xx xx Gastric and ectopic varices – newer endoscopic options ANNALS OF 2007, 20(2):95-109x xx x95

Review

Gastric and ectopic varices – newer endoscopic options

D. Christodoulou1,2, E. V. Tsianos2, P. Kortan1, N. Marcon1

The mortality of each episode of variceal bleeding is about SUMMARY 20 to 30 percent and as many as 70 percent of survivors Bleeding from esophageal and is the most life- have recurrent bleeding after their first variceal hemor- threatening of and portal hyper- rhage.4 Gastric varices (GV) are less common than esoph- tension. While for the endoscopic treat- ageal ones, with a prevalence of about 20 percent in pa- ment is well established and common practice is followed tients with portal .5;6 About 20% of all variceal worldwide, this is not the case for gastric varices. Gastric bleeds are due to gastric varices.7 About 15-25% of gastric varices bleed less frequently but more severely than esoph- varices bleed during their lifetime. Although GV bleed less ageal ones and are classified in certain subtypes according frequently and with lower pressure than esophageal vari- to their location and their size or configuration. In this re- ces, bleeding from GV is more severe and associated with view, the treatment options for bleeding esophageal and gas- higher mortality. GV are often associated with large drain- tric varices will be presented. Emphasis will be given on the ing splenorenal shunts that complicate the condition and treatment of gastric varices with cyanoacrylate. In addition, contribute to . Once gastric fundal a short description of ectopic varices will be made. varices bleed the mortality rate ranges from 25% to 55%. Patients with GV also have a higher risk of rebleeding and Key Words: treatment of gastric varices, ectopic varices, cya- a decreased rate of survival. Ectopic or extra-gastric vari- noacrylate, glue, variceal bleeding. ces account for 5-10% of cases of variceal bleeding.8 The endoscopic treatment of esophageal varices has INTRODUCTION been addressed successfully with the use of rubber band Development of gastroesophageal varices is one of the ligation and injection . Band ligation is the most common and severe complications of portal hyper- treatment of choice and has fewer complications than tension. The prevalence of varices is about 50% among sclerotherapy,9,10 but has also been related with higher rate all cirrhotics.1 Cirrhotics develop varices at a rate of 10% of recurrence of the esophageal varices11 and some authors per year. Once varices are present, the risk of them becom- have proposed adjuvant variceal sclerotherapy after band ing large and the risk of bleeding is about 10% per year. ligation to prevent recurrence of esophageal varices.12,13 Variceal hemorrhage will complicate the clinical course For gastric varices, the optimum endoscopic treatment re- of chronic in about 30% of patients2 and ac- mains to be defined. Band ligation and sclerotherapy with counts for 80 to 90 percent of bleeding in those patients.3 various agents has been tried with various results, but a high risk of rebleeding was found in most studies.14,15 The 1The Centre for Therapeutic and Endoscopic Oncology, treatment of gastric varices with cyanoacrylate gives very St Michael’s Hospital, University of Toronto, Canada, good results, with high hemostasis rate and reduced ear- 2Hepato-Gastroenterology Unit and Therapeutic Endoscopy Unit, ly and late rebleeding rate compared to other endoscop- 1st Division of Internal Medicine, School of Medicine, ic treatment modalities16;17. Despite being the endoscop- University of Ioannina – Greece ic treatment of choice in Germany, Italy, India, Canada and other countries for gastric varices, cyanoacrylate has Author for correspondence: not gained universal acceptance, especially in the Unit- Dr Epameinondas V. Tsianos, Professor of Medicine, 1st Department of Internal Medicine, Medical School of Ioannina, ed States for unclear reasons, in spite of the small risk of 45110 Ioannina, Greece, Tel.: +30 26510 97501, serious complications and risk of scope damage, if used Fax: +30 26510 97016, e-mail: [email protected] without adequate care. 96 D. Christodoulou, et al

In this review we will present our experience about treatment of gastric and ectopic varices and emphasis will be given to the endoscopic technique and the fine details of the procedure. Where glue is concerned, any endosco- pist who performs injection sclerotherapy and hemosta- sis injection of bleeding ulcers should be able to use this compound for gastric and ectopic varices.

Classification of gastric varices Gastric varices are generally divided into cardiac and fundic varices. Cardiac gastric varices are supplied by the cardiac branch of the left gastric , which enters the GOV: Gastroesophageal varices wall at a point 2 to 3 cm from the gastroesopha- IGV: Isolated gastric varices geal junction, sending out many branches that are distrib- uted in the cardia. Most of the cardia become parallel Figure 1. Classification of gastric varices. veins from the gastroesophageal junction as the flow be- comes hepatofugal, but dilated winding cardiac veins run in the submucosa and directly join esophageal varices 18. GEV2 – along the greater curvature extending towards Fundic varices are quite different from cardiac varices in the gastric fundus. angioarchitecture. Their supplying route is mostly the short B. Isolated gasric varices gastric vein, but in some it is the posterior or left gastric vein. The vascular anatomy of fundic varices is something IGV1 – isolated cluster of gastric varices in the gas- like a shunt running through the stomach wall. tric fundus. As mentioned, when occurs, an IGV2 – isolated gastric varices in other parts of the adaptive increase in flow through the portosystemic com- stomach. munications occurs to return blood to the heart. The vessels involved, especially the intrinsic veins around the gastro- GEV1 form when a branch of the left gastric vein pen- esophageal junction, become dilated and tortuous, form- etrates the gastric wall (cardiac vein) and joins the deep ing . Gastroesophageal varices occur in four submucosal veins into the gastric zone directly connected patterns: (a) varices in the fundus of the stomach; (b) gas- to submucosal veins in the palisade zone. GEV1 are usu- tric and palisade zone varices; (c) varices in the perforating ally associated with large esophageal varices, while GEV2 zones; (d) paraesophageal varices, which involve the extrin- are associated with large esophageal varices only in 50%. sic veins. In contrast to normal individuals, the valves in the IGV1 are associated with segmental portal hypertension perforating zone become incompetent, permitting reverse (such as that due to splenic vein ) or the pres- flow into the intrinsic plexus from the extrinsic veins.19 ence of spontaneous collaterals from the splenic vein to the renal vein to supply these varices. IGV1 drain into the In common clinical practice though, varices are clas- inferior