TIPS VS BRTO

review of literature for transjugular intrahepatic portosystemic shunt placement and balloon occluded retrograde transvenous obliteration in management of patients with varices hemorrhage

1. TIPS Vs BRTO Pratap Sagar Tiwari 1 Total slides : 52

2. Content TIPS: Intro/ History/ Procedure 1 BRTO: Intro/ History/ Procedure 2 Role of TIPS & BRTO in VH 3 TIPS Vs BRTO 4

3. Algorithm for the MX of AVH in pts with LC *Any of the following: varix spurting blood, varices with overlying clot or with white nipple sign, varices and no other lesion that would explain hemorrhage. **A short-term course (10 days) of PPI may reduce the size of post-banding ulcers. Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 3 /56

4. Algorithm for the MX of AVH in pts with LC ***Excluding pts >75 years old or who have HCC outside Milan criteria, creat of at least 3 mg/dL, previous combination pharmacological plus endoscopic treatment to prevent re-bleeding, bleeding from isolated gastric or ectopic varices, recurrent HE, pulmonary HTN, or heart failure or a combination of these. †Patient should not be discharged on prophylactic antibiotic (consider discontinuing at same time as vasoactive drugs). Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 4

5. Role of TIPS Guidelines[1,2,3] recommend TIPS placement in the following pts at the time of acute VH: 1. Rescue TIPS in pts with persistent bleeding or early re-bleeding despite treatment with vasoconstrictors plus EVL. 2. Early (within 24 to 72 hours) pre-emptive TIPS can be considered in high-risk pts (Child C with score < 14) without CI to TIPS. High risk pt : HVPG≥ 20 mmHg or those with active bleeding at endoscopy.[5] The feasibility of using MELD was evaluated in a retrospective cohort[4]. Among the 206 pts who received early TIPS, those with MELD of at least 19 had a significant survival benefit. de Franchis R, Baveno VI Faculty: Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015; 63(3): 743–52. European Association for the Study of the Liver: EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69(2): 406–60. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al.: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017; 65(1): 310–35. Lv Y, Zuo L, Zhu X, et al.: Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study. Gut. 2019; 68(7): 1297–1310. Monescillo A, Martínez- Lagares F, Ruiz-del-Arbol L, et al. Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding. Hepatology 2004; 40:793. 5

6. TIPS Vs SX in RAVH Author Comparison Number of patients Child- pugh (%) Postoperative morbidity (%) Mortality (%) 1-year survival (%) 2-year survival (%) 5-year survival (%) A B C VH SS HE Khaitiyar  et al.1 TIPS Vs DSRS 35 Vs 32 34 Vs 31 66 Vs 69 26 Vs 6 69 Vs 6 43 Vs 19 6 Vs 6 83 Vs 81 80 Vs 81 NA Henderson et al.2 TIPS Vs DSRS 67 Vs 73 58 Vs 56 42 Vs 44 11 Vs 6 82 Vs 11 51 Vs 49 1 Vs 7 93 Vs 88 88 Vs 81 61 Vs 62 Rosemurgy  et al.3 TIPS Vs HGPCS 66 Vs 66 18 Vs 14 38 Vs 36 44 Vs 50 30 Vs 8 48 Vs 11 NA 15 Vs 20 64 Vs 74 53 Vs 68 31 Vs 47 Orloff et al.4 TIPS Vs PCS 78 Vs 76 21 Vs 20 50 Vs 49 29 Vs 32 41 Vs 0 84 Vs 3 61 Vs 21 22 Vs 23 55 Vs 75 49 Vs 68 20 Vs 61 Khaitiyar JS, Luthra SK, Prasad N, Ratnakar N, Daruwala DK. Transjugular intrahepatic portosystemic shunt versus distal splenorenal shunt – A comparative study. Hepatogastroenterology . 2000;47:492–7. Henderson JM, Boyer TD, Kutner MH, Galloway JR, Rikkers LF, Jeffers LJ, et al. Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: A randomized trial. Gastroenterology. 2006;130:1643–51. Rosemurgy AS, Frohman HA, Teta AF, Luberice K, Ross SB. Prosthetic H-graft portacaval shunts vs transjugular intrahepatic portasystemic stent shunts: 18-year follow-up of a randomized trial. J Am Coll Surg. 2012;214:445–53. Orloff MJ, Vaida F, Haynes KS, Hye RJ, Isenberg JI, Jinich -Brook H. Randomized controlled trial of emergency transjugular intrahepatic portosystemic shunt versus emergency portacaval shunt treatment of acute bleeding esophageal varices in cirrhosis. J Gastrointest Surg. 2012;16:2094–111. SS: Shunt stenosis The outcomes of the meta-analysis based on these 4 trials stated the superiority of surgical shunting over TIPS. 6

7. Why not shunt surgery ? Indeed, surgical shunts were considered before and were compared to TIPSS as a rescue therapy for variceal bleeding in RCTs [1,2]. G. D'Amico and A. Luca, “TIPS is a cost effective alternative to surgical shunt as a rescue therapy for prevention of recurrent bleeding from EV,” Journal of Hepatology, vol. 48, no. 3, pp. 387–390, 2008. M. J. Orloff, “Fifty-three years' experience with randomized clinical trials of emergency portacaval shunt for bleeding esophageal varices in cirrhosis 1958-2011,” JAMA Surgery, vol. 149, no. 2, pp. 155–169, 2014. M. D'Amico, A. Berzigotti , and J. C. Garcia-Pagan, “Refractory acute variceal bleeding: what to do next?” Clinics in Liver Disease, vol. 14, no. 2, pp. 297–305, 2010. S. Fagiuoli , R. Bruno, and V. W. Debernardi , “Consensus conference on TIPS management: Techniques, indications, contraindications,” Digestive and Liver Disease, vol. 49, no. 2, pp. 121–137, 2017. J. M. Henderson, “Salvage therapies for refractory variceal hemorrhage,” Clinics in Liver Disease, vol. 5, no. 3, pp. 709–725, 2001. need to be performed by experienced surgeons. may prevent considering a later LT [3] a/with a higher mortality than TIPSS [4,5] Only bare stents were used in these studies, underestimating the benefits of TIPSS Surgical shunts TIPSS is the first-class therapeutic for refractory variceal bleeding. Covered TIPS is the treatment of choice to prevent EV rebleeding TIPS is effective in the prevention of bleeding recurrence from GV and should be considered in this setting. [ Consensus conference on TIPS management;2017] TIPSS can technically be done in 90-100% of cases. 7

8. 1960s Inadvertent portal access during transjugular cholangiography 1969 Rosch [1] discussed the potential of a “radiologic portocaval shunt” 1982 Colapinto [2] creates the first human balloon dilated TIPS 1988 Richeter [3] creates the first human Palmaz stent TIPS Early to mid-1990s Widespread clinical use with self-expanding bare stents HISTORY OF TIPS Rösch J, HanafeeWN , SnowH . Transjugular portal venography and radiologic portacaval shunt: an experimental study. Radiology 1969;92(5):1112–1114 Colapinto RF, Stronell RD, Gildiner M, et al. Formation of intrahepatic portosystemic shunts using a balloon dilatation catheter: preliminary clinical experience. AJR AmJ Roentgenol 1983;140(4): 709–714 Richter GM, Palmaz JC, Noldge G, et al. The transjugular intrahepatic portosystemic stent-shunt (TIPSS): a new nonoperative percutaneous procedure. Radiologie 1989;29:406–411 8

9. Mid- to late-1990s Animal experimentation using silicone and e-PTFE coated stents to improve TIPS patency [1-3] 2001 Procedure endpoint defined as a reduction in PSG to <12 mm Hg Early 2000s • Early human e-PTFE covered stent-graft experience[4-7] • Defining TIPS candidacy by prognostic parameters (e.g., MELD) 2005 AASLD places practice guidelines on the “role of TIPS in the MX of PHTN” 2009 AASLD adds BCS as an additional indication & considers e-PTFE covered stent grafts as standard of practice HISTORY OF TIPS 9 References are at the end of the slides

10. Transjugular intrahepatic portosystemic shunt (TIPSS): Introduction TIPS involve creation of a low-resistance channel between the hepatic vein and the intrahepatic portion of the portal vein (usually the right branch) using angiographic techniques. The tract is kept patent by deployment of an expandable metal stent across it, thereby allowing blood to return to the systemic circulation. A TIPS is placed to reduce portal pressure in pts with complications related to PHTN.[1,2]   Colombato L. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension. J Clin Gastroenterol. 2007 Nov-Dec. 41 Suppl 3:S344-51. Gaba RC, Omene BO, Podczerwinski ES, Knuttinen MG, Cotler SJ, Kallwitz ER, et al. TIPS for Treatment of Variceal Hemorrhage: Clinical Outcomes in 128 Patients at a Single Institution over a 12-Year Period. J Vasc Interv Radiol . 2011 Dec 16. Pic src : Sankar K, edt al. Transjugular Intrahepatic Portosystemic Shunts. JAMA. 2017;317(8):880. 10

