Primary prophylaxis of gastric variceal bleeding
In patients with GVs who have not bled, similar to the prevention of acute variceal bleeding from esophageal varices, the use of nonselective beta-blockers has been suggested. The role of endoscopic cyanoacrylate glue injection and endoscopic band ligation (EBL) as options for primary prophylaxis in gastroesophageal varices remain unclear. In a study conducted from a single center in India, endoscopic glue injection was found to be associated with lower bleeding and mortality compared to nonselective beta-blockers [20]. Kang et al. demonstrated the long-term efficacy of prophylactic cyanoacrylate glue therapy in 27 patients with high-risk GVs with 6-months cumulative survival of 75% [21]. The Baveno VI consensus and American Association for the Study of Liver Diseases recommend the use of non-selective beta-blockers [22].
Bhat and colleagues studied the primary prophylaxis of gastric variceal bleeding using EUS guided glue injection and found that only 5% bled at 449 days follow up. Further studies on EUS based therapy for prevention of bleeding in GV are lacking [23]. In the study by Koziel et al. on EUS-guided obliteration of GVs using vascular coils only or coils with CYA injections for primary and secondary prophylaxis for GV haemorrhage, technical success was 94% without serious complications [24]. Nonetheless, this was a small series with retrospective methodology and inherent bias. Primary TIPS is not recommended for prevention of GV bleeding. Balloon-retrograde transvenous occlusion (BRTO) and it's variant techniques such as coil-assisted retrograde transvenous occlusion (CARTO), plug-assisted retrograde transvenous occlusion (PARTO), balloon antegrade transvenous occlusion (BATO) and our group described novel techniques such as the ‘direct’ (D)-PARTO or direct coil-assisted antegrade transvenous occlusion (CAATO) are not evaluated in high-quality randomized trials for prevention of first gastric variceal bleeding and hence cannot be recommended as primary prophylaxis [25].
Management of acute gastric variceal bleeding and secondary prophylaxis
On diagnostic endoscopy, gastric variceal bleeding is confirmed in the presence of active bleeding from a visualized varix, presence of adherent clot or stigmata of recent haemorrhage over the GV and recurrent bleeding in a patient with PH and presence of GV in the absence of other identifiable sources of bleeding [26].
The general measures for initial optimization of clinical status to prevent further deterioration due to acute gastric variceal bleeding are similar to those followed in esophageal variceal bleeding. This includes airway protection through endotracheal intubation to prevent aspiration, maintaining minimum systolic blood pressure of 70 mm Hg for performing urgent diagnostic and therapeutic endoscopy and the judicious use of packed red cells for target hemoglobin levels between 7 and 8 g/dL (21% haematocrit). Volume expansion and coagulation correction using fresh frozen plasma or plasma expanders lead to severe adverse clinical events in patients with cirrhosis and variceal bleeding and must be avoided. A conventional dose of two fresh frozen plasma units can only replace 10% of the clotting factors. Large volume coagulation correction can lead to worsening PH, sepsis, sinister systemic immunomodulation, and rebleeding. In cirrhosis, a minimum platelet count 56,000/mL corresponds to adequate thrombin generation and is the ideal target for endoscopic interventions. Similarly, maintaining fibrinogen level > 120 mg/dL also improves haemostatic effects [27,28,29]. Although the use of vasoactive agents for the reduction in portal pressure and control of rebleeding specific to gastric variceal bleeding is unavailable in literature, the same line of supportive therapy as for esophageal variceal bleeding, is currently recommended. Wang et al. in their systematic review and meta-analysis showed that there was no difference between vasopressin/terlipressin and somatostatin/octreotide in the prevention of re-bleeding after the initial treatment of bleeding esophageal varices [30]. Antibiotic prophylaxis, lactulose for the prevention of hepatic encephalopathy along with other supportive measures that include varying degrees of organ support depending on the severity of systemic dysfunction is mandated in GV bleed [31]. In a patient with active bleeding that preclude endoscopic treatment, temporizing measures such as intragastric balloon tamponade can be utilized. These devices can only be placed for a maximum of 24 h within which definitive treatment has to be carried out. Given its large volume capacity, a Linton-Nachlas tube is considered ideal for gastric variceal bleeding [32].
