The prevalence of gastric varices varies between 5% and 33% among patients with portal hypertension with a reported incidence of bleeding of about 25% in 2 years and with a higher bleeding incidence for fundal varices.[1] Risk factors for gastric variceal hemorrhage include the size of fundal varices [more with large varices (as >10 mm)], Child class (C>B>A), and endoscopic presence of variceal red spots (defined as localized reddish mucosal area or spots on the mucosal surface of a varix).[2] Gastric varices bleed less commonly as compared to esophageal varices (25% versus 64%, respectively) but they bleed more  severely, require more blood transfusions and are associated with increased mortality.[3,4] The approach to  optimal treatment for gastric varices remains controversial due to a lack of large, randomized, controlled  trials and no clear clinical consensus. The endoscopic treatment modalities depend to a large extent on an accurate categorization of gastric varices. This classification categorizes gastric varices on the basis of their location in the stomach and their relationship with esophageal varices. [1,5]Gastroesophageal varices are associated with varices along the lesser curve (type 1), or along the cardia (type 2); isolated gastric varices are present in the fundus (type 1) or at ectopic sites in the stomach or the first part of the duodenum (type 2).[1,5]

Although, endoscopic variceal band ligation is the undisputed gold standard therapy for bleeding esophageal varices, this approach has been less successful for the treatment of bleeding gastric varices.[6] Treatment options for gastric varices includes the radiological insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS) and the endoscopic injection of sclerosing agents, such as absolute alcohol, ethanol oleate, sodium tetradecyl sulfate, tissue adhesives and thrombin.[7] N-butyl-2-cyanoacrylate (NBC) is the most commonly used tissue adhesive for the treatment of gastric varices in clinical practice and is superior to intravariceal injections using ethanol oleate or absolute alcohol.[7] American Association for the Study of Liver Diseases guidelines1 and the Baveno V consensus5 recommend endoscopic therapy with NBC as first-line treatment for bleeding isolated gastric varices and gastroesophageal varices type 2. Endoscopic variceal ligation or sclerosing agents can be used in bleeding from gastroesophageal varices type 1. A transjugular intrahepatic portosystemic stent shunt (TIPSS) should be considered in patients in whom hemorrhage from fundal varices cannot be controlled or in whom bleeding recurs despite combined pharmacological and endoscopic therapy or where endoscopic therapy is not available.

NBC is a liquid with a consistency similar to water and therefore it can be given by intravariceal injection. When added to a physiologic medium such as blood, NBC rapidly polymerizes, forming a hard substance. Hence, after injection into a varix, NBC plugs the lumen resulting in rapid hemostasis in cases of active bleeding and eradication of gastric varices. NBC is commonly used in Europe and Asia for the treatment of gastric varices but is not approved by FDA in the United States.

In this issue of Tropical Gastroenterology, Choudhuri et al[8] from India report impressive results using NBC, Nectacryl, for the treatment of bleeding fundal gastric varices (mostly isolated gastric varices and gastroesophageal varices type 2) as an emergency procedure for active bleeding in 62 patients and as an elective procedure for prevention of rebleeding in 108 patients. The overall hemostasis rate at 48hours was 82.3 % in actively bleeding group. Overall bleeding recurred in 14.5% of the patients. Definitive success was achieved in 89.9% of patients with a complete follow up who had been followed. No significant complications were noticed except for injection site ulceration in 32 patients. The major limitations of this study were a retrospective nature, 9% of patients were lost to followup and there was only one intervention group.

In another study from India, recently published in Gastrointestinal Endoscopy, Kumar et al[9] reported a success rate of initial hemostasis in 84.8% among 46 patients with actively bleeding gastric varices. Rebleeding was seen in 23.4% patients over a mean follow-up of 16 months. Large gastric variceal size, fundal location, and large esophageal variceal size were predictive of gastric variceal bleed. The mortality was 8.8% for all varices and Child-Pugh status was the only predictor of mortality. The only limitation of this study was that it had only one intervention group.

The technique of NBC injection was important in these 2 studies.[8,9] While former has used minimally diluted NBC with lipiodol in 4:1 ratio, the later used undiluted glue. Further, to prevent embolization, Kumar et al[9] limited maximum amount of cyanoacrylate per injection to 1 to 2 mL per varix and per session to 4 mL. Similarly, Choudhuri et al[8] have used 0.5 to 4ml of cyanoacrylate glue per aliquot that was primarily decided by the size of varix. These approaches have been taken in an attempt to reduce the embolic complications of cyanoacrylate glue. The rationale for diluting cyanoacrylate glue with lipiodol is to delay  the otherwise early polymerization reaction in order to complete the injection and remove the needle. Previous studies have used varied dilution with lipiodol (0.5:1.5 to 2:1).[10,11] There are several case reports of severe complications related to embolization including cerebral stroke,12 pulmonary embolism,[13] portal vein embolism,[14] splenic infarction,[15] retro-gastric abscess[16] and septicemia[17] which have raised concern about its safety. When embolic phenomena occur, fatalities have also been reported.[18,19,20]These two studies are important for eliminating the risk of embolization by using undiluted or minimally diluted NBC. In another study, the endoscopists switched from diluted NBC to undiluted NBC midway through the study, after noticing embolic complications with diluted NBC, and thereafter reported absence of embolic complications with undiluted NBC.[21]