11. Transjugular intrahepatic portosystemic shunt ©2018 UpToDate Creation of a vascular access by the puncture of the IJV, which must be performed under US guidance. Catheterization of one of the HVs, which can be also punctured percutaneously under real time US guidance when its ostium is not easily accessible. When HVs are occluded (BCS), PV branches can be reached by direct puncture from the IVC . Puncture through the liver parenchyma of one of the main branches of PV with or without real time USG guidance . Measurement of the porto -systemic pressure gradient (PPG) by a digital recording system properly set-up for venous pressure . IVC and not RA BP should be subtracted to PV pressure to calculate the gradient. S. Fagiuoli , R. Bruno, and V. W. Debernardi , “Consensus conference on TIPS management: Techniques, indications, contraindications,” Digestive and Liver Disease, vol. 49, no. 2, pp. 121–137, 2017. 11

12. Transjugular intrahepatic portosystemic shunt ©2018 UpToDate Balloon dilatation of the parenchymal tract between the hepatic (or IVC) and PVs. Deployment of the stent within the parenchymal tract. Hemodynamic assessment of the resultant PPG reduction followed by further balloon dilatation of the lumen to reach the desired target of pressure gradient. Reduction of PPG to <12 mm Hg should be achieved when the indication is bleeding from EV. S. Fagiuoli , R. Bruno, and V. W. Debernardi , “Consensus conference on TIPS management: Techniques, indications, contraindications,” Digestive and Liver Disease, vol. 49, no. 2, pp. 121–137, 2017. 12

13. TIPS PROCEDURE ©2018 UpToDate 13

14. TIPS PROCEDURE Intravenous heparin is given for prevention of shunt thrombosis (bolus dose of 2500–5000 U followed by constant infusion for 1–2 weeks, targeted at an aPTT of 60–80 seconds. A color Doppler USG is obtained 24 hours after the procedure to show shunt patency. It is usually repeated one week later if it is an uncovered stent or one month later if it is covered . After that, if there are no complications, the USG is repeated 3 months later and then every 6 months until the clinical outcome. 14 /56

15. Are blood products routinely required during TIPS placement? FFP, or pro- haemostatic agents are not required in cirrhotic pts undergoing TIPS, irrespective of INR value (1,2). Although the threshold of platelet count needed to ensure normal primary haemostasis in cirrhosis is not clearly defined, the 50X10 9 /L cut-off can be utilized for platelets infusion before TIPS (3). Bosch J, Thabut D, Albillos A, Carbonell N, Spicak J, Massard J, et al. Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial. Hepatology. 2008 May;47(5):1604–14. Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion. 2005 Sep;45(9):1413–25. Tripodi A, Primignani M, Chantarangkul V, Lemma L, Jovani M, Rebulla P, et al. Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion. Liver Int. 2013 Mar;33(3):362–7. 15

16. Post-TIPS assessment 16 /56 LOREM IPSUM >50 cm/s , ideally between 90 to 150 cm/s, but acceptable from 50 to 200~250 cm/s. Velocity in the shunt device Patency and flow direction in HVs (esp. the segment between the device and the IVC, of which we should determine the velocity) Direction of flow in PV: H epatopetal Direction of main IHPV branches: retrograde/ stagnant . Flow direction in PV & branches If the flow in SV is hepatofugal before TIPS, should be hepatopetal post-TIPS in a normal functionating device. Flow direction in Splenic Vein >30 cm/s. Note that it should ↑ significantly after TIPS (>50%). Velocity of the mid PV Reduction in the caliper of the collaterals; (paraumbilical, left gastric, SRS). Evaluation of the collateral vessels Stent configuration / position

17. EARLY EVENTS: Bacteriemia Bacteriemia after TIPS (defined by fever >38.5°C, or leucocytosis >15.000 / ul and positive blood cultures) ranges between 2-25%(2-4,6) and in a prospective RCT was not influenced by antibiotic prophylaxis (1) A longer duration of procedure, multiple stenting and the maintenance of a central venous line are a/with a higher risk of infection after TIPS. In pts with uncomplicated procedure, the transjugular venous access should be removed at the end of the intervention (1,5). A single dose of long acting cephalosporin ↓ the incidence of bacterial infection (20% to 2.6%) justifying its use in anticipated complex procedures (2). Deibert P, Schwarz S, Olschewski M, Siegerstetter V, Blum HE, Rössle M. Risk factors and prevention of early infection after implantation or revision of transjugular intrahepatic portosystemic shunts: results of a randomized study. Dig Dis Sci. 1998 Aug;43(8):1708–13. Gulberg V, Deibert P, Ochs A, Rossle M, Gerbes AL. Prevention of infectious complications after transjugular intrahepatic portosystemic shunt in cirrhotic patients with a single dose of ceftriaxone.Hepatogastroenterology . Jan;46(26):1126–30. Ghinolfi D, De Simone P, Catalano G, Petruccelli S, Coletti L, Carrai P, et al. Transjugular intrahepatic portosystemic shunt for hepatitis C virus-related portal hypertension after liver transplantation. Clin Transplant. Jan;26(5):699–705. Moon E, Tam MDBS, Kikano RN, Karuppasamy K. Prophylactic antibiotic guidelines in modern interventional radiology practice. Semin Intervent Radiol . 2010 Dec;27(4):327–37. Mizrahi M, Roemi L, Shouval D, Adar T, Korem M, Moses A, et al. Bacteremia and “ Endotipsitis ” following transjugular intrahepatic portosystemic shunting. World J Hepatol. 2011 May 27;3(5):130–6. Navaratnam AM, Grant M, Banach DB. Endotipsitis : A case report with a literature review on an emerging prosthetic related infection. World J Hepatol. 2015 Apr 8;7(4):710–6. 17

18. LATE EVENTS: Endotipsitis Defined by the presence of sustained bacteriemia a/with the evidence of thrombus or vegetations inside the TIPS. This clinical condition is rare (1%). Early endotipsitis (< 120 days of the procedure) is usually related to Gram-positive organisms and the antibiotic therapy must be long-lasting (at least 3 months) to avoid recurrence (1). In pts with uncontrolled or recurrent infection LT should be considered(2). There is no evidence for adopting long-term prophylaxis for the prevention of endotipsitis . Navaratnam AM, Grant M, Banach DB. Endotipsitis : A case report with a literature review on an emerging prosthetic related infection. World J Hepatol. 2015 Apr 8;7(4):710–6. Kochar N, Tripathi D, Arestis NJ, Ireland H, Redhead DN, Hayes PC. Tipsitis : incidence and outcome-a single centre experience. Eur J Gastroenterol Hepatol. 2010 Jun;22(6):729–35. Sanyal AJ, Reddy KR. Vegetative infection of transjugular intrahepatic portosystemic shunts. Gastroenterology. 1998;115:110-115. The term “ endotipsitis ” was proposed by Sanyal and Reddy [3], who defined it as: (1) the presence of continuous bacteremia indicating an infectious focus in continuity with the venous circulation and (2) failure to find an alternate source of infection despite an extensive search.  18

19. Hepatic encephalopathy HE is one of the major complications of TIPS. The incidence of overt episodic or recurrent HE post-TIPS varies between 15 and 67% in a 2-year follow-up . The incidence of persistent overt HE is around 8% (1) and that of covert HE around 35% (2-9,12,13). Prophylaxis of post-TIPS HE with either lactulose or rifaximin is not routinely recommended (9). Stent lumen reduction or occlusion is effective in case of persistent overt post-TIPS HE (10,11). References are present at the end of the slides. 19

