This document discusses the management of variceal bleeding, specifically focusing on esophageal and gastric varices. It provides an overview of endoscopic and medical therapies for controlling acute esophageal variceal bleeding such as endoscopic band ligation, sclerotherapy, and pharmacologic therapies like octreotide. For gastric varices, it describes different classification systems and challenges in managing bleeding, noting endoscopic therapies like sclerotherapy, ligation, and glue injection can control acute bleeding but have high rebleeding risks. It emphasizes a multidisciplinary approach is often needed for gastric variceal management.

1. Variceal Bleeding “ The Bad & the Ugly” Bushra Ibnauf Sulieman, MD MS Consultant, Gastroenterology & Hepatology Department of Medicine King Faisal Specialist Hospital & Research Center - Jeddah

2. Case 50 year-old male with liver cirrhosis transferred from a local hospital with hematemesis and melena EGD revealed grade III esophageal varices and gastric varices with stigmata of recent bleeding Underwent medical and endoscopic therapy with good results.

3. Objectives Portal Hypertension “ The Bad”: Esophageal Varices Management of Esophageal Varices “ The Ugly”: Gastric Varices Management of Gastric Varices

4. Portal Blood Flow

5. Portal Hypertension Portal venous pressure = portal venous flow x portal venous resistance Hepatic venous pressure gradient (HVPG) is the difference in pressure between the portal vein (wedged hepatic venous pressure) and free hepatic vein pressure HVPG = surrogate for portal pressure Increased HVPG > 5 mm Hg = Portal HTN

6. Causes of Portal Hypertension

7. Clinical manifestation of Portal Hypertension Varices – Esophageal, gastric , rectal Portal hypertensive gastropathy / enteropathy Splenomegaly and Hypersplenism - Pancytopenia Ascites Peripheral edema

8. Garcia-Tsao, Current Management of the Complications of Cirrhosis And Portal Hypertension. Gastroenterology Feb 2001;120:726-748

9. Objectives Portal Hypertension “ The Bad”: Esophageal Varices Management of Esophageal Varices “ The Ugly”: Gastric Varices Management of Gastric Varices

10. Esophageal Varices

11. Esophageal Varices 40% of cirrhotics have esophageal varices 5% per year will develop new varices 10-15% per year will have progression from small to large varices Incidence of variceal bleeding is 24% at 2 years in non-selected patients 20-25% will die from first variceal bleed Bosch J. Hepatology 2003 Kamath P. Vlin Gastro and Hep 2005

12. Natural History of Esophageal Varices Treated Untreated

13. Screening for Varices All cirrhotic patients should undergo upper endoscopy screening for varices Predictors of bleeding - Location (near the GE junction or gastric fundus) - Size (Grade I, II, III) - Appearance (red signs) - Clinical features (Child history of bleeding) - Variceal pressure (>15mm Hg 50% risk of bleeding) Grade I risk of bleeding 2 years small 7%, medium/large 30% North Italian Endoscopic Club for the Study and Treatment Of Esophageal Varices. NEJM 1988

14. OBJECTIVES Portal Hypertension Esophageal Varices Management of esophageal Varices Gastric Varices Management of gastric Varices

15. Management of Esophageal Varices Endoscopic Sclerotherapy Endoscopic Variceal Ligation Medical Therapy-Octreotide Antibiotics TIPS Surgery

16. Endoscopic Sclerotherapy Injection of a sclerosant (ethanol oleate) solution into the varices using a freehand technique Local complications: ulceration, bleeding, dysmotility, stricture Regional complications: esophageal perforation and mediastinitis Systemic: sepsis and aspiration Not recommend for primary prophylaxis due to increased mortality

17. Endoscopic Band Ligation Technique Recommended for BOTH primary and bleeding Complications: pain, stricture..RARE

19. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995;123:280-7 Lo GH, Lai KH, Cheng JS, Hwu JH, Chang CF, Chen SM, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995;22:466-71. S. Kitano, D. Baatar. Endoscopic treatment for esophageal varices: Will there be a place for sclerotherapy during the forthcoming era of ligation?. GI Endoscopy August 2000 Volume 52 • Number 2 EVL vs EIS in the control of acute variceal bleeding Study/year Steigmann et al. 1992 Laine et al. 1993 Gimson et al. 1993 Lo et al 1997 Hou et al 1995 Sarin et al. 1997 Treatment EIS EVL EIS EVL EIS EVL EIS EVL EIS EVL EIS EVL No. of patients 13 14 9 9 23 21 26 36 16 20 7 5 Success rate (%) 77 86 89 89 92 91 76 97 88 100 86 80 Control period* (hr) 8 NA 12 72 24 NA