phrenic vein by gastrorenal shunts, gastrophrenic sified simply by their location into esophageal and gastric shunts or gastropericardiac shunts, a part of which proj- varices. Esophageal varices are graded according to size. A ects into the intragastric space. About 50% of cases of ec- common system of classification is as follows: F1 – small straight varices; F2 – enlarged, tortuous, but occupying topic varices, including IGV2 are associated with portal less than one third of the lumen; F3 - large, coil shaped vein thrombosis. The mechanisms responsible for this phe- 22 and occupying more than one third of the lumen.20 nomenon are unknown. Gastric varices (GV) are also classified primarily by It was also shown, using portovenography, that the left their location, as follows, according to the Baveno Con- gastric vein participates as the blood supply in 70% of the sensus Conference III, where Sarin’s classification was isolated gastric varices (IGV1) and in 100% of the esoph- accepted 21 (Fig 1): ageal varices. The posterior gastric vein participates as the blood supply of 70% of the isolated gastric varices and in A. Gastroesophageal varices – gastric varices in con- 24% of the esophageal varices. The main blood drainage tinuity with esophageal varices route in all patients with esophageal varices is the azygos GEV1 – along the lesser curvature (usually 2 to 5 cm and/or the hemiazygos vein, and all of the cardiac vari- in length). ces drained into esophageal varices. The main drainage Gastric and ectopic varices – newer endoscopic options 97 routes in patients with isolated gastric varices are gastro- risk factor of variceal bleeding. The risk of bleeding from renal shunt (85%), gastrophrenic shunt (10%) and gastro- GV was shown to correlate with variceal size (>10 mm), pericardiac shunt (5%).22 Child class and the presence of a red spot on the varices, according to the following formula: Prognostic index = The New Italian Endoscopic Club (NIEC) has previ- 0.53 X Child class + 0.78 X varix size + 0.72 X red spot, ously classifed gastroesophageal gastric varices as type I where Child class A = 0, B = 1 and C = 2; the varix size is GV and isolated gastric varices and ectopic gastric vari- scored as small (<5mm) = 0, medium (5 to 10 mm) = 1 and ces as type II GV, but this classification is becoming less large (>10 mm) = 2; and the red spot is scored as absent = popular. Another Japanese classification of gastric varices (GV) is as follows: according to their form they are clas- 0 and present = 1. The risk of bleeding from IGV1 corre- sified into three types (a) F1- tortuous, (b) F2 – nodular lates directly with the above prognostic index. In contrast and (c) F3 – tumorous ; according to their location they to esophageal varices, the correlation of GV bleeding with 5 are classified into five areas: anterior (La), posterior (Lp), elevated portal venous gradient pressure is less intense. lesser (Ll) and greater curvature (Lg) of the cardia, and the In acute upper gastrointestinal bleeding due to GV, fundic area (Lf). For example, GV F2Lf means that there identification of the varices and of the bleeding source dur- are gastric varices of nodular form at the fundic area. This ing emergency endoscopy is sometimes difficult because classification is considered more complex and correlates the fundal pool of blood and clots does not allow proper less to the pathophysiology of varices and their progno- and detailed examination. It has been shown that the in- sis, so it is less popular, but is preferred by some authors ability to clear a fundal pool of blood at emergent upper 23 because of its analytical descriptive value. endoscopy is associated with significant morbidity and mortality.26 If the fundal pool of blood is not cleared at ini- Diagnosis of gastric varices and risk factors tial endoscopy, fundal lesions missed at emergent endos- for bleeding copy can be identified in 41% of patients on follow-up ex- In most cases the gastric as well as the esophageal var- amination, with many being clinically significant. Urgent 1 ices are diagnosed by endoscopy. The experienced en- endoscopy and aggressive evacuation of the stomach in doscopist can identify GV easily in the vast majority of suspected variceal bleeding may necessitate the use of air- cases. If there is doubt and the nature of an enlarged sus- way protection by endotracheal intubation or an overtube. picious fundal “fold” cannot be determined, endoscopic A large caliber therapeutic endoscope with high saline ir- 24 ultrasound is the test of choice for confirmation. Alter- rigation for evacuation of clots usually facilitates exami- natively, transabdominal ultrasound with Doppler, com- nation and endoscopic therapy of lesions at the cardia and puted tomography scan with contrast, magnetic resonance fundus. A cap at the end of the scope, as used with EMR, , portovenography and interventional angiog- may help suction of blood and clot evacuation. raphy can be used to identify GV, with the latter test be- ing the most sensitive to recognize the presence and the Treatment of gastric varices anatomy of gastric and esophageal varices. The management of gastric varices has not been as well Large size of the varices, presence of ascites, advanced studied as that of esophageal varices. Controversy exists chronic liver disease (Child-Pugh class C cirrhosis), high on the evaluation and possible pharmacologic and endo- portal pressure (hepatic venous pressure gradient > 12 mm scopic treatment in those who have never bled. In adition Hg) and red marks indicate high risk of variceal bleed- there have currently not been any randomized controlled ing.5,25 In acute upper gastrointestinal bleeding, the iden- studies on the role of endoscopy and pharmacotherapy in tification of esophageal varices is not difficult, but the ap- the management of patients that have bled. We prefer to pearance of esophageal varices on endoscopy is important, eradicate these varices endoscopically to stop active bleed- if there is no bleeding present at the time of the procedure. ing and reduce rebleeding rate. Signs indicating recent variceal bleeding or high risk of bleeding are the red wale marks (longitudinal red streaks Primary prophylaxis on varices), the cherry-red spots (red, discrete, flat spot The general objective of pharmacologic therapy for on varices), the hematocystic spots (red, discrete, raised variceal bleeding is to reduce portal pressure and conse- spots) and at a lesser degree diffuse erythema of the var- quently, intravariceal pressure. So, the rationale for use of ices. The presence of a venous plug or nipple on a varix pharmacologic therapy is similar for acute bleeding, pri- indicates the probable site of rupture. mary prophylaxis and secondary prophylaxis.3 Isolated gastric varices (IGV1) are by themselves a The primary pharmacologic prophylaxis for varices is 98 D. Christodoulou, et al recommended for patients with large varices. Non-selec- sis and are part of generalized