20. Contraindications to TIPS positioning The absence of vascular accesses represents the only technical CI to TIPS (1). The presence of PVT resulting in a portal cavernoma is not an absolute CI in presence of a “portal” landing zone with adequate flow and calibre to receive the device (2,3) Gazzera C, Fonio P, Gallesio C, Camerano F, Doriguzzi Breatta A, Righi D, et al. Ultrasound-guided transhepatic puncture of the hepatic veins for TIPS placement. Radiol Med. 2013 Apr;118(3):379–85. Senzolo M, Tibbals J, Cholongitas E, Triantos CK, Burroughs AK, Patch D. Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation. Aliment Pharmacol Ther . 2006 Mar 15;23(6):767–75. Van Ha TG, Hodge J, Funaki B, Lorenz J, Rosenblum J, Straus C, et al. Transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis and concomitant portal vein thrombosis. Cardiovasc Intervent Radiol . Jan;29(5):785–90. Chiva T, Ripoll C, Sarnago F, Rincón D, Gómez- Camarero J, Galindo E, et al. Characteristic haemodynamic changes of cirrhosis may influence the diagnosis of portopulmonary hypertension. Liver Int. 2015 Feb;35(2):353–61. S. Fagiuoli , “Consensus conference on TIPS management" 2017 Clinical contraindications to TIPS placement are: Advanced liver disease (CP > 11, serum bilirubin > 5 mg/dl, MELD >18) (4). Severe organic renal failure (serum creat > 3 mg/dl) Heart failure Severe porto -pulmonary HTN ( mPAP >45mmHg) Recurrent or persistent overt HE grade > 2 (WH scale) despite adequate RX Uncontrolled sepsis 20

21. Relative technical CIs are anatomical conditions a/with a reduction in technical success rate or with an ↑ risk of complications, such as liver tumours , the presence of multiple hepatic cysts . The clinical appropriateness of TIPS positioning should be evaluated on a case-by-case basis according with the relevance of the indication and the presence of general CIs. Indeed, in the context of a life-threatening condition such as AVH , a broader range can be adopted (CP C score < 14). 21

22. TIPS: Bare stent Vs PTFE-covered stent A major complication after TIPS insertion using bare stent grafts is the development of HE , which can occur in up to 50% of pts .[1,2] The incidence of this complication can be significantly reduced to about 18% with the use of PTFE-covered stent grafts of 8 mm ,[3] a result confirmed by a recent RCT comparing 8 mm and 10mm stent grafts.[4] Dysfunction of TIPS with bare stent grafts because of stent thrombosis and stenosis can develop in up to 80% of cases .[1] This complication has been significantly reduced with the use of PTFE-covered stents .[5] References are present at the end of the slides. 22 Note: Use of polytetrafluoroethylene coated stents was first reported in 1995 [6]

23. TIPS: Covered Vs Bare Bureau et al. 2015[2] Perarnau  et al. 2015[3] 39 Vs 41 66 Vs 71 After median follow-up of 300 days; Shunt dysfunction: 13% Vs 44%,P < 0.001. HE @1 yr : 21% Vs 41% (NS). The 1-year and 2-year survival rates: 70.9 % and 64.5 % Vs 59.5 % and 40.5 % (NS) The use of CS improves shunt patency without increasing the risk of HE. Median follow-up :23.6 and 21.8 months, respectively. Shunt dysfunction :RR= 0.60; 95% CI:0.38-0.96, p=0.032. The 2-year rate of shunt dysfunction: 44.0% vs. 63.6% . Risk of HE: 0.89; 95% CI: 0.53-1.49,NS 2-year survival: 70% vs. 67.5%, NS CS provided a significant 39% reduction in dysfunction compared to BS. No significant difference with regard to HE or death. Multi center single blind RCT Stent diameter data: NA Multi center single blind RCT CS: 10.5 ± 0.9 versus  BS: 11.7 ± 0.8 mm In the recent meta-analysis by Qi et al[1], covered stents not only significantly improved the shunt patency, but also significantly ↓the risk of death . Additionally, the risk of HE was not ↑ by the use of covered stents . 23 References are present at the end of the slides.

24. Prevention of recurrent variceal bleeding: bTIPS Vs Medical therapy + EVL Zheng et al. 2015 12 RCT; 883 pts Decreased incidence of RVH; OR=0.32 , 95% CI:0.24-0.43, P<0.00001 Deaths due to rebleeding; OR=0.35 , 95% CI:0.18-0.67, P=0.002 Increased rate of HE; OR=2.21 , 95% CI:1.61-3.03, P<0.00001 TIPS is currently the first choice to prevent rebleeding except that TIPS is worse than endoscopic therapy for HE. Zheng M., Chen Y., Bai J., Zeng Q., You J., Jin R., et al. (2008) Transjugular intrahepatic portosystemic shunt versus endoscopic therapy in the secondary prophylaxis of variceal rebleeding in cirrhotic patients: meta-analysis update. J Clin Gastroenterol 2009; 42: 507–16. Most indications for TIPS were established in the era of bare stents . For example, a meta-analysis(12 HQ RCT;883 pts) by Zheng et al [1] suggested that TIPS with bare stents should be superior to endoscopic and pharmacological treatment for decreasing the risk of variceal rebleeding, but inferior in relation to HE . 24

25. Prevention of recurrent variceal bleeding: cTIPS Vs Medical therapy + EVL Sauerbruch  et al. 2015 Luo et al. 2015 Holster et al. 2016 92 Vs 95 37 Vs 36 37 Vs 35 RVH within 2 yrs : 7% Vs 26%; p = 0.002 HE: 18% vs 8%; p = 0.05. No difference in survival curve. TIPS was more straightforward and prevented RVH more effectively, but did not improve the survival. The 2-year probability of remaining free of RVH: 77.8% Vs 42.9%; p = 0.002 HE; no sig differences; p = 0.53. The 2-year survival: 72.9% Vs 57.2% ;p = 0.23 TIPS had a significantly lower risk of RVH, but a similar risk of HE and death.  Median follow‐up of 23 months, RVH: 0% vs 29 %; p = 0.001 Mortality: 32% vs. 26%; p = 0.418 Early HE: 35% vs. 14%; p = 0.035 TIPS had a significantly lower risk of RVH, but the risk of HE and death was not sig different. Multicenter prospective RCT Germany Multicenter prospective RCT Netherlands Single center prospective RCT China 25 References are present at the end of the slides.

26. Balloon-occluded retrograde transvenous obliteration Picture credit:Shou-Dong Lee, Cheng Hsin General Hospital 26

27. Transvenous obliteration Transvenous obliteration is an old idea that was practiced in the 1970s in the pre TIPS era as an procedure for the MX of bleeding EV and GOV from a percutaneous transhepatic approach .[1-5] These percutaneous transhepatic obliteration were mostly performed utilizing coils, Gelfoam , and/or sclerosants ( such as absolute alcohol and 30–50% glucose solution ) without utilizing occlusive balloons to modulate blood flow.[1-5] These procedures, utilizing current terminology, are now referred to as PTO [6,7], which is a type of balloon-occluded antegrade transvenous obliteration (BATO). Choi YH, Yoon CJ, Park JH, Chung JW, Kwon JW, Choi GM. Balloon-occluded retrograde transvenous obliteration for gastric variceal bleeding: its feasibility compared with transjugular intrahepatic portosystemic shunt. Korean J Radiol 2003;4(2):109–116 Funaro AH, Ring EJ, Freiman DB, Oleaga JA, Gordon RL. Transhepatic obliteration of esophageal varices using the stainless steel coil. AJR Am J Roentgenol 1979;133(6):1123–1125 Scott J, Dick R, Long RG, Sherlock S. Percutaneous transhepatic obliteration of gastro- oesophageal varices. Lancet 1976;2(7976):53–55 Lunderquist A, Simert G, Tyle´n U, Vang J. Follow-up of patients with portal hypertension and esophageal varices treated with percutaneous obliteration of gastric coronary vein. Radiology 1977;122(1):59–63 Lunderquist A, Vang J. Transhepatic catheterization and obliteration of the coronary vein in patients with portal hypertension and esophageal varices. N Engl J Med 1974; 291(13):646–649 Lunderquist A, Vang J. Sclerosing injection of esophageal varices through transhepatic selective catheterization of the gastric coronary vein. A preliminary report. Acta Radiol Diagn ( Stockh ) 1974;15(5):546–550 Tajiri T, Onda M, Yamashita K, et al. Interventional radiology for portal hypertension. PTO.TIO. Nippon Geka Gakkai Zasshi 1996;97(1):70–77 27

28. PERCUTANEOUS TRANSHEPATIC OBLITERATION OF G-E VARICES The PV was localised in both anteroposterior and lateral planes by venography, or grey-scale ultrasound. Under local anaesthesia the liver is punctured during apnea in the mid-axillary line below the costophrenic reflection by means of a cholangiography needle with a radio-opaque catheter. The needle is advanced under image guidance in the direction of the PV. The needle is removed and the radio-opaque catheter gradually drawn with suction applied until blood is freely aspirated. A test injection of contrast medium is made to confirm the position of the catheter in the PV or one of its branches. The catheter is advanced over a guide wire as far as possible along the SV. The portal pressure is measured and a portal venogram obtained. Scott J, Dick R, Long RG, Sherlock S. Percutaneous transhepatic obliteration of gastro- oesophageal varices. Lancet 1976;2(7976):53–55 28 /56