20. Medical Therapy-Octreotide Long acting analog of Somatostatin Dec release of vasodilator hormones such as glucagon Red venous inflow, portal pressures, azygous flow, and intravariceal pressres decrease within seconds 50 mcg bolus followed by 50mcg/h IV for 3-5 days Other uses: HRS, PUD, carcinoid

21. ) D. A. Corley, J. P. Cello, W. Adkisson, W. -F. Ko, K. Kerlikowske, Octreotide for acute esophageal variceal bleeding: A meta-analysis Gastroenterology March 2001 • Volume 120 • Number 4 Octreotide Outcome Alternative therapy RR (95% CI) NNT (95% CI) c P value for homogeneity No. of trials (total patients) Total mortality (at end of follow-up) Any therapy 0.89 (0.69–1.14) N/A 0.3 11 (948) Vasopressin/terlipressin 0.8 (0.54–1.19) N/A 0.88 4 (236) Placebo/no therapy b 0.81 (0.48–1.35) N/A 0.6 4 (424) Sclerotherapy 1.1 (0.73–1.66) N/A 0.02 2 (248) Sustained control of bleeding (during fo-up) Any therapy 0.63 (0.51–0.77) 8 (5–16) 0.2 13 (1077) Vaso/terli 0.58 (0.42–0.81) 6 (3–13) 0.97 5 (279) Placebo/no therapy b 0.46 (0.32–0.67) 6 (4–9) 0.4 5 (510) Sclerotherapy c 0.94 (0.55–1.62) N/A 0.6 2 (248) Any complications Any therapy 0.77 (0.6–1.00) N/A <0.001 11 (948) Vaso/terl 0.52 (0.33–0.82) 6 (2– 0.13 4 (236) Placebo/no therapy b 1.06 (0.72–1.55) N/A 1 4 (424) Sclerotherapy 0.91 (0.5–1.65) N/A <0.001 2 (248)

22. EIS vs Pharmacotherapy • Eligible RCTs were comparing EIS vs vasopressin ( + NG), terlipressin, somatostatin or octereotide. • Efficacy: failure to control bleeding, rebleeding, mortality, transfusions, AE. • 15 RCTs (8 comparing EIS vs octreotide). • No difference in bleeding control or rebleeding. • No significant difference in mortality. • EIS (? Possibly EVL) does not improve the outcome of cirrhotic patients with variceal bleeding when compared with medical therapy and is associated with more AE. Gennaro D’Amico, Giada Pietrosi, Ilaria Tarantino, Luigi Pagliaro Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: A cochrane meta-analysis. Gastroenterology May 2003 • Volume 124 • Number 5

23. Endoscopy vs Endoscopy PLUS Pharmacotherapy • Eight RCTs with 939 patients. • Endpoints: initial hemostasis, 5-day hemostasis, 5-day mortality and AE. • Combined treatment improved initial control, 5-day hemostasis. NNT 8 and 5. • Mortality not significantly decreased. • Severe AE similar. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: A meta-analysis .Rafael Bañares, Agustín Albillos. Hepatology Volume 35, Issue 3 , March 2002

24. Antibiotics • Four end points: infection, bacteremia and /or SBP, incidence of SBP and death. • Five trials including 534 patients. • 264 treated with Antibiotics prophylaxis for 4-10 days. Mean follow-up 14 days. • Prophylaxis significantly decreased all endpoints. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: A meta-analysis. Brigitte Bernard, M.D. 1 * , Jean-Didier Grangé , Eric Nguyen Khac , Xavier Amiot , Pierre Opolon , Thierry Poynard . Hepatology Volume 29 Issue 6 , June 1999 Pages 1655 - 1661

25. TIPS Performed by IR May increase risk of encephalopathy Does not improve survival or quality of life Poor outcome after TIPS has been found in pts with high MELD May be technically challenging in patients with thrombosis