portal hypertension, beta- tive beta-blockers, namely propranolol or nadolol are the blockers may be useful and we recommend them in the drugs of choice for primary prophylaxis, because of their usual fashion of monitoring. The role of beta-blockade in ability to reduce splachnic blood flow and portal pressure. patients with left sided portal hypertension related to por- Non-selective beta-blockers block b1-adrenergic receptors, tal vein thrombosis is unclear. with subsequent activation of a-adrenergic receptors and A real dilemma is in considering endoscopic oblitera- splachnic vasoconstriction. They also block b2-adrenergic tion with cyanoacrylate glue in those patients with large receptors eliminating b2-receptor mediated . isolated gastric varices who have never bled. This has not Due to their combined action, non-selective beta-blockers been studied. For large grape-like clusters of (isolated) are more effective than selective beta-blockers. These med- gastric varices with or without red marks our practice is to ications should be given at adequate doses, to reduce heart commence glue obliteration (see below). In patients with rate at 55 per min or 25 percent from baseline rate. It has been proven, for esophageal varices that if portal pressure portal hypertension due to cirrhosis and endoscopic oblit- is reduced below 12 mm Hg, the risk of variceal bleeding eration we continue surveillance every 6 months with en- is minimized. Propranolol is given at a dose of 80-320 mg doscopy as well as prophylaxis with beta-blockers. per day in divided doses or as a long-acting preparation and Our practice is also in patients with GV who have nev- nadolol at a dose of 20-80 mg once daily. A problem is that er bled and are on pharmacotherapy to repeat endosco- beta-blockade is not well tolerated in up to 30% of cirrhot- py every 1 year. In patients with large isolated GV who ics and more so in these with Child C cirrhosis.27 have never bled but varices were ablated we perform en- Nitrates, mainly isosorbide mononitrate can reduce doscopic follow-up to assure total obliteration every 2 to portal pressure by causing splachnic vasoconstriction and 3 months. We may have to repeat injection with glue if can also reduce hepatic resistance, but are recommended the GV are found not obliterated (see below). It is unclear only in combination with beta-blockers, because of their whether beta blockade should be continued after success- potential to accentuate the peripheral vasodilation in cir- ful endoscopic obliteration of GV with cyanoacrylate. rhotics. In fact the combination of beta-blockers and ni- Treatment of acute variceal bleeding trates was shown to reduce portal pressure in more patients than beta-blockers alone. The problem is again, that pa- Acute variceal bleeding is a medical emergency and tients with Child-Pugh stage C cirrhosis cannot tolerate prompt medical and endoscopic treatment is required. The beta-blockers and their combination with nitrates. mortality rate can be as high as 30-35%. The first step in suspected variceal bleeding is to follow the general mea- In 1999, Sarin et al, showed that in patients with high- sures about upper gastrointestinal bleeding, closely moni- risk esophageal varices, endoscopic ligation of the varices tor and resuscitate the patient. The patient is best treated in is safe and more effective than propranolol for the primary an intensive care unit for close monitoring. Airway protec- 28 prevention of variceal bleeding. Although there was some tion is of paramount importance. In patients who are com- 29 criticism about this interventional approach, it has been bative, comatose or in endotracheal intubation should accepted as an alternative approach for patients with con- be considered to protect the airway and allow performance traindications, intolerance or non-compliance to medical of endoscopic procedure. Sufficient fluid replacement, of- treatment. Neither TIPSS nor sclerotherapy is recommend- ten accompanied by blood and fresh frozen plasma trans- ed for primary prophylaxis of esophageal varices. fusions, is provided to ensure adequate tissue perfusion and What about primary prophylaxis in patients with gas- oxygenation. For these means it is also useful to adminis- tric varices who have never bled? This is a controversial ter oxygen. area that has never been studied for isolated gastric vari- As soon as the initial measures are taken to maintain ces. The factors that influence a decision to start on phar- adequate oxygenation and blood circulation, pharmacolog- macotherapy include size of the varices, grade of liver ic therapy is started. One possible option is vasopressin, disease and red marks. As most gastric varices that are which reduces splanchnic blood flow and portal pressure. found in the cardia, are a continuity of esophageal veins, The addition of nitroglycerin to vasopressin results in im- one would think that beta-blockers would act in a similar proved therapeutic efficacy and fewer side effects. Vaso- fashion to traditional esophageal varices. pressin, due to its side effects, is not used currently if any The role of primary prophylaxis on isolated gastric of the alternative treatment options are available. The new- varices, which tend to have a lower pressure than esopha- er synthetic analogue of vasopressin, terlipressin, which is geal varices, is unclear. If the varices are related to cirrho- used for the treatment of , has fewer Gastric and ectopic varices – newer endoscopic options 99 side effects and longer half-life than vasopressin, so it can tion of endoscopy. There is also no data on the duration of be used in bolus form. It appears as effective as somatosta- treatment in patients with GV. Our practice is to discontin- tin or endoscopic treatment for suspected variceal bleed- ue them after endoscopic treatment with cyanoacrylate. ing, but it is not widely available at present.30 Endoscopic treatment Somatostatin, a naturally occurring peptide, and its One should try to optimize the conditions of perform- synthetic analogues and vapreotide, stop var- ing upper endoscopy in patients with suspected variceal iceal hemorrhage in up to 80 percent of patients and are bleeding without wasting time (Figure 2). If the patient is generally considered to be equivalent to vasopressin, ter- lipressin and endoscopic therapy for the control of acute combative, unstable or lethargic, endotracheal intubation variceal bleeding.31,32 Somatostatin and its analogues act should be considered. If the patient is stable and well ori- by reducing splanchnic blood flow and by reducing por- ented, the procedure can usually be carried out without en- tal pressure through effects on vasoactive peptides (glu- dotracheal intubation, after explaining the procedure to the cagon, substance P etc). They are given by continuous in- patient, obtaining informed consent and administering ad- travenous infusion and practically have no side effects, so equate sedation. As already mentioned, it