29. PERCUTANEOUS TRANSHEPATIC OBLITERATION OF G-E VARICES The major variceal supply veins (LGV and short gastric) are selectively catheterised and thrombosed. 30 ml of 50 % dextrose is injected to traumatise the intima of the veins, increasing quantities of human thrombin (500-3000 units) is injected to induce complete thrombosis , and small pieces of gelatin foam are injected to stabilise the thrombus. Contrast medium is then injected to confirm successful obliteration, and if this had been achieved the catheter is carefully withdrawn. A portal venogram is obtained to ensure complete obliteration of all variceal supply veins and PV patency. Finally, before complete withdrawal of the catheter from the liver, the hepatic puncture wound is plugged by an injection of gelatin foam into the subcapsular parenchyma. Scott J, Dick R, Long RG, Sherlock S. Percutaneous transhepatic obliteration of gastro- oesophageal varices. Lancet 1976;2(7976):53–55 29

30. BRTO 2006 John Kaufman 1991-1993 Kanagawa et al 1984 Olson et al 1970 First BRTO in US, with 3% Sotradecol [4] Practiced and published BRTO procedure, coining the term ‘‘ balloon-occluded retrograde transvenous obliteration ’’ (B-RTO).[3] Ethanolamine-oleate Transvenous obliteration is an old idea that was practiced in the 1970s in the pre-TIPS era as an procedure for the MX of bleeding varices from a percutaneous transhepatic approach.[1] First published document of an attempt at balloon-occluded sclerotherapy ( absolute alcohol ) of the GRS for the MX of GVs.[2] Term used for the procedure was ‘‘ transrenal -vein reflux ethanol sclerosis’’. Scott J, Dick R, Long RG, Sherlock S. Percutaneous transhepatic obliteration of gastro- oesophageal varices. Lancet 1976;2(7976):53–55 Fukatsu H, Kawamoto H, Harada R, et al. Gastric fundal varices with an exposed microcoil after the combined BRTO and PTO therapy. Endoscopy 2007;39(Suppl 1):E247–E248 Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloonoccluded retrograde transvenous obliteration. J Gastroenterol Hepatol 1996;11(1):51–58 Saad, W. E. A. (2011). The History and Evolution of Balloon-occluded Retrograde Transvenous Obliteration (BRTO): From the United States to Japan and Back. Seminars in Interventional Radiology, 28(03), 283–287. doi:10.1055/s-0031-1284454 30

31. Gastric Varices Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term followup study in 568 portal hypertension patients. Hepatology 1992;16:1343–1349. (also for table shown) De Franchis RBaveno VI faculty. Expanding consensus in portal hypertension: report of the BAVENO VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752. T. Kim, H. Shijo , H. Kokawa et al., “Risk factors for hemorrhage from gastric fundal varices,” Hepatology, vol. 25, no. 2, pp. 307–312, 1997.  Pic src : Mehta, G., Abraldes , J. G., & Bosch, J. (2010).  Developments and controversies in the management of oesophageal and gastric varices. Gut, 59(6), 701–705. The Sarin classification is most commonly used for risk stratification and MX of GV. [1] GV are present in about 20% of pts with LC. GOV 1 are commonly managed following guidelines for EV.[2] Cardiofundal varices (GOV2 & IGV1) bleed less frequently. However, is often more severe, more difficult to control and shows a ↑ risk of rec bleeding and mortality (up to 45%) compared to EV.[1]  In CFV, the 5-year cumulative incidence of bleeding is 44% in the natural course, and the 1-year survival rate is 48% in case of bleeding. [3] 31

32. Anatomy of gastric varices Kim M, Lee K-Y. Understanding the pathophysiology of portosystemic shunt by simulation using an electric circuit. Biomed Res Int. 2016;2016(81):ID 2097363.7 Gonzalez JM, et al. Management of fundic varices. Endoscopic aspects. Rev esp enfeRm Dig 2015. 107;8, pp. 501-508 A B The afferent channel for gastric varix is mostly from LGV or posterior gastric veins. [1-3] The efferent channel for most GVs (80–85%) is the GRS , which opens into the LRV .[2,4] Watanabe K, Kimura K, Matsutani S, Ohto M, Okuda K. Portal hemodynamics in patients with gastric varices: A study in 230 patients with esophageal and/or gastric varices using portal vein catheterization. Gastroenterology. 1988;95:434–40. Chikamori F, Kuniyoshi N, Shibuya S, Takase Y. Correlation between endoscopic and angiographic findings in patients with esophageal and isolated gastric varices. Dig Surg. 2001;18:176–81. Kimura K, Ohto M, Matsutani S, Furuse J, Hoshino K, Okuda K. Relative frequencies of portosystemic pathways and renal shunt formation through the “posterior” gastric vein: Portographic study in 460 patients. Hepatology. 1990;12:725–8. Koito K, Namieno T, Nagakawa T, Morita K. Balloon-occluded retrograde transvenous obliteration for gastric varices with gastrorenal or gastrocaval collaterals. AJR Am J Roentgenol . 1996;167:1317–20. 32

33. Anatomy of gastric varices The two main infra-diaphragmatic portosystemic shunts: the gastrocaval and gastrorenal shunts. The common afferent ( portovenous feeders) to the GV are LGV (also known as the coronary vein), the PGV, and the SGV. The SGV and PGV arise from the SV, and the LGV arises from the confluence of the SV and the mesenteric vein(s) (SMV). The LGV may also arise from the proximal main PV. The efferent limbs of the GV, which drain the GV into the systemic circulation, either drain directly into the IVC (the GRS) or into the LRV (GRS). The asterisk denotes a direct communication between the SV and the shunt/left renal vein , demonstrating a SRS. Al- Osaimi AMS, Caldwell SH. Medical and endoscopic management of gastric varices. Semin Interv Radiol 2011 ;28:273–282. 33

34. Anatomy of gastric varices Basic anatomy of a GV, with the portal circulation shaded dark gray and the systemic circulation shaded light gray. The figure demonstrates the para- and supradiaphragmatic portosystemic venous circulation, representing alternative access routes to the BRTO procedure. The GRS in this drawing is rudimentary. Rt BCV,right brachiocephalic vein; Lt BCV, left brachiocephalic vein; Lt SV, left subclavian vein; Peric V, Pericardiol or pericardio -phrenic vein; AzA , azygous arch; AV, azygous venous system or azygo-paraesophageal venous system; IPV, inferior phrenic vein: descending portion ( DpIPV ) and transverse portion ( TpIPV ); Saad WEA, Sze DY. Variations of balloonoccluded antegrade transvenous obliteration (BATO) and alternative/ adjunctive routes for BRTO. Semin Interv Radiol 2011;28:314–324 34

35. Anatomy of gastric varices (B) The balloon-occlusion catheter being advanced from a transfemoral approach and positioned and inflated in the transverse portion of the inferior phrenic vein via the left brachiocephalic and pericardial veins ,with ultimate filling of the GV with contrast (black). (C) Balloon-occlusion catheter being advanced from a transfemoral approach and positioned and inflated in the descending portion of the inferior phrenic vein via the azygous arch and azygous- paraesophageal venous system , ultimately filling the GV with contrast (black). Saad WEA, Sze DY. Variations of balloonoccluded antegrade transvenous obliteration (BATO) and alternative/ adjunctive routes for BRTO. Semin Interv Radiol 2011;28:314–324 (A) The balloon-occlusion catheter being advanced from a transfemoral approach and positioned and inflated in the transverse portion of the inferior phrenic vein and filling of the GV with contrast (black). 35

36. Anatomy of gastric varices The basic and surgical anatomy of a gastric varix, with the portal circulation shaded gray and the systemic circulation shaded black. A combined balloon-occluded antegrade transvenous obliteration (BATO) and BRTO access is illustrated. The BATO access is via a TIPS. The BRTO access is via the traditional transfemororenal access. Saad WEA, Sze DY. Variations of balloonoccluded antegrade transvenous obliteration (BATO) and alternative/ adjunctive routes for BRTO. Semin Interv Radiol 2011;28:314–324 36

37.  The Kiyosue classification of GV (a) Classification based on drainage pathway A.Arora , S.Rajesh , Y. S.Meenakshi , B. Sureka,K.Bansal , and S. K. Sarin, “ Spectrumof hepatofugal collateral pathways in portal hypertension: an illustrated radiological review,” Insights into Imaging, vol. 6, no. 5, pp. 559–572, 2015. Type A consists of a portosystemic shunt as the only drainage Type B: PSS along with additional small portosystemic collaterals Type C: there is presence of multiple large PSS Type D consists of multiple small portosystemic collaterals as the drainage pathways without proper shunt formation. 37