26. TIPS • Eleven randomized trials (811 patients). • endpoints prevention of rebleeding, survival, and the effects on resource use and the quality of patients' lives. • The median follow-up ranged from 10 to 32 months. • rebleeding was significantly more frequent with ET (47%) compared with TIPS (19%). • no difference in mortality. • Post-treatment encephalopathy occurred significantly less often after ET (19%) than after TIPS (34%). • 95% control of bleeding, 18% early rebleeding, 38% mortality. Papatheodoridis GV, Goulis J, Leandro G. Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding. Hepatology 1999;30:612-622. Transjugular intrahepatic portosystemic shunt: Current status 1 Gastroenterology May 2003 • Volume 124 • Number 6

27. Recommendations Screening EBL for prophylaxis with beta blockers Endoscopic therapy (EIS or EVL) is the therapy of choice in the management of acute variceal hemorrhage. • The association of pharmacologic therapy, used as soon as the diagnosis is suspected (even before endoscopy) and continued for 5 days after the diagnosis is established, may represent the best approach to treatment. Antibiotics • Shunt surgery or TIPS is indicated in patients in whom hemorrhage from esophageal varices cannot be controlled or in whom bleeding recurs despite two sessions of endoscopic therapy (associated or not with pharmacologic therapy).

28. Gastric Varices • Less common than EV, 20% of patients with PHT. • Mortality as high as 20% within 6 weeks of index bleed. • Management is challenging: - no consensus regarding the optimum treatment . - GV are not a homogenous entity. - bleeding tends to be more severe, to require more transfusions, and to have a higher mortality rate than EV bleeding. - high rebleeding rate (34% to 89%) - optimal management of GV requires a multidisciplinary approach . A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices . Barbara M. Ryan,Reinhold W. Stockbrugger, J. Mark Ryan. Gastroenterology April 2004 • Volume 126 •Number 4

29. Classification Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343-1349.

30. Gastric Varices

31. Genealized PHT A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices . Barbara M. Ryan,Reinhold W. Stockbrugger, J. Mark Ryan. Gastroenterology April 2004 • Volume 126 •No 4

32. Natural History • The role of portal pressure in GV bleeding. • Effect of EV eradication on GV. - GV develop in 9-20% (EUS 26-43%) - Caudal migration • Risk for bleeding from GV. - 2 year risk 25% (EV 20-40%) - Fundal (78 % IGV1, 55% GOV2), GOV1 and IGV2(10%) - require more transfusion - risk factors Kim T, Shijo H, Kokawa H, Tokumitsu H, Kubara K, Ota K, Akiyoshi N, Iida T, Yokoyama M, Okumura M. Risk factors for hemorrhage from gastric fundal varices. Hepatology 1997;25:307-312. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343-1349.

33. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices . Barbara M. Ryan,Reinhold W. Stockbrugger, J. Mark Ryan. Gastroenterology April 2004 • Volume 126 •No 4 Treatment modality/gastric variceal type Primary hemostasis (%) Secondary rebleeding (%) Variceal eradication (%) Endoscopic variceal sclerotherapy GOV1 90–100 5.5 95 GOV2/IGV1 40–60 20–90 40–70 Endoscopic variceal obturation 90–100 23–50 50–100 Endoscopic variceal ligation 45–100 0–50 45–100 TIPS 90–100 10–30 — B-RTO 100 0–10 85–100 Balloon-occluded endoscopic injection sclerotherapy — 0 75–90

34. EVS • Less successful (?high volume blood flow). • Sclerosant volume GOV2, IGV1 > GOV1 > EV. • Control bleeding in 60-100%. • Rebleeding up to 90%. • Lease successful in fundal bleeding. • Secondary prophylactic eradictaion ~40% (mixed). Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven-year experience. Gastrointest Endosc 1997;46 :8-14.

35. EVL • Nylon or stainless steel snares or standard rubber bands. • Larger GV may need detachable snares. • One RCT. • Case series reported EVL to be safe and efficacious. • Hemostasis in acute GV bleeding 83-100%, low rebleeding rate 0-19%, GV eradication 77-100%. • Largest series (41pts). • Technically difficult. Lo GH, Lai KH, Cheng JS, Chen MH, Chiang HT. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001;33:1060-1064

36. Endoscopic Variceal Obturation • refers to the injection of agents such as n-butyl-2-cyanoacrylate (Histoacryl), isobutyl-2-cyanoacrylate (Bucrylate), or thrombin. • solidify and/or induce thrombosis in the varix with ultimate sloughing off of the glue cast weeks to months post-injection, resulting in late ulceration. • Not FDA approved. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices . Barbara M. Ryan,Reinhold W. Stockbrugger, J. Mark Ryan. Gastroenterology April 2004 • Volume 126 •No 4