Endoscopic band ligation
Endoscopic band ligation (EBL) is the initial treatment of choice in the management of acute esophageal variceal bleeding. Initially, several small patient series demonstrated that EBL was safe and effective for bleeding GV. Two randomized controlled trials comparing EBL to cyanoacrylate glue therapy showed that initial haemostasis was lower and rebleeding rates higher (63% and 72% at 2 and 3 years respectively) in the former. In the absence of cyanoacrylate glue, EBL can be considered in patients with Type 1 GOV bleeding for initial control of bleeding until further definitive management can be undertaken [33, 34].
Sclerotherapy
Injection sclerotherapy for GV has been demonstrated to be less effective than what is noted with esophageal varices. The agents used for sclerotherapy include ethanolamine oleate, sodium tetradecyl, glucose solutions, and acetic acid. High blood flow within the GV results in the early flush of injected sclerosants, reducing its efficacy. In such situations, larger volumes of injection can be contemplated. However, in reality, it leads to adverse events such as febrile illness, severe retrosternal discomfort, ulcerations, mediastinitis, embolization in the presence of large portosystemic shunts and perforations that can result in approximately 50% mortality. The rebleeding rates with sclerotherapy alone can be as high as 90%, of which 50% bleeds are secondary to injection site ulcerations. Sclerotherapy has greater success for control of bleeding and prevention of rebleeding in esophageal variceal disease [35, 36]. Currently, EBL or cyanoacrylate glue injection is considered the treatment of choice for Type 1 GOV bleeding and cyanoacrylate glue injection for Type 2 GOV and isolated GV. Some authors have used EBL along with sclerotherapy for management of Type 1 GOV bleeding with an injection of 1 mL of sclerosant above the site intended for band ligation. The success rate for haemostasis with this approach is close to 90% with the risk of rebleeding in 33%. EBL should only be performed in patients with bleeding from small Type 1 GOV in which both the mucosal and contralateral wall of the vessel undergoes complete suction into the ligator, without which the likelihood of band detachment is high leading to ulceration of the overlying vessel and catastrophic secondary bleeding [35, 36].
Endoscopic cyanoacrylate glue therapy
N-butyl-2-cyanoacrylate (NBC) is a monomeric tissue adhesive that rapidly polymerize on contact with blood leading to hardening of varix, cast formation, and obturation. The NBC is the most commonly employed agent for glue therapy and undergoes polymerization within 20 s of contact with blood inside the variceal lumen. Lipiodol (ethiodized oil composed of iodine combined with ethyl esters of fatty acids of poppyseed oil, primarily as ethyl monoiodostearate and ethyl di-iodostearate) or normal saline is sometimes used to avoid occlusion in the endoscopy channel. A 1:1 mixture is usually recommended and can reduce the risk of embolization. It is recommended that a 3.7 mm width channel endoscope be utilized for ease in glue administration. Some newer glue products such as 2-octyl-cyanoacrylate and NBC mixed with methacryloyloxy-sulfolane do not require dilutional agents due to the slow polymerization time [37, 38]. In a Cochrane Database Review, a meta-analysis of three randomized controlled trials comparing cyanoacrylate glue therapy versus EBL demonstrated both therapies to be effective for control of bleeding, but significantly lower rates of rebleeding was noted with the former. These studies included mostly Type 1 GOV bleeds and utilized NBC [39].
Endoscopic thrombin injection and inorganic haemostatic powder spray
Another treatment modality infrequently used in gastric variceal bleed control is thrombin injection in which catalysation of fibrinogen to fibrin with additional platelet function augmentation enhances cot formation within the bleeding varix. This is an attractive alternative to glue therapy where expertise is unavailable and has fewer side effects and systemic complications. Five millilitres of thrombin have the potency to coagulate one litre of blood in less than a minute. Even though thrombin treatment was found beneficial in controlling bleeding from GV, especially Type 2 GOV in small single-center series, high-quality studies were lacking [40,41,42,43]. Recently, Lo and colleagues, in a prospective randomized trial, showed that endoscopic thrombin injection was similar to glue injection in achieving successful haemostasis of acute GV bleeding but with higher incidence of complications associated with the latter [44]. Few reports demonstrating the use of inorganic absorbent powder TC-325 haemostatic spray (Hemospray®, Cook Medical, IN, USA) in patients with refractory gastric variceal bleeding after the failure of glue injection therapy has been published in the literature. The issue with haemostatic powder spray is that it can act only in the presence of active bleeding during endoscopy [45].