38.  The Kiyosue classification of GV (b) Classification based on the inflow pathway A.Arora , S.Rajesh , Y. S.Meenakshi , B. Sureka,K.Bansal , and S. K. Sarin, “ Spectrumof hepatofugal collateral pathways in portal hypertension: an illustrated radiological review,” Insights into Imaging, vol. 6, no. 5, pp. 559–572, 2015. Type 1 consists of single afferent vein for the varices Type 2 has multiple afferent vessels contributing to the variceal formation Type 3 is similar to Type 2 but with additional small collateral/shunts directly communicating with outflow tract. 38

39. Coil-assisted retrograde transvenous obliteration 39 /56

40. The concept of BRTO The concept of BRTO involves accessing the GRS via the LRV through the femoral or jugular route and injecting a sclerosant agent such as ethanolamine oleate, absolute alcohol, gelfoam , or sodium tetradecyl sulphate into the varices after inflating a balloon in the GRS to obstruct the shunt outflow, thereby obliterating the varices[1-4] References are at the end of the slides Taken from: https://articl.net/resource/balloon-occluded-retrograde-transvenous-obliteration-brto In the presence of a completely thrombosed main PV , GRS act as the primary outflow of the splenic and mesenteric veins. So, occlusion of the GRS, which is a by-product of the BRTO procedure, would potentially cause mesenteric venous hypertension, mesenteric ischemia, and possibly thrombosis of the entire splanchnic portal venous circulation . Although PVT is not an absolute CI to BRTO, it is a hemodynamic dilemma that has not been investigated fully. Chronic occlusion of the main PV with cavernous transformation may provide sufficient outflow for the portal venous system after occluding the portosystemic shunts, and therefore it may be acceptable to proceed with the BRTO procedure with the risks and benefits of the procedure taken into consideration .[5] 40

41. Clinical Outcomes of BRTO Procedure for the management of Gastric Varices In most studies, GV rebleeding rates of pts who had undergone a successful BRTO range from zero-12% after a median follow-up of 33 to 75 wks , and rates for complete obliteration of GV range from 86-100%. References are at the end of the slides 41

42. Clinical Outcomes of BRTO Procedures for GV The 30-day mortality rates range from zero to 4.1%, and the most common cause of death is progressive liver failure .[1-9]  Most of these complication were related with use of ethanolamine oleate . Sodium tetradecyl sulfate (STS) foam is also widely used for BTRO procedure,[2,3] and complication of BRTO has also changed. For example, STS foam does not lead to AKI . But it could make air embolism. Procedural complications: Gross hematuria with AKI (up to 4.8%) Pulmonary embolism (1.5%–4.1%) Anaphylaxis to ethanolamine oleate (up to 5%) Cardiac arrhythmias (up to 1.5%) Rapidly declining hepatic function (5%–7%) References are at the end of the slides 42

43. PHTN complications related to BRTO Fukuda T, Hirota S, Sugimura K. Long-term results of balloon-occluded retrograde transvenous obliteration for the treatment of gastric varices and hepatic encephalopathy. J Vasc Interv Radiol . 2001; 12:327–36. Ninoi T, Nishida N, Kaminou T, Sakai Y, Kitayama T, Hamuro M, et al. Balloon-occluded retrograde transvenous obliteration of gastric varices with gastrorenal shunt: long-term follow-up in 78 patients. AJR Am J Roentgenol . 2005; 184:1340–6. Ninoi T, Nakamura K, Kaminou T, Nishida N, Sakai Y, Kitayama T, et al. TIPS versus transcatheter sclerotherapy for gastric varices. AJR Am J Roentgenol . 2004; 183:369–76. Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. J Gastroenterol Hepatol. 1996; 11:51–8. Sonomura T, Sato M, Kishi K, Terada M, Shioyama Y, Kimura M, et al. Balloon-occluded retrograde transvenous obliteration for gastric varices: a feasibility study. Cardiovasc Intervent Radiol . 1998; 21:27–30. Kitamoto M, Imamura M, Kamada K, Aikata H, Kawakami Y, Matsumoto A, et al. Balloon-occluded retrograde transvenous obliteration of gastric fundal varices with hemorrhage. AJR Am J Roentgenol . 2002; 178:1167–74. Arai H, Abe T, Shimoda R, Takagi H, Yamada T, Mori M. Emergency balloon-occluded retrograde transvenous obliteration for gastric varices. J Gastroenterol. 2005; 40:964–71. Cho SK, Shin SW, Lee IH, Do YS, Choo SW, Park KB, et al. Balloon-occluded retrograde transvenous obliteration of gastric varices: outcomes and complications in 49 patients. AJR Am J Roentgenol . 2007; 189:W365–72. Hiraga N, Aikata H, Takaki S, Kodama H, Shirakawa H, Imamura M, et al. The long-term outcome of patients with bleeding gastric varices after balloon-occluded retrograde transvenous obliteration. J Gastroenterol. 2007; 42:663–72. Another most important complications a/with BRTO is the aggravation of EV . Reported rates of worsening EV vary up to 63%, with 11% to 24% subsequent variceal bleeding rate.[1-9]  Other complications from increased PHTN after BRTO Development of PHG (5%–13%) Ascites (0%–44%) Hydrothorax (0%–8%).[1-9] 43

44. HCC after BRTO Yokohama et al. The Incidence of Hepatocellular Carcinoma after Balloon-Occluded Retrograde Transvenous Obliteration. Volume 2015, Article ID 605292, 7 pages Group A % Group B % Non BRTO % 1 YR 20.9 35.8 6.3 3 YR 41.1 80.0 19.2 5 YR 60.7 42.5 The study demonstrated a high incidence of HCC after BRTO in LC pts with viral hepatitis infection. This suggested the potential for BRTO to accelerate hepatocarcinogenesis. Yooyama et al investigated the incidence of HCC after BRTO in pts with chronic viral hepatatits related CLD (HCV:66, HBV:5) . Group A, pts without H/O HCC before BRTO (n=40) and group B, pts with H/O RX for HCC and DX with no HCC appearance when BRTO was performed (n=31). Non-BRTO group: 51 pts with chronic viral hepatatits related and without H/O HCC 44

45. Clinical Outcomes of the TIPS procedure for GV There are limited data addressing TIPS for the treatment of GV , as most TIPS studies have included all EV with or without GV. There are 8 studies evaluating the placement of a TIPS for bleeding GV.[1-8]  References are at the end of the slides 45 /56

46. cTIPS Vs BRTO : in treatment of pt bleeding from gastric varices Sabri et al. 2014[1] Sauk et al. 2014[2] 27 Vs 23 27 Vs 25 Technical success rate: 100% Vs 91%, p = 0.21 Major complications: 4% Vs 9%, p = 0 .344 HE: 15% Vs 0%, p = 0.12 At 12 mnths , incidence of rebleeding: 11% Vs 0%, p = 0.25 BRTO appears to be equivalent to TIPS in the short-term for management of bleeding GV Procedural complications: 7% Vs 12%, p = 0.463 Resolution of GV on follow-up: 60% Vs 87%, p= 0.079 Rebleeding rates: 7% Vs 12%, p = 0.463 HE: 22% Vs 0%, p = 0.012 Development of new ascites: 4% Vs 4%, p = 0.937 BRTO is an effective method in the RX of GV with similar outcomes and complication rates as TIPS, but with a lower rate of HE. Single center retrospective cTIPS versus  BRTO (EO or Sotradecol foam) Single center retrospective cTIPS versus  BRTO (foam sclerosant) Bare stents were used in earlier studies, which, are known to have lower patency when compared to covered stents, and likely account for the higher rebleeding rates. More recently, Sabri et al [1] and Sauk et al [2] did a retrospective study to compare cTIPS with BRTO for MX of pts bleeding from GV. 46 References are at the end of the slides

47. TIPS or BRTO ? As discussed from the review of the literature, both TIPS and BRTO can effectively treat GV with low rebleeding rates, however careful pt selection is required to best treat the pt’s individual clinical situation. For pts with GV and severe HE or If a pt’s MELD score is high If there is recurrent gastric variceal bleeding even after TIPS revision In pts in whom a TIPS placement is technically difficult If there is a centrally located tumor and no window for the TIPS stent to land without violating the tumor For eg : In pts with cavernous transformation of a chronically thrombosed main PV, a TIPS procedure could be technically difficult. 47

