protocols. In addition, screening may also be appropriate in selected patients with bridging fibrosis because 16% may have esophageal varices (Sanyal et al, 2006). The likelihood of finding varices in a particular patient largely depends on the severity of the underlying liver disease, with a prevalence of 60% and 30% in decompensated and compensated patients, respectively (D’Amico et al, 1995; Sanyal et al, 2006). Once endoscopy has been performed, the presence or absence of varices has been established, and the varices have been graded according to severity, the requirement for further screening, surveillance, and therapy may be determined. In general, treatment recommendations for medium varices are the same as for large varices. The general protocol for screening and treatment is outlined in Table 75A.1.

Table 75A.1 Screening and Surveillance Recommendation for Esophageal Varices

Patient Characteristics Screening Interval
Cirrhosis, no prior varices on screening At diagnosis of cirrhosis
Compensated cirrhosis, no varices on screening Every 2 to 3 years
Decompensated cirrhosis, no varices on screening Yearly
Compensated cirrhosis, small varices on screening Every 1 to 2 years
Decompensated cirrhosis, small varices on screening Yearly
Medium or large varices on screening No further endoscopy
Received band ligation  

In cirrhotic patients without varices, the risk of varices subsequently developing is approximately 8% per year (Groszmann et al, 2005; Merli et al, 2003). The recommended screening interval to detect varices in such patients is within 3 years. With a yearly risk of new varices of 8%, the cumulative risk of developing new varices over 3 years would only be about 25%, and during this interval the risk of bleeding is quite small (1% per year) (Groszmann et al, 2005; Merli et al, 2003). Because the risk of developing varices is higher in patients with decompensation, the screening interval may be shortened in this instance (North Italian Endoscopic Club, 1988). Prophylactic therapy with β-blockers to prevent the development of varices or bleeding in cirrhotics without varices is not effective, as was determined by two randomized studies, one with propranolol (Cales et al, 1999) and one with timolol (Groszmann et al, 2005). Because both studies failed to show a benefit with nonselective β-blockers in these populations, the pharmacologic prevention of varices, or “preprimary prophylaxis,” is not possible at present.

In the patient with small varices identified at initial endoscopy, the yearly risk of developing large varices is 7% to 12% (Cales et al 1999; Merkel et al, 2004) and the risk of hemorrhage is only 5%. Repeat endoscopy should be performed at 2 years or yearly in the case of decompensation. Prophylactic treatment with β-blockers in patients with small varices has led to mixed results. In these studies, one trial reported a higher 2-year rate of developing large varices (31%) with treatment compared with placebo (14%), but the dropout rate in the study was very high. The other trial reported a lower rate of progression to large varices with β-blockers (11%) versus placebo (37%) after 3 years. The risk of bleeding was lower (12%) at 5 years with treatment compared with placebo (22%). However, the benefit of β-blockers was mitigated by the fact that the rate of bleeding in the placebo group, which was started on β-blockers once large varices were discovered, was the same as treatment once β-blocker therapy was initiated. In addition, the rate of withdrawal because of side effects was higher with β-blockers (10%) compared with placebo (1%). Because of these mixed results, patients with small varices should receive prophylactic β-blocker therapy only if they have risk factors for bleeding, such as advanced liver disease or red wale markings. In patients not receiving β-blockers, repeat endoscopy is recommended every other year or annually for decompensation, and repeat endoscopy is not required for patients taking β-blockers.

In patients with medium or large varices identified at screening endoscopy, prophylactic therapy is clearly recommended, as described below. This group of patients clearly derives the greatest benefit from therapy. The primary treatment options are obliteration with esophageal variceal band ligation (EVL) or reduction of portal pressure with oral pharmacologic agents. There is currently no role for decompressive therapy, transjugular intrahepatic portosystemic shunt (TIPS), or surgical shunting for prophylaxis of variceal bleeding. In addition, endoscopic sclerotherapy has no role in prophylaxis (see Chapter 70B).