Most evidence for the use of cyanoacrylate in gastric variceal bleeding comes from series based in India, Japan, Europe, and the United States, which report good initial hemostasis rates of over 93% (range, 71-100), rebleeding rates of 23% (range, 7.6-52) and mortality of 28% (range, 3.7-82.5) in 24 trials.[7] Both studies have shown efficacy of NBC on abovementioned parameters according to the literature. Case series have also highlighted the utility of cyanoacrylate treatment in specific clinical situations such as pregnancy,[22] in children[22,23] and in infants.[24] Repeated injections are required to obliterate the varices and secondary bleeding. In a recent study, blocker were compared with NBC injection for the prevention of secondary bleed. Patients with gastroesophageal varices type 2 with eradicated esophageal varices or isolated gastric varices type 1 who had bled from gastric varices were randomised to NBC injection (n=33) or b-blocker treatment (n=34). The probability of gastric variceal rebleeding rate in the NBC group was significantly lower than in the b-blocker group (15% vs 55%, p=0.004) and the mortality rate was lower (3% vs 25%, p=0.026) during a median follow-up of 26 months. This study further confirms the findings reported earlier that gastric variceal eradication should be the aim with NBC injections on a regular follow-up.[25] Weeks to months after the injection, the mucosa overlying the glue cast sloughs off and the plug is extruded into the stomach; this may be followed by bleed in a rare patient due to ulcer formation at the extrusion site. We minimize the chances of ulcer bleed of this kind by giving proton pump inhibitors in a single dose; however the efficacy of this approach needs to be confirmed with a prospective randomized controlled trial.

Three studies have compared endoscopic NBC injection with TIPPS placement for the management of gastric variceal bleeding.[26,27,28] Lo et[27] found that TIPSS was more effective than NBC injection in preventing rebleeding from gastric varices, with similar survival and frequency of complications.  Mahadeva and colleagues[26] retrospectively analyzed that NBC injection was more cost effective than TIPSS in the management of acute gastric variceal bleeding. A major limitation of this study was the short follow-up of just 6 months with cyanoacrylate and 12 months with TIPSS, which must be taken into account when interpreting the findings. Procaccini et al[28] compares TIPSS insertion versus NBC injection with TIPSS insertion as a rescue treatment and concluded that in patients with similar characteristics, therapy with NBC performed as well as a TIPSS in controlling and preventing gastric variceal hemorrhage with no significant differences in survival. Patients receiving cyanoacrylate therapy experienced significantly less long-term morbidity related to therapy than patients who received a TIPSS and was primarily attributable to the development of hepatic encephalopathy. However there was no information whether the hepatic encephalopathy occurred de novo or it resulted from deterioration of preexisting encephalopathy after TIPSS insertion. In view of the heterogeneous results of abovementioned 3 studies, a prospective, multicenter, randomized trial would be required to confirm the role of TIPSS in the management of gastric variceal bleeding. Until such a study is performed and the results are available, the recommendations of current guidelines as mentioned-above should be followed.[1,5] While the role of NBC injection in the management of the treatment of bleeding fundal gastric varices has been clearly established, there is limited data on its role for the primary prophylaxis. In a study, 11 (37.9%) patients with large fundal varices with red color signs, especially cherry red spots, underwent prophylactic sclerotherapy for gastric varices with NBC. The results were the same as for the secondary prophylaxis for the gastric variceal bleeding.[21] Subsequently, Chang et al[29] evaluated safety and long-term outcomes of prophylactic NBC injection for non-bleeding gastric varices with a high risk of bleeding in 33 patients [large tumorous (n=27), red color sign (n=14) or rapidly growing in size (n=1)]. Obliteration of gastric varices was achieved in all of the treated patients. The mean duration of follow-up was 12.2 months and eradication of gastric varices was achieved in 21 (95%) of 22 patients who were followed-up more than 3 months. Index gastric varices recurred in three of 21 patients (14%) and re-bleeding in index gastric  varices after NBC injection occurred in two of 26 patients (8%). This study shows that prophylactic NBC injection can be a promising procedure for eradication of non-bleeding gastric varices in case with a high risk of bleeding. In another study by Mishra et al,[30] cyanoacrylate injection was more effective than b-blocker therapy in preventing gastric variceal bleed and improving mortality. Size of gastric varix >20mm, a MELD score of >17, presence of portal hypertensive gastropathy and the treatment method predicted ‘high risk’ of first bleed from gastric varices. These preliminary investigations favor endoscopic intervention with NBC injections for the primary prophylaxis of gastric variceal bleed.

Has the time come for cyanoacrylate injection to become the standard treatment for gastric varices? The answer is ‘Yes’. However, issues related to the role of NBC in the primary prophylaxis and the place of TIPSS in the management of gastric varices need further large multicenter randomized trials.

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