37. • Gatsroesophageal varices are present in ~ 50 % of cirrhotics. • Correlates with severity of liver disease. • Bleeding rate is 10-30% /year. • Mortality 30-50%. • Threshold portal pressure and wall tension. Garcia-Tsao, Current Management of the Complications of Cirrhosis And Portal Hypertension. Gastroenterology Feb 2001;120:726-748

38. EVO vs EVS • 37 patients with PTH and isolated GV (17 active bleed). • Randomized to ETOH EVS and cyanoacrylate glue. • Endpoints: variceal obliteration, rebleeding or death. • Results: - Obliteration 100% vs 44% (p<0.05) - shorter time and less volume (p<0.05) - arrest acute bleeding 89% vs 62% (p<0.05) - less need for rescue surgery (p>0.05) Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002;97:1010-1015

39. EVO vs EVL • Cirrhotic patients with a history of gastric variceal bleeding were randomized to 2 groups. • EVO (31 patients), EVL (29 patients). • Treatment was repeated regularly until obliteration of GV. • Active bleeding occurred in 15 EVO group and 11 EVL group. • initial hemostatic rate (no bleeding for 72 hrs) was 87% in EVO vs 45% in EVL. • No of sessions and obliteration rate similar. • Rebleeding higher in EVL(54%) vs EVO(31%) p <0.005 • Transfusions higher in EVL. Lo GH, Lai KH, Cheng JS, Chen MH, Chiang HT. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001;33:1060-1064

40. TIPS • The current role of TIPS in acute GV bleeding is as second-line rescue therapy when EVO has failed. • has been shown to control acute refractory GV bleeding in 90% to 100% of cases. • Rebleeding occurs in 10% to 30% of patients within 1 year. • Early and Late Rebleeding. • New-onset encephalopathy. 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;114:981-987. Song HG, Lee HC, Park YH, Jung S, Chung YH, Lee YS, Yoon HK, Sung KB, Suh DJ. [Therapeutic efficacy of transjugular intrahepatic portosystemic shunt on bleeding gastric varices]. Taehan Kan Hakhoe Chi 2002;8:448-457.

41. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices . Barbara M. Ryan,Reinhold W. Stockbrugger, J. Mark Ryan. Gastroenterology April 2004 • Volume 126 •No 4

42. Balloon-occluded retrograde transvenous obliteration

43. Balloon-occluded endoscopic injection sclerotherapy Matsumoto A, Hamamoto N, Kayazawa M. Balloon endoscopic sclerotherapy, a novel treatment for high-risk gastric fundal varices: a pilot study. Gastroenterology 1999;117:515-516.

44. Surgery • portocaval shunts (selective vs nonselective) • 30 patients (6 with Child A/B, 24 had PVT). • Bleeding was controlled in 87% (26/30) of cases . • Two patients (7%) died (both had cirrhosis). • 2 patients developed shunt thrombosis. • ? Role in presence of GRS. Thomas PG, D’Cruz AJ. Distal splenorenal shunting for bleeding gastric varices. Br J Surg 1994;81:241-244.

46. Conclusions • Primary GV are found in approximately 20% of patients with PHT. • 10% to 20% of PHT patients will develop GV after endoscopic therapy of EV. • Accurate classification of GV is essential in determining the optimal management of these patients. • GOV1 have a low risk for hemorrhage, but the risk for bleeding from fundal varices can be as high as 65% within 1 year, comparable with the risk for EV bleeding. • GV bleeding tends to be more profuse and to require more transfusions. • A PPG of 12 mm Hg is not required for GV bleeding to occur and a large proportion (35%) bleed below this threshold, probably related to the high incidence of spontaneous gastrorenal shunts among GV patients. • EVO has a proven track record in treating acute GV bleeding and should be used as first-line treatment of acute fundal GV bleeding. • TIPS is a valuable adjunct to management of acute refractory or recurrent GV bleeding, but its role in managing patients with a PPG of 12 mm Hg and its appropriateness in patients with advanced liver disease remains to be clarified. • A number of radiologic or combination endoscopic-radiologic techniques have been pioneered in Japan and need further appraisal. • Multi-center RCTs needed.