is usually better they are the drugs of choice in acute variceal bleeding. Oc- to perform the procedure in the intensive care unit, where treotide is cheaper than somatostatin and is given in gen- monitoring and facilities for treatment of procedure-related eral as 50 mcg bolus and then as an infusion of 50 mcg complications are optimal. The use of a large channel en- per hour.33 The same dose is used for the other synthetic doscope and repeated lavage of the stomach with tap water analogue, vapreotide.34 The treatment should be continued during the procedure is required to clear the stomach and 38 for 5 days and provides an excellent safety interval for the optimize the view for therapeutic intervention. commencement of endoscopic treatment. However, an in- In brief, for esophageal varices, there are two options teresting meta-analysis showed that although somatostatin of endoscopic treatment, sclerotherapy and band ligation. and its analogues improve the efficacy of endoscopic treat- The high efficacy of both these methods in the treatment ment to achieve initial control of variceal bleeding and 5- of esophageal varices has been well established.39 Sclero- 35 day hemostasis, yet they fail to affect mortality. therapy is an effective method in the treatment of esopha- A recent study showed that the administration of re- geal varices, with excellent results in variceal eradication. combinant factor VIIa in cirrhotic patients with acute var- The main disadvantage remains the high morbidity of the iceal bleeding, which can rapidly correct the prolonged procedure due to deep ulceration, which may lead to re- prothombin time, significantly decreased the proportion bleeding, stricture formation or perforation.40 Our the last of patients with Child-Pugh B or C cirrhosis in whom var- decade, endoscopic band ligation was found superior to iceal bleeding failed.36 Dosing with recombinant factor sclerotherapy for the treatment of esophageal varices, es- VII appeared safe, but further studies are needed to veri- pecially on the basis of lower rates of rebleeding, mortal- fy these findings.37 ity, complications, speed of application and the need for fewer endoscopic treatments.41 The main disadvantage of The role of pharmacologic therapy for the treatment band ligation remains the observed higher rate of variceal of GV is less clear. Although GEV1 constitute more than recurrence than that seen in sclerotherapy. Some authors 80% of all GV, only 11% of GEV1 ever bleed. For GEV1, have recently tried to combine ligation and sclerotherapy all the above guidelines for pharmacologic treatment are standing and endoscopic obliteration of esophageal vari- ces often leads to disappearance of GEV1 too. In contrast, even though IGV1 constitute only 8% of all GV, 80% of IGV1 bleed. IGV1 are often fed by large splenorenal col- laterals that partially decompress the portal vein. For this reason, IGV1 are associated with lower portal venous pres- sure gradient and are less responsive to the reduction of portal pressure by medical treatment. Nevertheless, phar- macologic treatment, with somatostatin or octreotide is of value in acute bleeding from GV. In conclusion, there is no clear data on the use of vaso- active drugs for gastric varices, but these drugs, especially somatostatin and analogues may be used for the prepara- Figure 2. Endoscopic views of gastric varices (A, B). 100 D. Christodoulou, et al

(mainly additional sclerotherapy after successful sessions most effective method for the treatment of GV. In a ran- of band ligation) to reduce the recurrence rate of esopha- domized, controlled study of various agents for endoscopic geal varices. The results are variable, but usually combi- injection sclerotherapy of bleeding canine GV, cyanoacry- nation treatment has a lower recurrence rate.13,42 It seems late was found to be the best agent overall in terms of im- that gentle sclerotherapy after successful band ligation to mediate efficacy, low volume requirement, time required eradicate those varices too small to band may be a ben- for initial hemostasis and reduction of gastric variceal eficial procedure with reduced rebleeding rates, but this size.47 A randomized controlled trial showed that cyano- has not become standard practice and ligation alone with acrylate was more effective and achieved GV obliteration a careful follow-up is currently recommended as the en- faster than injection sclerotherapy with alcohol.6 doscopic treatment of first choice. In addition, endoscop- Kind et al, treated 174 cirrhotic patients with actively ic ultrasound with colour Doppler has been used to iden- bleeding GV with cyanoacrylate (Bucrylate) and then by tify the perforating veins and then perform sclerotherapy weekly sessions until their varices were eradicated.48 Con- 43 successfully. comitant esophageal varices were treated by sclerothera- In contrast to the treatment of esophageal varices, en- py with 1% polidocanol. The hemostasis, early rebleeding doscopic treatment of gastric varices (GV) is still a matter rate and hospital mortality rate after bucrylate treatment of debate.44 Endoscopic sclerotherapy of GV with absolute were 97.1%, 15.5% and 19.5% respectively. In about 75% alcohol was found in an interesting study to be partially of patients GV were successfully obliterated, while fail- effective for the treatment of variceal bleeding (success ure to obliterate was frequently related to prehepatic block rate 66.7%) and achievement of gastric variceal oblitera- (, splenic vein thrombosis, or mes- tion.8 These results were better for GEV1, intermediate for enteric vein thrombosis). Hemostasis of rebleeding cases GEV2 and disappointing for IGV1. Besides common com- was achieved with bucrylate in all patients. plications (fever, pain, dysphagia), two patients developed Akakoshi et al, treated 52 patients with bleeding GV deep gastric ulcers following treatment that bled to death. with cyanocrylate.49 After initial treatment, patients were Gastric variceal ligation has been reported successful for followed-up endoscopically and retreatment was admin- the control of acute bleeding and obliteration of GV by istered as necessary. The rate of initial hemostasis was 15 some authors, but the risk of severe rebleeding was pres- 96.2%, while cumulative non-bleeding rates were 64.7%, ent and led to death in one patient. In conclusion, endo- 52.7% and 48.2% at 1, 5 and 10 years respectively. When scopic sclerotherapy and band ligation affect only part of rebleeding occurred, 80.0% was within 1 year after initial GV and necrosis caused by sclerotherapy or ligation may injection. The treatment failure-related mortality rate was induce massive bleeding from still open varices. For this 4.0% (2 of 52). The cumulative survival rates were 66.9%, reason, some authors developed very complex techniques 60.4% and 55.5% at 1, 5 and 10 years respectively. The for the treatment of GV. Yoshida et al, used a detachable mortality depended on either malignancy or liver