Endoscopic-ultrasound guided therapy for gastric varices
EUS color Doppler can help distinguish GV from gastrointestinal tumors and prominent gastric folds and allows real-time confirmation of GV obliteration through precise identification of perforating feeder vessels and accurate delivery of tissue adhesive decreasing the amount of glue injected and reducing the risk of embolization (Fig. 5). Romero-Castro et al. performed a proof-of-concept study on EUS-guided glue therapy for bleeding GV and utilized lipiodol to localize feeder vessels before glue use accurately [46]. Lee et al. showed that late rebleeding rate beyond 48 h was significantly lower in patients with GV bleeding receiving EUS guided glue injections every 2-weeks until eradication [47]. In another single center study, 90% of patients experienced complete haemostasis after glue injection into the afferent vessels confirmed on color Doppler, without rebleeding events in the short term [48].
EUS-guided coiling of GV was shown to enhance haemostasis in multiple series. The metal coils, made from synthetic stainless-steel fibre induce clot formation and thrombosis of varix. Usually, a 19-G access needle is utilized, but 22-G needles for the deployment of smaller coils are also available. Levy and colleagues were the first to report on EUS-guided coiling of ectopic GV. A multicenter cohort study by Romero-Castro and colleagues demonstrated that there were no significant differences between glue injection compared to coiling for haemostasis of bleeding GV at 180-days. Nevertheless, the mean endoscopic session time and the number of sessions required for variceal obturation was lower in patients receiving EUS-guided coiling [49, 50]. The combined use of EUS-guided coil placement along with cyanoacrylate glue injection results in en-mass ‘scaffold’ formation which is associated with very efficient control of bleeding and reduction in the rate of rebleeding. Combined EUS-guided therapy promoted gastric variceal eradication in 96% of treated patients with a single sitting with only 16% experiencing rebleeding over a follow-up period of 6-months without any minor or major adverse events [51]. Similar findings were demonstrated by Bhat et al. in their study on 100 patients. However, adverse events in the form of pulmonary embolism and self-limited abdominal pain occurred in 5% [52]. A recently performed systematic review and meta-analysis showed that EUS combination therapy with coil embolization and glue injection was a preferred strategy for the treatment of GV over EUS-based monotherapy [53].
Endovascular therapy for bleeding gastric varices
Transjugular intrahepatic portosystemic shunt (TIPS)
The role of TIPS in controlling acute variceal bleeding in the event of rebleeding or uncontrolled bleeding from esophageal varices is well documented. Even though TIPS can promote haemostasis in acute GV bleeding, varices can persist and bleed at lower portal pressures than esophageal varices. Previous retrospective studies have shown that in patients with GV haemorrhage undergoing TIPS placement in the absence of adjuvant variceal embolotherapy, the GV remained patent in 65% with rebleeding in 27% and 90-days mortality of 15%. Another study also reported that 50% of patients post TIPS had persistence of GV with 27% rebleed rates [54, 55]. A meta-analysis comparing TIPS to endoscopic variceal sclerotherapy (EVS) in the management of GV bleeding in terms rebleeding, hepatic encephalopathy and survival demonstrated improved benefits of TIPS in the prevention of GV rebleeding that was associated with an increased risk of encephalopathy with comparable survival between study groups [56].
Various theories have contemplated the ineffectiveness of TIPS alone for complete control of bleeding from GV. The ‘proximity’ theory states that esophageal varices are well decompressed after TIPS since the left gastric vein supplying the varices are small and close enough to benefit from decompression through shunt creation. The GV, on the other hand, is farther away, larger, and associated with multiple afferents depending on the collateral anatomy of the variceal complex. As per the ‘throughput’ theory, low-pressure shunts from large-calibre inflow and outflow vessels associated with GV compete with and effectively decompress the TIPS stent leading to the persistence of varices. The ‘recruitment’ theory states that new afferent vessels form after treatment of a gastric variceal system post TIPS due to the complexity in afferent and efferent flow pathways, all of which do not undergo decompression or undergo only partial embolization unexpectedly. In such situations, shunt occlusion and TIPS may be more effective than TIPS alone [57, 58].