48. TIPS or BRTO ? As discussed from the review of the literature, both TIPS and BRTO can effectively treat GV with low rebleeding rates, however careful pt selection is required to best treat the pt’s individual clinical situation. If there is EV in addition to GV , a TIPS procedure or BRTO after endoscopic ligation of the EV can be performed. For pts with GV and intractable ascites or hydrothorax , TIPS is a better option. If the BRTO procedure is complicated by vein rupture or balloon rupture with subsequent clinical failure , TIPS could be placed . 48

49. Role of adjunct therapy ? BRTO TIPS BRTO and TIPS are two procedures that are considered for the RX of bleeding GV.[1,2,3] TIPS creates a portosystemic shunt and thus decompresses the portal circulation BRTO involves occlusion of a commonly associated spontaneous portosystemic shunt that usually causes increased PP Saad W EA Al- Osaimi A M Caldwell S et al.For the Expert Panel on Interventional Radiology for the American College of Radiology ACR Appropriateness Criteria(r): Radiologic Management of Gastric Varices. Available at: http://www.acr.org/~/media/ACR/Documents/AppCriteria/Interventional/RadiologicManagementGastricVarices.pdf. Saad W E, Darcy M D. Transjugular intrahepatic portosystemic shunt (TIPS) versus balloon-occluded retrograde transvenous obliteration (BRTO) for the management of gastric varices. Semin Intervent Radiol . 2011;28(3):339–349. Saad W E, Wagner C C , Lippert A. et al.Protective value of TIPS against the development of hydrothorax/ascites and upper gastrointestinal bleeding after balloon-occluded retrograde transvenous obliteration (BRTO) Am J Gastroenterol. 2013;108(10):1612–1619. Kessler J, Trerotola S O. Use of the Amplatzer Vascular Plug for embolization of a large retroperitoneal shunt during transjugular intrahepatic portosystemic shunt creation for gastric variceal bleeding. J Vasc Interv Radiol . 2006;17(1):135–140. Gaba R C, Bui J T, Cotler S J. et al.Rebleeding rates following TIPS for variceal hemorrhage in the Viatorr era: TIPS alone versus TIPS with variceal embolization. Hepatol Int. 2010;4(4):749–756. Lunderquist A, Vang J. Transhepatic catheterization and obliteration of the coronary vein in patients with portal hypertension and esophageal varices. N Engl J Med. 1974;291(13):646–649. The effectiveness of adjunctive variceal embolization after decompressing the portal circulation with a TIPS is a matter of debate. Adjunctive embolization is performed after TIPS if the varices are still visualized during the post-TIPS portal venogram,[4,5]  Variceal embolization likely helps reduce the risk of bleeding in the setting of subsequent TIPS dysfunction as well.[6] 49

50. Prevention of recurrent variceal bleeding: TIPS + Emb Vs TIPS alone Tesdal  et al. 2005[1] Chen et al. 2013[2] Qi et al. 2013[3] 53 Vs 42 54 Vs 52 6 studies The 2-year and 4-year rebleeding rates 16 and 19%, Vs 39 and 47%; p  = 0.02  TIPS and adjunctive embolotherapy of gastroesophageal collateral vessels significantly lower the rebleeding rate in comparison to TIPS alone. 6-month rebleeding rate: 6 vs. 20%;  p  = 0.02  The TIPS+E regimen may reduce the risk of RVH during the first 6 months by preventing shunt dysfunction, which may improve liver function. lower incidence of RVH: OR 2.02, 95% CI 1.29-3.17, p = 0.002 Shunt dysfunction: OR 1.26, 95% CI 0.76-2.08, p = 0.38 HE: OR 0.81, 95% CI 0.46-1.43, p = 0.4 Death: OR 0.90, 95% CI 0.55-1.47, p= 0.68  Adjunctive variceal embolization during TIPS procedures might be beneficial in the prevention of RVH. bTIPS and variceal embolization Vs bTIPS alone (RS) mTIPS and variceal embolization Vs mTIPS alone (MA) cTIPS and variceal embolization Vs cTIPS alone (PS) 50 References are at the end of the slides

51. Prevention of recurrent variceal bleeding: BRTO Vs BRTO + TIPS Saad et al. 2013[1] 27 Vs 9 Pre-BRTO ascites / HH resolved in7 % Vs 56 % ; P = 0.006 The ascites / HH free rate at 6, 12, and 24 months 58 % , 43 % ,29 % , and 100 % , 100 % , 100 %; p= 0.01 RVH at 6, 12, and 24 months was 9 % , 9 % , 21 % vs. 0 % , 0 % , 0 %; p= 0.03 The 1-year survival of both groups (80 – 88 % ) was similar; p> 0.05 BRTO Vs BRTO + TIPS; (RS) One study directly compared the outcomes of BRTO only versus the outcomes of combining BRTO and TIPS; this study demonstrated the superior outcomes of combining TIPS with BRTO instead of BRTO alone .[1]  Moreover, when comparing the available literature, the combined TIPS–BRTO procedure has demonstrated superior results to TIPS alone in the MX of GV.[2-6]  Saad W E, Wagner C C , Lippert A. et al.Protective value of TIPS against the development of hydrothorax/ascites and upper gastrointestinal bleeding after balloon-occluded retrograde transvenous obliteration (BRTO) Am J Gastroenterol. 2013;108(10):1612–1619. Sabri S S , Abi- Jaoudeh N, Swee W. et al.Short -term rebleeding rates for isolated gastric varices managed by transjugular intrahepatic portosystemic shunt versus balloon-occluded retrograde transvenous obliteration. J Vasc Interv Radiol . 2014;25(3):355–361. Mahadeva S, Bellamy M C, Kessel D, Davies M H, Millson C E. Cost-effectiveness of N-butyl-2-cyanoacrylate ( histoacryl ) glue injections versus transjugular intrahepatic portosystemic shunt in the management of acute gastric variceal bleeding. Am J Gastroenterol. 2003;98(12):2688–2693. Ninoi T, Nakamura K, Kaminou T. et al.TIPS versus transcatheter sclerotherapy for gastric varices. AJR Am J Roentgenol . 2004;183(2):369–376. Choi Y H, Yoon C J, Park J H, Chung J W, Kwon J W, Choi G M. Balloon-occluded retrograde transvenous obliteration for gastric variceal bleeding: its feasibility compared with transjugular intrahepatic portosystemic shunt. Korean J Radiol . 2003;4(2):109–116. Lo G H, Liang H L, Chen W C. et al.A prospective, randomized controlled trial of transjugular intrahepatic portosystemic shunt versus cyanoacrylate injection in the prevention of gastric variceal rebleeding. Endoscopy. 2007;39(8):679–685. 51

52. In conclusion , there is growing evidence that embolizing or obliterating varices arising from the portal system leads to reduced rebleed rates. Moreover, combining TIPS and BRTO is more effective than either procedure alone when managing gastric varices. 52

53. 53

54. References: History Saxon RR, Mendel- Hartvig J, Corless CL, et al. Bile duct injury as a major cause of stenosis and occlusion in transjugular intrahepatic portosystemic shunts: comparative histopathologic analysis in humans and swine. J Vasc Interv Radiol 1996;7(4):487–497 Nishimine K, Saxon RR, Kichikawa K, et al. Improved transjugular intrahepatic portosystemic shunt patency with PTFE-covered stent-grafts: experimental results in swine. Radiology 1995; 196(2):341–347 Haskal ZJ, Davis A, McAllister A, Furth EE. PTFE-encapsulated endovascular stent-graft for transjugular intrahepatic portosystemic shunts: experimental evaluation. Radiology 1997;205(3): 682–688 Barrio J, Ripoll C, Bañares R, et al. Comparison of transjugular intrahepatic portosystemic shunt dysfunction in PTFE-covered stent-grafts versus bare stents. Eur J Radiol 2005;55(1):120–124 Charon JP, Alaeddin FH, Pimpalwar SA, et al. Results of a retrospective multicenter trial of the Viatorr expanded polytetrafluoroethylene-covered stent-graft for transjugular intrahepatic portosystemic shunt creation. J Vasc Interv Radiol 2004;15(11):1219–1230 Maleux G, Nevens F, Wilmer A, et al. Early and long-term clinical and radiological follow-up results of expanded-polytetrafluoroethylene-covered stent-grafts for transjugular intrahepatic portosystemic shunt procedures. Eur Radiol 2004;14(10):1842–1850 Hausegger KA, Karnel F, Georgieva B, et al. Transjugular intrahepatic portosystemic shunt creation with the Viatorr expanded polytetrafluoroethylene-covered stent-graft. J Vasc Interv Radiol 2004;15(3):239–248 Angeloni S, Merli M, Salvatori FM, et al. Polytetrafluoroethylenecovered stent grafts for TIPS procedure: 1-year patency and clinical results. Am J Gastroenterol 2004;99(2):280–285 54