function snare to strangulate the main gastric varix, sclerothera- (Child-Pugh classification). The authors concluded that cy- py with ethanolamine oleate to inject the smaller GV and anoacrylate was highly effective and should be considered 45 then rubber bands to ligate these smaller varices. Lee et the first choice of treatment for bleeding GV, but still the al, used detachable snares for gastric varices larger than 2 rate of rebleeding was found rather high. cm in diameter and elastic bands for smaller gastric varices and had an overall hemostatic result of 82.9% and variceal Huang er al, treated 90 patients with bleeding GV with eradication rate after repeated treatments of 91.7%.46 Such cyanoacrylate injection for hemostasis within a 6-year pe- 23 combined techniques can be highly effective, although riod. Most of the varices were large and were located at they are operator-dependent, but can be used whenever the fundus and the posterior wall of the body (94.4%). no better alternative treatment is available. After injection of cyanoacrylate, patients were followed endoscopically with retreatment as necessary. The rate of In geographic areas where glue is available there is no hemostasis at one week was 94.4%. From three days to role for sclerotherapy and/or band ligation. Band ligation 16 months after the initial injection, rebleeding occurred can be used only for small gastric varices. If the gastric in 23.3% of the patients. Recurrent bleeding was stopped varices are cardiac, not large and an extension of esopha- with reinjections of cyanoacrylate in 16.7% of the patients, geal varices (GEV1 or GEV2) they can be treated in com- resulting in a rate of definitive hemostasis of 93.3%. The bination with the esophageal varices with rubber banding. rebleeding rate correlated with the form of the varices, There is growing evidence that treatment with cyanoacry- with F3 – tumorous having the highest rebleeding rate. The late (tissue glue N-butyl-2-cyanoacrylate, bucrilate) is the mortality related to treatment failure was 2.2%. Gastric and ectopic varices – newer endoscopic options 101

In another interesting study by Iwase et al, it was found nadolol and isosorbide mononitrate was more effective that patients with localized-type GV had a better clinical than endoscopic ligation for the prevention of recurrent course, in terms of recurrent bleeding, variceal eradica- bleeding and was associated with a lower rate of major tion and survival, than those with diffuse-type GV, after complications.53 The probability for recurrent bleeding was endoscopic ablation with cyanoacrylate 50. These clinical lower for patients with a hemodynamic response to med- effects were related to the vascular anatomy of the GV as ical therapy, defined as a decrease in the hepatic venous determined by endoscopic ultrasound varicography and pressure gradient of more than 20 percent from the base- 3-dimensional CT. Type 1 vascular anatomy (one vari- line value or to less than 12 mm Hg. Despite these find- cose vessel without noticeable ramifications) was much ings, the overall mortality rate was not significantly differ- more common (86%) in localized-type GV, whereas type ent between the two groups. In addition, it should be taken 2 vascular anatomy (multiple varicose vessels with com- into consideration that patients with Child-Pugh C cirrho- plex connecting ramifications) was found almost exclu- sis are often unable to tolerate the medical treatment. sively (91%) in diffuse-type GV. Overall, endoscopic ab- Primary and secondary prophylaxis from gastric vari- lation with cyanoacrylate was found to be an effective and ceal bleeding with beta-blockers with or without nitrates is safe procedure for patients with bleeding GV. also used if tolerated, but is probably less effective than pro- Another study, by Lee et al,24 investigated the use of phylaxis for esophageal varices. The role of secondary pro- endosonography (EUS) in monitoring cyanoacrylate in- phylaxis with cyanoacrylate has been discussed above and jection to obliterate GV. Initial gastric variceal bleeding in our opinion is essential to minimize the rebleeding rates was controlled with cyanoacrylate injection. Then, ap- after initial endoscopic treatment with cyanoacrylate. proximately half of the patients received “on demand” repeat injection of cyanoacrylate only in response to re- Techique of injection of cyanoacrylate current bleeding, while the other half underwent biweek- According to the literature and in our experience cya- ly EUS followed by repeated injection of cyanoacrylate noacrylate injection in bleeding GV is effective and safe until all GV were obliterated. Although the rates of early treatment and obviously the best endoscopic approach, (<48 hour) bleeding recurrence were similar with repeat- wherever cyanoacrylate is available. Herein we will de- ed or on demand injection (7.4% versus 12.8%), late re- scribe in detail the technique we use for cyanoacrylate currence of bleeding was significantly reduced in the re- injection. Every endoscopist who has performed sclero- peated injection group (18.5% versus 44.7%). There was therapy or even injected bleeding ulcers should be able to also a numerical trend toward improved survival in the re- do cyanoacrylate injection, if certain key points are taken peated-injection group. This study emphasized that EUS, into consideration. especially with color Doppler is a useful method for the 1. It is always better to do the procedure after initial re- evaluation of GV and endoscopic obliteration with cyano- suscitation of the patient. If the procedure is done soon acrylate glue. In addition, EUS is helpful in the imaging of after acute bleeding the patient should be on somatosta- paraesophageal and gastric varices after sclerotherapy or tin or octreotide infusion, because it is always easier to band ligation of esophageal varices.51 EUS appears to be perform the injection under controlled circumstances. more accurate and less invasive than percutaneous tran- If the patient is agitated, non-cooperative or unstable, shepatic in the assessment of periesophageal endotracheal intubation should be considered. If the pa- and paraesophageal collateral veins. tient is in stable condition, the procedure should be ex- plained along with its risks and the patient should be ad- Secondary prophylaxis vised to remain calm to facilitate the manipulations. For the secondary prophylaxis of variceal bleeding 2. If it is known that a gastric variceal bleed is to be from esophageal varices, (prevention of recurrent bleed- treated, the cyanoacrylate solution should be prepared. ing), endoscopic band ligation appears to be the treatment The endoscopist and endoscopic assistant should wear of choice, alone or combined with beta-blockers, with or gloves and have eye protection during cyanoacrylate without isosorbide mononitrate.3 Nevertheless, two large mixture preparation. Commercially available sclero- studies have questioned the efficacy of endoscopic treat- therapy injection catheters, with a 6 mm 21-gauge nee- ment for secondary prophylaxis. The first, published in dle are used. The injection catheters are flushed with 1996 found that as compared with sclerotherapy, nadolol lipiodol. Lipiodol is a contrast agent that prevents cy- plus isosorbide mononitrate significantly decreased the anoacrylate to become solidified prematurely. The cy- risk of rebleeding from esophageal varices.52 The second, anoacrylate is then mixed with Lipiodol in a ratio of published in 2001, showed that combined therapy with 1:1 (0.5 ml of cyanoacrylate, Histoacryl, with 0.5 ml 102 D. Christodoulou, et al