Retrograde or antegrade transvenous embolization of gastric varices
The American College of Radiology Appropriateness Criteria Committee on interventional radiology recently recognized BRTO as an alternative to TIPS in specific clinical situations for treatment of GV. As per current conservative practice, BRTO is reserved for those patients who are ineligible for TIPS. However, with improvement in understanding of hemodynamic physiology associated with the variceal disease, this has changed to incorporate a combination of endovascular therapies. A meta-analysis on post-procedure outcomes in 1016 patients who underwent BRTO for management of bleeding GV demonstrated technical success, i.e., complete thrombosis of the GV on short-term follow up imaging and control of active bleeding among 96.4% patients. Absence of rebleeding and no bleeding in high-risk GV was notable in 97.3% on follow up. However, most studies were retrospective in nature and included patients who underwent primary prophylactic BRTO for high-risk GV [59]. In another meta-analysis, on clinical outcomes in GV bleeding among 353 patients undergoing TIPS (n = 143) or BRTO (n = 210), it was found that no significant differences were notable with respect to technical success, haemostasis and complication rates between both treatments. Nevertheless, rebleeding and hepatic encephalopathy were significantly lesser in those who underwent BRTO [60]. Adverse events associated with conventional BRTO include fever, chest pain, gastrointestinal symptoms, haemoglobinuria, ascites, and pleural effusion. It was shown that the occlusion of a large gastrorenal shunt could increase the hepatic venous pressure gradient by up to 44% from the baseline. BRTO was found to aggravate pre-existing esophageal varices (ranging from 30 to 68%), leading to variceal bleeding even though associated death is never reported. In this context, a pre-shunt-occlusion endoscopy and prophylactic band ligation of large or high-risk esophageal varices are prudent.
In some patients, with GV bleeding, the combination of endovascular procedures could be more efficacious than singular treatments which in turn depends on the variceal collateral pathway anatomy. For example, as per the afferent flow classification, patients with Kiyosue type 1 GV can be easily managed with only shunt embolization. In contrast, TIPS placement would benefit those patients with GV and associated multiple collateral afferents in the absence of a dominant shunt (Type 2 of Kiyosue classification). Alternatively, in patients with afferent and efferent shunts as well as multiple collaterals (such as Kiyosue or Saad Caldwell Type C2), a combination of TIPS and shunt embolization could be more beneficial. Shunt embolization, along with TIPS placement, negates the high flow through the shunt, reduces rebleeding rates, improves TIPS efficacy, shunt patency and flow and decreases the incidence of hepatic encephalopathy [32, 58, 59]. In patients with large portosystemic shunts, it is not uncommon to notice an attenuated portal vein that is difficult to cannulate for the TIPS procedure. Shunt embolization improves portal vein inflow and increases portal vein diameter making a technically challenging TIPS procedure far more comfortable to perform. A combination of multiple embolization techniques, such as inflow modulation through coils or balloon occlusion followed by sclerosant injection and outflow modulation utilizing a plug, can lead to complete embolization of the variceal system with a reduction in sclerosant migration to untargeted regions. There are no published multicenter series of randomized trials on TIPS and combination shunt embolization procedures. Saad and colleagues reported outcomes in 36 patients undergoing BRTO procedure for gastric variceal bleeding in whom 9 underwent simultaneous TIPS placement. It was shown that the ascites and hydrothorax free rate for BRTO versus BRTO + TIPS at six months and one year was 58% and 29% compared to 100% and 100%, respectively. A significant reduction in recurrence of haemorrhage was also noted in the combination group demonstrating the fact that TIPS improved the PH burden developing after BRTO. Another prospective randomized controlled trial of TIPS alone versus TIPS with adjunctive left gastric vein embolization found a significant reduction in 180 days overall rebleeding rate in the embolization group [61, 62]. In a meta-analysis that compared the incidence of shunt dysfunction, variceal rebleeding, encephalopathy, and death between patients treated with TIPS alone and those treated with combined variceal embolization it was shown that variceal embolization during TIPS procedure improved the prevention of rebleeding, but no significant differences were identified concerning shunt dysfunction, encephalopathy, or mortality [63]. Thus, the treatment of gastric variceal bleeding has evolved through the years and is currently far from the current standard recommendations to better suit the patient, dependent on the hemodynamic classification and with reasonable control of portal hypertensive complications. An algorithm for treatment decisions regarding gastric variceal bleeding is shown in Fig. 6.
Conclusion
Gastric variceal haemorrhage is associated with high rebleeding rates and mortality than esophageal variceal bleeding. Endoscopic cyanoacrylate glue therapy is the current standard recommendation for the management of gastric variceal bleeding. However, with a better understanding of the anatomic and hemodynamic components associated with the gastric variceal system, advanced options for bettering clinical outcomes are in evolution. These include EUS assisted combination approaches and multiple endovascular techniques including TIPS and shunt embolization or their combinations that can be offered to patients, depending on the underlying liver disease severity, collateral pathway anatomy, affordability and availability of technical expertise.