Noninvasive Means of Diagnosing Esophageal Varices

Although upper endoscopy is the most effective screening tool for esophageal varices, the invasive nature of this procedure has led investigators to find alternative noninvasive imaging techniques, as well as methodologies for risk stratifying patients for screening, as shown in Table 75A.2. Noninvasive screening techniques have several potential advantages over endoscopy. They are generally better accepted by patients, which could potentially increase adherence to screening protocols. In addition, these methods are typically less expensive than endoscopy. Finally, varices are absent in most patients (60%) with compensensated cirrhosis. Because the diagnostic yield in this cohort of patients is low, alternative noninvasive screening could risk stratify patients eligible for invasive screening. The four general types of alternative screening modalities are 1) blood chemistries, 2) cross-sectional imaging, 3) transient elastography, and 4) alternative endoscopic techniques, such as ultrathin endoscopy and capsule endoscopy.

Table 75A.2 Diagnosis of Esophageal Varices

Technique Comments
Recommended Diagnostic Strategy
Upper endoscopy Gold standard of treatment
Alternative Diagnostic Strategies
Blood chemistries Not recommended
Cross-sectional imaging Not recommended
Transient elastography Not recommended
Potential for Risk Stratification
Ultrathin endoscopy May be useful, rarely applied
Capsule endoscopy For patients who cannot or will not undergo conventional endoscopy

The least invasive means of screening for varices is through analysis of blood chemistries. Numerous biochemical parameters have been considered to evaluate the presence of esophageal varices, including platelet count, prothrombin time, serum albumin, and Child-Turcotte-Pugh (CTP) class. However, none of these surrogate markers used alone or in combination is sufficiently reliable for use in clinical practice (D’Amico & Morabito, 2004; de Franchis, 2008; Qamar et al, 2008).

In recent years, cross-sectional imaging, including multidetector computer tomography (CT) and gadolinium-enhanced magnetic resonance (MRI), have been evaluated for esophageal variceal screening. However, compared with CT, there is relatively little experience with MRI (Annet et al, 2006; Goshima et al, 2009; Matsuo et al, 2003). Multidetector CT provides better images than conventional CT, thereby increasing the yield in identifying varices (Kim et al, 2009). In a direct comparison of multidetector CT and conventional endoscopy, both modalities identified varices, and radiologists accurately predicted the presence of large varices 93% of the time (Perri et al, 2008). However, the information from CT imaging was much less detailed compared with endoscopy. The absence of varices was accurately predicted by CT in only about 50% of patients; in more than one third of cases, it inaccurately identified small varices when large varices were seen endoscopically. Aside from limited sensitivity and specificity in variceal screening, CT has several other drawbacks . It cannot provide information about the red wale markings or other stigmata associated with increased risk for bleeding. In addition, exposure to ionizing radiation is significant, especially with repeated CT imaging (de Franchis, 2008; Thabut et al, 2008). However, one potential advantage of CT over endoscopy is its ability to identify other relevant abdominal pathology, namely hepatocellular carcinoma. Currently, cross-sectional imaging is not sufficiently reliable for use in routine clinical screening protocols for esophageal varices.

Transient elastography is an ultrasound technique that noninvasively measures tissue elasticity. This technique is studied primarily for measuring liver stiffness as a means to determine the presence and severity of hepatic fibrosis (Abenavoli et al, 2007; Del Poggio & Columbo, 2009). The test can easily be performed by nonphysicians with a dedicated device by generating a low-amplitude shear wave that propagates through the liver parenchyma. The velocity of propagation is directly proportional to liver stiffness and is automatically calculated by the device and expressed in units of pressure (kPa): the higher the value, the stiffer and more fibrotic the tissue and, by correlation, the more pressure required to deform the tissue. Although universally accepted ranges have not been developed, the general ranges for cutoff values for normal are up to 8 kPa and more than 13 to 18 kPa for cirrhosis.

Aside from being noninvasive and easily performed, the advantages of elastography include assessment of a larger hepatic area than liver biopsy and general correlation with the extent of histologic fibrosis. The disadvantages regarding variceal screening are that it is not a direct assessment of varices, and the test may be inaccurate or unreliable in patients with ascites and in obese patients. In fact, up to 10% of cases may not return any reading (Foucher et al, 2006; Sandrin et al, 2003).