of Lipidol) in a 1 ml syringe. Usually, 4 to 5 syringes fashion is the key of success (Figures 3,4). Cyanoacry- of 1cc are prepared with the mixture. Also, some 10 late (“the crazy glue”) is a powerful sticky agent that can cc syringes are prefilled with water for injection and obliterate large GV if adequate amount is injected intra- some others with Lipiodol. variceally. Excessive injections should be avoided though, to reduce the risk of complications. The endoscopic pro- 3. Then the patient is well sedated and the endoscopic cedure is repeated after 7-14 days and thereafter as appro- procedure starts. After complete endoscopic examina- priate (usually in 1, 3 months and 1 year). During repeat tion, a clear endoscopic view of the fundus is obtained endoscopy, the injected varices are gently touched with a by sucking remaining clots of blood and by flushing blunt accessory, such as the closed tip of a biopsy forceps. through the biopsy channel with normal saline. Then Obliterated varices are very firm and non-elastic, while the injection catheter is inserted with the instrument patent varices have a soft feel expected by venous struc- in a straight view and after the catheter reaches the tures. The injection of the mixture of cyanoacrylate-lip- tip the instrument is retroflexed again, slightly with- iodol into the varix can be seen in fluoroscopy, because drawn to approach the fundal area and rotated appro- lipiodol is radioopaque and a contrast agent. priately to aim with the injection catheter the fundal varix at its bulge or near the sign of recent bleeding. Some prefer to use glue alone without lipiodol for the Then the injection catheter is advanced and its needle treatment of gastric varices, after flushing the injection is advanced by the assistant. The length of the needle catheter with lipiodol. Although this strategy can minimize is tested at this point by the endoscopist and should be the risk of migration of glue to other organs, it carries out long enough for intravariceal injection (usually about a much higher risk of plugging the accessory channel of 5-6mm). the instrument or the injection catheter, so most experts prefer the mixture of glue with lipiodol. 4. Some at this point prefer to prefill the injection catheter with 0.5 cc of the cyanoacrylate solution, a manipula- Newer agents are being investigated for the endoscopic tion which aims to replace the lipiodol solution inside treatment of GV 54. Both human and bovine thrombin have the injection catheter with cyanoacrylate mixture (the achieved adequate control of variceal bleeding in initial injection catheter in its full length of lumen contains experimental studies. These results have been confirmed about 1 cc of fluid). Others avoid this short step. in human studies with limited numbers of patients with either esophageal or gastric varices 55. This treatment ap- 5. The injection catheter is inserted into the varix, 1 cm of pears to be very safe and effective and the only reported cyanoacrylate-lipiodol mixture is rapidly injected and complication was recurrence of bleeding. Human throm- immediately 2-3 cc of water for injection (and not nor- bin was evaluated in a more recent study for the treat- mal saline) is injected into the varix (simply by replac- ment of fundal GV, some of which were previously unsuc- ing the injecting syringe of cyanoacrylate-lipiodol with cessfully treated with TIPS 56. Treatment was found safe one of the syringes containing water for injection). and effective for the management of acute gastric varice- 6. The injection catheter is slowly withdrawn from the al bleeding. The main disadvantage of the study was the varix and its lumen is flushed first with water for in- rather limited number of patients. Although no complica- jection again and then with a small amount of lipi- tions were noted, 3 of 12 patients had recurrence of their odol, to protect its potency. At no stage is the catheter bleeding. Treatment was applied in 1 to 4 sessions. Anoth- tip brought close or into the tip of the endoscope and er agent that was evaluated only in experimental studies no suction is applied after the injection stage, to avoid obstruction of the accessory channel of the instrument by the cyanoacrylate. If suction is required, this is done gently and away from cyanoacrylate remnants into the gastric lumen and after some time has passed to allow glue to solidify. 7. The procedure is repeated as above, until all fundal varices are treated. If the injection catheter becomes obstructed after glue injection, it is carefully removed and replaced by a new one. Taking into account these guidelines and performing the procedure in a relaxed, coordinated and controlled Figure 3. Gastric varices after glue injection. Gastric and ectopic varices – newer endoscopic options 103

sient cough and mild chest pain. Microembolization into the pelvic region has also been reported. Another serious complication of cyanoacrylate injection is fistula and ab- scess formation. Battaglia et al reported two cases of vis- ceral fistula as a complication of treatment of esophageal and gastric varices with cyanoacrylate.61 In the first of these two cases, a fistula between the gastric fundus and the left pleural cavity was seen 6 months after two sessions of in- jection of cyanoacrylate were carried out to control a severe recurrent gastric variceal bleeding. Complete recovery and closure of the fistula was achieved by conservative mea- sures. In the second case an esophageal-mediastinal fistula Figure 4. Final result of the case shown in Figure 4 (disappear- was developed after glue injection of large esophageal var- ance of gastric varices). ices in a patient with hepatocellular carcinoma. Conserva- tive and surgical treatment failed and the outcome was fa- is poly-N-acetyl-glucosamine, a substance isolated from tal. However, in another study three cases of fistula arising marine microalgae and that seems to have similar proper- from the (esophageal-pleural, gastric- ties with thrombin 57. pleural, colonic-cutaneous) were successfully treated after injection of cyanoacrylate into the fistulous tract! 