55. References: Hepatic encephalopathy Riggio O, Angeloni S, Salvatori FM, De Santis A, Cerini F, Farcomeni A, et al. Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts. Am J Gastroenterol. 2008 Nov;103(11):2738–46. Nolte W, Wiltfang J, Schindler C, Münke H, Unterberg K, Zumhasch U, et al. Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology. 1998 Nov;28(5):1215–25. Berlioux P, Robic MA, Poirson H, Métivier S, Otal P, Barret C, et al. Pre- transjugular intrahepatic portosystemic shunts (TIPS) prediction of post-TIPS overt hepatic encephalopathy: the critical flicker frequency is more accurate than psychometric tests. Hepatology. 2014 Feb;59(2):622–9. Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology . 2007 Sep;133(3):825–34. Chalasani N, Clark WS, Martin LG, Kamean J, Khan MA, Patel NH, et al. Determinants of mortality in patients with advanced cirrhosis after transjugular intrahepatic portosystemic shunting. Gastroenterology. 2000 Jan;118(1):138–44. Kim HK, Kim YJ, Chung WJ, Kim SS, Shim JJ, Choi MS, et al. Clinical outcomes of transjugular intrahepatic portosystemic shunt for portal hypertension: Korean multicenter real-practice data. Clin Mol Hepatol. 2014 Mar;20(1):18–27. Bai M, Qi X-S, Yang Z-P, Yang M, Fan D-M, Han G-H. TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis. World J Gastroenterol. 2014 Mar 14;20(10):2704–14. D’Amico G, Luca A, Morabito A, Miraglia R, D’Amico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis. Gastroenterology. 2005 Oct;129(4):1282–93. Riggio O, Masini A, Efrati C, Nicolao F, Angeloni S, Salvatori FM, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol. 2005 May;42(5):674–9. Fanelli F, Salvatori FM, Rabuffi P, Boatta E, Riggio O, Lucatelli P, et al. Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft. AJR Am J Roentgenol . 2009 Dec;193(6):1696–702. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715–35. Casado M, Bosch J, García- Pagán JC, Bru C, Bañares R, Bandi JC, et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology. 1998 Jun;114(6):1296–303. Rössle M, Gerbes AL. TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update. Gut. 2010 Jul;59(7):988–1000. 55

56. References: TIPS: Bare stent Vs PTFE-covered stent Casado M, Bosch J, Garcia-Pagan JC, Bru C, Banares R, Bandi JC, et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology 1998;114:1296–1303. Riggio O, Angeloni S, Salvatori FM, De Santis A, Cerini F, Farcomeni A, et al. Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts. Am J Gastroenterol 2008;103:2738–2746. Sauerbruch T, Mengel M, Dollinger M, Zipprich A, Rossle M, Panther E, et al. Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving small-diameter stents vs. hemodynamically controlled medical therapy. Gastroenterology 2015;149:660–668. Wang Q, Lv Y, Bai M, Wang Z, Liu H, He C, et al. Eight millimetre covered TIPS does not compromise shunt function but reduces hepatic encephalopathy in preventing variceal rebleeding. J Hepatol 2017;67: 508–516. Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004;126:469–475. Nishimine K, Saxon RR, Kichikawa K, Mendel- Hartvig J, Timmermans HA, Shim HJ, Uchida BT, Barton RE, Keller FS, Rösch J. Improved transjugular intrahepatic portosystemic shunt patency with PTFE-covered stent-grafts: experimental results in swine. Radiology. 1995;196:341-347. 56

57. References: TIPS: Covered Vs Bare Qi X, et al. Covered versus bare stents for transjugular intrahepatic portosystemic shunt: an updated meta-analysis of randomized controlled trials. Therap Adv Gastroenterol. 2017 Jan; 10(1): 32–41. Bureau C., Garcia-Pagan J., Otal P., Pomier-Layrargues G., Chabbert V., Cortez C., et al. (2004) Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 126: 469–475. Perarnau J., Le Gouge A., Nicolas C., D’Alteroche L., Borentain P., Saliba F., et al. (2014) Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial. J Hepatol 60: 962–968 57

58. References: Prevention of recurrent variceal bleeding: cTIPS Vs Medical therapy + EVL Sauerbruch T., Mengel M., Dollinger M., Zipprich A., Rossle M., Panther E., et al. (2015) Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving small-diameter stents versus hemodynamically controlled medical therapy. Gastroenterology 149: 660.e1–668.e1. Luo X., Wang Z., Tsauo J., Zhou B., Zhang H., Li X. (2015) Advanced cirrhosis combined with portal vein thrombosis: a randomized trial of tips versus endoscopic band ligation plus propranolol for the prevention of recurrent esophageal variceal bleeding. Radiology 276: 286–293. Holster I., Tjwa E., Moelker A., Wils A., Hansen B., Vermeijden J., et al. (2016) Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + β-blocker for prevention of variceal rebleeding. Hepatology 63: 581–589. 58

59. References: The concept of BRTO Taken from: https://articl.net/resource/balloon-occluded-retrograde-transvenous-obliteration-brto Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. J Gastroenterol Hepatol. 1996;11:51–8. Kiyosue H, Mori H, Matsumoto S, Yamada Y, Hori Y, Okino Y. Transcatheter obliteration of gastric varices: Part-1: Anatomic classification. Radiographics . 2003;23:911–20. Kiyosue H, Mori H, Matsumoto S, Yamada Y, Hori Y, Okino Y. Transcatheter obliteration of gastric varices: Part-2: Strategy and techniques based on hemodynamic features. Radiographics . 2003;23:921–37. Olson E, Yune HY, Klatte EC. Transrenal -vein reflux ethanol sclerosis of gastroesophageal varices. Am J Roentgenol . 1984;143:627–8. Al- Osaimi AMS, Sabri SS, Caldwell SH. Balloon-occluded retrograde transvenous obliteration (BRTO): preprocedural evaluation and imaging. Semin Intervent Radiol 2011;28:288–295 59

60. References: Clinical Outcomes of BRTO Procedures for GV Ninoi T, Nakamura K, Kaminou T, Nishida N, Sakai Y, Kitayama T, et al. TIPS versus transcatheter sclerotherapy for gastric varices. AJR Am J Roentgenol . 2004; 183:369–76. DOI: 10.2214/ajr.183.2.1830369. PMID: 15269027. Sabri SS, Abi- Jaoudeh N, Swee W, Saad WE, Turba UC, Caldwell SH, et al. Short-term rebleeding rates for isolated gastric varices managed by transjugular intrahepatic portosystemic shunt versus balloon-occluded retrograde transvenous obliteration. J Vasc Interv Radiol . 2014; 25:355–61. Sauk S, Niemeyer M, Kim SK, Korenblat K. Outcomes from balloon-occluded retrograde transvenous obliteration (BRTO) versus transjugular intrahepatic portosystemic shunt (TIPS) in the management of isolated gastric varices: a retrospective study in single US medical center. J Vasc Interv Radiol . 2014; 25(Suppl 3):S80. Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. J Gastroenterol Hepatol. 1996; 11:51–8. Sonomura T, Sato M, Kishi K, Terada M, Shioyama Y, Kimura M, et al. Balloon-occluded retrograde transvenous obliteration for gastric varices: a feasibility study. Cardiovasc Intervent Radiol . 1998; 21:27–30. Kitamoto M, Imamura M, Kamada K, Aikata H, Kawakami Y, Matsumoto A, et al. Balloon-occluded retrograde transvenous obliteration of gastric fundal varices with hemorrhage. AJR Am J Roentgenol . 2002; 178:1167–74. Arai H, Abe T, Shimoda R, Takagi H, Yamada T, Mori M. Emergency balloon-occluded retrograde transvenous obliteration for gastric varices. J Gastroenterol. 2005; 40:964–71. Cho SK, Shin SW, Lee IH, Do YS, Choo SW, Park KB, et al. Balloon-occluded retrograde transvenous obliteration of gastric varices: outcomes and complications in 49 patients. AJR Am J Roentgenol . 2007; 189:W365–72. Hiraga N, Aikata H, Takaki S, Kodama H, Shirakawa H, Imamura M, et al. The long-term outcome of patients with bleeding gastric varices after balloon-occluded retrograde transvenous obliteration. J Gastroenterol. 2007; 42:663–72. 60