Several studies have evaluated transient elastography in the noninvasive diagnosis and staging of esophageal varices. Theoretically, as liver stiffness and hepatic fibrosis progress, the likelihood of developing esophageal varices should increase. However, this methodology is subject to the same problems as other noninvasive techniques. Using a cutoff value of 12.5 kPa, Castera and colleagues (2009) studied 298 patients with hepatitis C virus (HCV) infection and reported only 76% sensitivity and 78% specificity in the diagnosis of esophageal varices. In another study, investigators compared two cutoff values for liver stiffness in predicting the presence of esophageal varices in 61 patients with advanced fibrosis from HCV (Vizzutti et al, 2007). At a lower cutoff of 17.6 kPa, the sensitivity was 90% and specificity was 43%. At the higher cutoff of 27.4 kPa, more patients with varices were missed (sensitivity of 70%), but specificity improved to 78%. Similar results were reported by Kazemi and colleagues (2006), who examined the correlation between liver stiffness and presence of large esophageal varices.

Although more studies are needed, current data suggest that the diagnostic accuracy of transient elastography is sufficiently limited that it cannot supplant upper endoscopy as a recommended screening technique for esophageal varices (de Franchis, 2008; Del Poggio, 2009). In fact, it seems unlikely that it would ever replace endoscopy as the primary screening tool. However, because it is a less invasive technique, elastography could possibly be used as an adjunct screening methodology. Patients could be monitored for changes in their transient elastography profile between recommended endoscopic screening intervals to potentially identify specific patients at higher risk for variceal progression. However, such screening and surveillance recommendations are only speculative at this point.

During the past decade, the utility of alternative video endoscopic devices has been studied in screening for esophageal varices. One of these modalities is the ultrathin endoscope inserted without sedation via a transnasal and transoral approach. The primary advantage of this procedure compared with conventional endoscopy is the avoidance of conscious sedation with its attendant risks, cost, and inconvenience. Unlike cross-sectional imaging or transient elastography, video endoscopy (ultrathin and capsule endoscopy) provides direct visualization of the esophageal mucosa that may improve estimation of variceal size and red wale markings, which is not possible with cross-sectional imaging. The primary disadvantage of alternative endoscopy is that compared with conventional endoscopy, these devices have a limited field of view and cannot perform interventions such as biopsy or banding.

Limited data are available on ultrathin endoscopy in variceal screening, and most studies, but not all, show that this technique is more easily performed, has greater patient acceptance, and provides an acceptable diagnostic yield compared with conventional endoscopy (Catanzaro et al, 2002; Madhotra et al, 2003; Saeian et al, 2002). However, these results are based on a very small number of patients. Despite some initially promising findings, ultrathin endoscopy has largely fallen out of favor; at most centers, ultrathin unsedated endoscopy is not used for screening or surveillance of esophageal varices.

Esophageal capsule endoscopy is perhaps the most promising option for minimally invasive screening of esophageal varices. This technique involves the ingestion of a capsule videoscope that transmits images as it traverses the esophagus. The patient is supine after ingestion of the device and is gradually placed in the upright position, which increases the transit time in the esophagus to provide better imaging. Compared with conventional endoscopy, capsule endoscopy offers the advantages of direct visualization of the esophagus, the absence of sedation, and less procedural discomfort and time.

Several drawbacks are associated with capsule endoscopy. Interventions obviously cannot be performed, the device cannot be manipulated to change its field of view, and it cannot insufflate the esophagus, which most physicians have found to be a critical step in the proper diagnosis and staging of varices. Finally, capsule endoscopy does not properly visualize gastric varices, which could therefore be missed.

Capsule endoscopy has been studied in the detection and grading of esophageal varices, and de Franchis and colleagues (2008) reported a study comparing capsule endoscopy with conventional endoscopy in 288 patients. The capsule and esophageogastroduodenoscopy (EGD) findings were concordant in 86% of cases. However, capsule endoscopy failed to identify varices in 28 cases, of which 24 (13%) were small and 4 (2.2%) were large varices, although the capsule was significantly more preferred by patients over EGD. Lapalus and colleagues (2009) reported similar results in a cohort of 120 cirrhosis patients, with 77% sensitivity and 88% specificity in the detection of grade 2 and higher esophageal varices and/or red signs compared with upper endoscopy. Smaller studies comparing capsule endoscopy and EGD have yielded similar results (Eisen et al, 2006; Frenette et al, 2008; Lu et al, 2009; Pena et al, 2008). Models comparing cost effectiveness of esophageal capsule endoscopy and EGD imply that they are equivalent strategies (White & Kilgore, 2009).

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