62 Complications from cyanoacrylate injection In another study, it was reported that about 30% of Cyanoacrylate injection of gastric varices, although patients who undergo endoscopic injection with cyano- highly effective and with a good safety profile, has been acrylate for GV develop transient and usually uneventful criticized for its potential to cause rare but severe compli- bacteremia. The accessory channel of the endoscope was cations. The most common complications of the proce- the major source for bacteria.63 For patients with a poor dure include transient chest pain and self-limiting fever. reserve and severe blood loss, the cost and benefit of the Transient difficulty in swallowing, as in upper endoscopic prophylactic use of antibiotics should be considered until procedure and bleeding from the site of injection can also evaluated in future trials. be considered complications, but the most severe, but for- tunately also the most rare complication is systemic em- Finally, in one case a 10 mm pedunculated polypoid bolization. Most cases of embolization by cyanoacrylate lesion was noted in the gastric curve of the stomach after have been presented as case reports and the frequency of previous cyanoacrylate injection of GV. After polypecto- this complication in the published series of patients was my, the lesion proved to be a chronic inflammatory pro- extremely low or zero. Embolization has been reported the cess surrounding refractory foreign body material, proba- lungs, and brain 40. Brain embolization was seen in bly sequestrated cyanoacrylate within submucosal vessels patients with a right to left heart compartments commu- 64. In another report, the injection needle was disengaged nication, because glue enters the systemic circulation di- from its plastic sheath and got stuck into the varix after rectly and then usually follows the route of the internal cyanoacrylate injection, but was removed without com- carotid into the brain. Tan et al reported a case of plications with a biopsy forceps.65 This potential compli- near fatal multiple pulmonary and splenic in- cation is seen most commonly in cases where cyanoacry- farction with septicemia after 2 sessions of elective oblit- late is used without lipiodol. eration of gastric varices with cyanoacrylate 58. A case of As it was noted, complications with cyanoacrylate are portal and splenic vein thrombosis after cyanoacrylate in- rare. The procedure can be life saving for patients with a jection was also reported 59, as well as another one with dismal prognosis. To increase the safety of the procedure, splenic infarction 60. Slower injection of cyanoacrylate injections should be gives strictly intravariceally and the into a previously treated gastric varix is recommended dilution ratio between cyanoacrylate and lipiodol should by the authors to avoid this complication. Usually splenic be 1:1. Injections should be limited to a few milliliters of infarction can be treated conservatively, but 7% will re- the mixture, 1cc at each injected site (usually up to 4-5 quire a splenectomy. ml, but preferably between 2-3 ml). If larger amounts are Microembolization into the lungs is more common. required to obliterate the varices, this should be done se- This incident usually self-limiting and patients are either as- quentially. The personnel handling cyanoacrylate should ymptomatic, or experience minor symptoms, such as tran- use gloves and eye protection. 104 D. Christodoulou, et al

Radiologic technique / Combined radiologic bleeding because of the risk of encephalopathy and fail- endoscopic technique ure to improve survival. Furthermore, TIPS occlusion can Balloon-occluded retrograde transvenous obliteration lead to significant recurrence of variceal bleeding. Anoth- (B-RTO), developed by Kanagawa et al, represents a new er study recommended TIPS as a rescue measure for un- 73 treatment for gastric fundal varices that achieves variceal controlled or recurrent bleeding from GV. Occlusion of obliteration with infrequent recurrence 66. This angiograph- the shunt was associated though with recurrence of the ic technique was initially carried out via the femoral vein, bleeding and de novo encephalopathy occurred in 16 per- but can be performed using a transjugular approach.67 An cent of patients. angiographic catheter with a balloon of either 11mm or In our experience, most episodes of gastric variceal 20mm in diameter is inserted via the femoral or can be controlled endoscopically with the use of jugular vein into the spontaneous gastrorenal shunt that cyanoacrylate and recurrent episodes can be treated like- is found in more than 90% of patients with gastric vari- wise. TIPS though can be used, where available, as an ces. With the occluded balloon, sclerosant (usually 10ml emergency treatment for the immediate short-term control of 5% ethanolamine oleate) can be injected to obliterate of uncontrolled gastric fundal variceal bleeding or esopha- the fundal varices and the balloon is left in place for 24 geal bleeding and can serve as a bridge to liver transplan- hours, to permit thrombosis of the varix. The technique is tation.74 Their long-term effect is questionable though. highly effective, but it is interventional and is usually re- served for patients to whom endoscopic approach fails. In Surgical therapy addition, the balloon transvenous obliteration of spleno- The surgical treatment for variceal bleeding current- renal shunt has been used as a safety measure to apply ei- ly is reserved only for patients who are not compliant to ther conventional sclerosant or cyanoacrylate endoscopi- medical and endoscopic treatment and are not candidates 68 cally into the GV with excellent results. This combined for . Devascularization procedures radiologic – endoscopic technique has a role in compli- (transection of esophageal varices and devascularization cated cases of gastric variceal bleeding, but further stud- of the stomach) can be used in patients who have splach- ies are required for its evaluation. nic vein thrombosis and require great expertise. In addi- tion these procedures have a high morbidity and mortality Transjugular intrahepatic portosystemic shunts 75 (TIPS) rate. Elective and non-elective portosystemic shunts have been used in the past quite frequently for the portal decom- Transjugular intrahepatic portosystemic shunts (TIPS) pression and treatment of refractory varices, but now with are another treatment option that should be reserved for re- the evolution of advanced endoscopic techniques they are current variceal bleeding. TIPS are intrahepatic shunts be- only rarely performed in patients who are not good candi- tween the hepatic and portal vein created by angiographic dates for liver transplantation. Elective distal splenorenal methods.69 This low-resistance channel between the por- shunts do not preclude liver transplantation in the future tal and hepatic venous systems decompresses the portal and are associated with a lesser degree of encephalopathy vein in a way similar to a side-to-side portocaval shunt and preserve liver function, but their effectiveness in por- and avoids the need of general anesthesia and surgery. tal decompression is limited. Portocaval shunts