61. References: Clinical Outcomes of BRTO Procedure for the management of Gastric Varices Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. J Gastroenterol Hepatol. 1996; 11:51–8. Sonomura T, Sato M, Kishi K, Terada M, Shioyama Y, Kimura M, et al. Balloon-occluded retrograde transvenous obliteration for gastric varices: a feasibility study. Cardiovasc Intervent Radiol . 1998; 21:27–30. Kitamoto M, et al. Balloon-occluded retrograde transvenous obliteration of gastric fundal varices with hemorrhage. AJR Am J Roentgenol . 2002; 178:1167–74. Ninoi T, et al. TIPS versus transcatheter sclerotherapy for gastric varices. AJR Am J Roentgenol . 2004; 183:369–76. Arai H, Abe T, Shimoda R, Takagi H, Yamada T, Mori M. Emergency balloon-occluded retrograde transvenous obliteration for gastric varices. J Gastroenterol. 2005; 40:964–71. Cho SK, et al. Balloon-occluded retrograde transvenous obliteration of gastric varices: outcomes and complications in 49 patients. AJR Am J Roentgenol . 2007; 189:W365–72. Hiraga N, Aikata H, Takaki S, Kodama H, Shirakawa H, Imamura M, et al. The long-term outcome of patients with bleeding gastric varices after balloon-occluded retrograde transvenous obliteration. J Gastroenterol. 2007; 42:663–72. Sabri SS, et al. Short-term rebleeding rates for isolated gastric varices managed by transjugular intrahepatic portosystemic shunt versus balloon-occluded retrograde transvenous obliteration. J Vasc Interv Radiol . 2014; 25:355–61. Sauk S, Niemeyer M, Kim SK, Korenblat K. Outcomes from balloon-occluded retrograde transvenous obliteration (BRTO) versus transjugular intrahepatic portosystemic shunt (TIPS) in the management of isolated gastric varices: a retrospective study in single US medical center. J Vasc Interv Radiol . 2014; 25(Suppl 3):S80. 61

62. References to: Clinical Outcomes of the TIPS Procedure for GV Chau TN, Patch D, Chan YW, Nagral A, Dick R, Burroughs AK. “Salvage” transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding. Gastroenterology. 1998; 114:981–7. Barange K, Péron JM, Imani K, Otal P, Payen JL, Rousseau H, et al. Transjugular intrahepatic portosystemic shunt in the treatment of refractory bleeding from ruptured gastric varices. Hepatology. 1999; 30:1139–43. Rees CJ, Nylander DL, Thompson NP, Rose JD, Record CO, Hudson M. Do gastric and oesophageal varices bleed at different portal pressures and is TIPS an effective treatment? Liver. 2000; 20:253–6. Choi YH, Yoon CJ, Park JH, Chung JW, Kwon JW, Choi GM. Balloon-occluded retrograde transvenous obliteration for gastric variceal bleeding: its feasibility compared with transjugular intrahepatic portosystemic shunt. Korean J Radiol . 2003; 4:109–16. Ninoi T, Nakamura K, Kaminou T, Nishida N, Sakai Y, Kitayama T, et al. TIPS versus transcatheter sclerotherapy for gastric varices. AJR Am J Roentgenol . 2004; 183:369–76. Lo GH, Liang HL, Chen WC, Chen MH, Lai KH, Hsu PI, et al. A prospective, randomized controlled trial of transjugular intrahepatic portosystemic shunt versus cyanoacrylate injection in the prevention of gastric variceal rebleeding. Endoscopy. 2007; 39:679–85. Sabri SS, Abi- Jaoudeh N, Swee W, Saad WE, Turba UC, Caldwell SH, et al. Short-term rebleeding rates for isolated gastric varices managed by transjugular intrahepatic portosystemic shunt versus balloon-occluded retrograde transvenous obliteration. J Vasc Interv Radiol . 2014; 25:355–61. Sauk S, Niemeyer M, Kim SK, Korenblat K. Outcomes from balloon-occluded retrograde transvenous obliteration (BRTO) versus transjugular intrahepatic portosystemic shunt (TIPS) in the management of isolated gastric varices: a retrospective study in single US medical center. J Vasc Interv Radiol . 2014; 25(Suppl 3):S80. 62

63. References to cTIPS Vs BRTO : in treatment of pt bleeding from gastric varices Sabri SS, Abi- Jaoudeh N, Swee W, Saad WE, Turba UC, Caldwell SH, et al. Short-term rebleeding rates for isolated gastric varices managed by transjugular intrahepatic portosystemic shunt versus balloon-occluded retrograde transvenous obliteration. J Vasc Interv Radiol . 2014; 25:355–61. Sauk S, Niemeyer M, Kim SK, Korenblat K. Outcomes from balloon-occluded retrograde transvenous obliteration (BRTO) versus transjugular intrahepatic portosystemic shunt (TIPS) in the management of isolated gastric varices: a retrospective study in single US medical center. J Vasc Interv Radiol . 2014; 25(Suppl 3):S80. 63

64. References: Prevention of recurrent variceal bleeding: TIPS + Emb Vs TIPS alone Tesdal IK, Filser T, Weiss C, Holm E, Dueber C, Jaschke W. Transjugular intrahepatic portosystemic shunts: adjunctive embolotherapy of gastroesophageal collateral vessels in the prevention of variceal rebleeding. Radiology 2005; 236: 360–7. Chen S, Li X, Wei B et al. Recurrent variceal bleeding and shunt patency: prospective randomized controlled trial of transjugular intrahepatic portosystemic shunt alone or combined with coronary vein embolization. Radiology 2013; 268: 900–6. Qi, X., Liu, L., Bai, M., Chen, H., Wang, J., Yang, Z., Fan, D. (2014). Transjugular intrahepatic portosystemic shunt in combination with or without variceal embolization for the prevention of variceal rebleeding: A meta-analysis. Journal of Gastroenterology and Hepatology, 29(4), 688–696.

65. TIPS in HPS/SOS? At present, there is no sufficient evidence to support the use of TIPS for the treatment of hepatopulmonary syndrome. TIPS is not indicated in Sinusoidal Occlusion Syndrome in Bone Marrow Transplanted Patients, but may be considered in individual basis in Solid Organ Transplant Recipient as stand-alone treatment or as bridge to liver transplantation in a setting of multidisciplinary evaluation . 65

66. TIPS in refractory/ recidivant ascites/HRS/HH ? TIPS is more effective than conservative/medical treatment to resolve refractory/ recidivant ascites , greatly reducing the need of paracentesis. TIPS should be considered in all pts with refractory/ recidivant ascites. TIPS is effective to treat type-II HRS associated to refractory/ recidivant ascites. Cannot be recommended in unselected patients with type-I HRS . TIPS can be considered in refractory hydrothorax aiming at resolution of hydrothorax and reduction in number of thoracentesis. The effect of TIPS on survival are still not clearly defined in RH. Thus, the final decision to insert a TIPS should be reached on an individual pt basis after a multidisciplinary clinical evaluation. 66

67. TIPS in PVT ? TIPS is feasible in pts with PVT with and without cirrhosis , but it bears higher failure and complication rates when portal cavernoma, fibrous transformation of the main portal vein or intrahepatic branches thrombosis, are present . Extension of the TIPS stent into the portal or SMV should be considered when recanalization of PV/SMV is incomplete and the pt is not a LT candidate. TIPS can be considered to treat PVT in both cirrhotic and non-cirrhotic pts with progression of thrombosis despite adequate anticoagulant treatment , or when there is an absolute CI to anticoagulation, or with no response after a maximum of 6 months of anticoagulation treatment. 67

68. TIPS in NCIPH ? TIPS can be considered in NCIPH, applying the same indications utilized for the management of portal hypertensive complications.. Caution is needed in patients with refractory ascites, kidney failure and comorbidities. 68

69. TIPS in BCS ? In BCS pts, in a stepwise approach, TIPS with covered stent is indicated in case of failure of anticoagulation (and angioplasty when feasible), represented by persistent ascites, AKI or elevated transaminases . Listing for LT should be considered in case of a prognostic index score greater than 7 in pts candidate to TIPS for BCS. When TIPS is attempted to treat hyper acute BCS with ALF presentation, the listing process for LT should not be delayed. BCS-TIPS PI (only for patients who underwent TIPS procedure): age × 0.08 + bilirubin × 0.16 + INR × 0.63[1]. Garcia- Pagán JC, Heydtmann M, Raffa S, Plessier A, Murad S, Fabris F, Vizzini G, Gonzales Abraldes J, Olliff S, Nicolini A, et al. TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients. Gastroenterology. 2008;135:808–815.  69

70. Kim k,et al. Transjugular intrahepatic portosystemic shunts versus balloon-occluded retrograde transvenous obliteration for the management of gastric varices: Treatment algorithm according to clinical manifestations. Gastrointestinal Intervention 2016; 5(3): 170-176. 70