are highly There is no doubt about the short-term efficacy of TIPS effective for the treatment of recurrent of refractory vari- in reducing the high portal pressure. The main problems ces, and also for the treatment refractory ascites, but are though with the use of TIPS are the increased incidence associated with high procedural morbidity and mortality, of clinically significant encephalopathy, which affects at high risk of encephalopathy (up to 40-50%) and acceler- least 25% of patients and the high rate of shunt occlusion, ated progression of the underlying .69 which is about 31% in one year and 47% in two years.70 Doppler ultrasonography can be used to assess the paten- Summary cy of TIPS and balloon dilatation or replacement of the So in this review, all the treatment options for GV were occluded of TIPS may be required. presented with a short reference to the current standard Two meta-analyses with a high number of patients of treatment for esophageal varices, since these compli- showed that TIPS are more effective in preventing esopha- cations of cirrhosis are anatomically and physiologically geal variceal bleeding than endoscopic therapy with either related. Emphasis was given to the treatment of GV with sclerotherapy or band ligation.71,72 The final conclusion cyanoacrylate and we presented in detail the endoscopic of those studies was that TIPS could not be recommend- technique we use to treat this severe complication of cir- ed as first-line treatment for the prevention of variceal rhosis. In our experience (unpublished data) cyanoacrylate Gastric and ectopic varices – newer endoscopic options 105 is highly effective and safe for the obliteration of bleed- formed. Embolization of the duodenal varix and surgery ing GV, but the question of whether primary prophylaxis have also been used. In our opinion, treatment with cya- of GV with cyanoacrylate should be performed remains noacrylate for duodenal varices is one of the best options to be addressed by future studies. and can achieve obliteration and disappearance of the du- odenal varices (Figure 5). TIPS, where available, seem to Ectopic varices be a reasonable approach for those rare cases where en- Ectopic varices represent porto-systemic collateral doscopic treatment with cyanoacrylate fails.78 veins that develop in patients with portal hypertension. Apart from the common pathways that lead to the devel- Jejunal and ileal varices opment of gastric and esophageal varices, varices can de- These varices are usually seen in patients with pre- velop in many other sites. Ectopic varices involve other vious surgery involving the small bowel (e.g. Billroth II pathways, such as the inferior mesenteric vein (with com- gastrectomy, small bowel resection). They can rarely be munications through the superior hemorrhoidal to the in- the cause of severe recurrent gastrointestinal bleeding of ferior hemorrhoidal and iliac veins and the splenic hilar obscure origin. Diagnosis is usually established by en- veins (with communication to retroperitoneal veins, which teroscopy, double-balloon enteroscopy, small bowel cap- then communicate with veins on the abdominal wall, in- sule endoscopy and angiography 79. Therapeutic options ferior phrenic veins and renal veins).76 are similar to duodenal varices. The absence of esopha- geal varices does not exclude the presence of small bowel Although the usual consequence of portal hypertension varices, because about one third of patients with ectopic is esophageal and gastric varices, ectopic varices can be varices do not have esophageal varices.76 seen. The most common sites are the , , , colon, and at the site of the stoma in pa- Colonic varices tients with previous bowel resection.76,77 The incidence of Colonic varices can rarely be the cause of gastroin- bleeding from ectopic varices is between 1 to 5%. Patients testinal bleeding in patients with or without portal hyper- with extrahepatic portal hypertension have the highest in- tension. Diagnosis is made by emergency , cidence of bleeding from ectopic varices, and the preva- red blood cell scan and angiography. The colonic varices, lence of bleeding in this population may be as high as 40%. similarly to the other ectopic varices can develop after The highest incidence of ectopic varices has been report- sclerotherapy for esophageal varices. Diagnosis is made ed in those patients with previous abdominal surgery and by endoscopy, endosonography and angiography. Usual- portal hypertension and in patients who have undergone ly endoscopy, after moderate preparation of the patient, successful endoscopic obliteration of esophageal varices can identify the colonic varices in case of bleeding. For by band ligation or sclerotherapy. Approximately 7-10% the treatment of bleeding colonic varices, cyanoacrylate of patients with portal hypertension have visceral varices has been reported to be effective in case reports80 and is remote from the gastroesophageal junction. Visceral var- the preferred treatment by the authors. iceal hemorrhage usually occurs at sites where especially large adhesions form. Postmortem and angiographic stud- ies have shown that the majority of patients with gastro- esophageal varices have ectopic varices as well. Creation of an ileostomy or colostomy allows for communication between the splanchnic and and this results in development of peristomal varices in many patients with portal hypertension.

Duodenal varices Duodenal varices present usually with and . Usually, esophageal varices are present as well or have been treated in the past. Endoscopic treatment of esophageal varices can predispose in the development of ectopic duodenal varices. For the treatment of duode- nal varices, sclerotherapy or band ligations have been used with variable results. In other cases, transjugular intrahe- Figure 5. Endoscopic view of a duodenal varix injected with patic portosystemic shunts (TIPS) were successfully per- glue. 106 D. Christodoulou, et al

Stomal varices ERCP, biliary varices may be mistaken for cholangiocar- About 50 percent of patients with portal hypertension cinoma. If biliary varices are found, Doppler sonography and stomas develop stomal varices and stomal varices should also be performed to rule out portal vein thrombo- bleed in one third of cases. Variceal bleeding from stomal sis. The surgeon should be informed about the presence varices usually occurs at the mucosal cutaneous junction.81 of biliary varices in case of planned , be- 85,86 Diagnosis is usually established by endoscopy and some- cause intraoperative bleeding can be severe. times confirmed by angiography. The bleeding can be con- trolled by local applications of silver nitrate and pressure REFERENCES over the stoma. Sclerotherapy has been used with good results, but we believe that cyanoacrylate may be more 1. Luketic VA, Sanyal AJ. Esophageal varices. I. Clinical pre- sentation, medical therapy and endoscopic therapy. Gastro- effective. 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