GI Grand Rounds USC Gastrointestinal and Liver Diseases February 10th, 2006

1. GI Grand Rounds USC Gastrointestinal and Liver DiseasesFebruary 10th, 2006 Presented by Yoshi Makino, M.D. Moderated by Dr. Andrew Stolz

2. Case Presentation Patient W.L. is a 57 year old Chinese male, with PMH sig for chronic Hep B, cirrhosis and HCC diagnosed in 10/2005, presenting with hematemesis and melena x 1 day. Pt denies prior history of UGI bleed.

3. Case Presentation PMH: Hepatitis B cirrhosis (dx 2004) HCC (dx 10/2005) DM, hyperlipidemaa Otherwise per HPI PSH: L inguinal hernia repair SH: Denies EtOH/tobacco/illicit drug use Born in mainland China, then lived in Venezuela for 24 years, before moving to United States 15 years ago FH: Non-contributory: Hep B status unknown

4. Case Presentation Allergies: NKDA Medications Epivir 100 mg PO daily Hepsera 10 mg PO daily Aldactone 50 mg PO daily Experimental Chemo Agent GW572016: EGFR1/EGFR2/HER-2 inhibitor Megace/MVI/Folate ROS: Non-contributory

5. Physical Exam Vital: T 97.8 / P 121 / R 20 / BP 120/64 Orthostatics (+) Gen: thin, cachectic male, A+O x 4 in NAD HEENT: temporal wasting, no conjuctival pallor Cardiac: sinus tachy Lungs: CTA(B) Abdomen: Mod firm, distended, with shifting dullness Non tender, (+)BS Ext: 2+ pitting edema to BLE Rectal: normal tone, (+)melena, OB(+) Skin: No spider angiomas seen Neuro: No asterixis, no focal deficits

6. Laboratories (1/24/06)

7. EGD Images (1/25/06)

8. EGD Images (1/25/06)

9. EGD Images (1/25/06)

10. EGD Results (1/25/06) 4 columns of Grade 1 Esophageal Varices with no stigmata of recent bleeding Large, grape-like, plump gastric varices, with one large varix with a �white nipple� sign No active bleeding nor oozing noted Mild portal hypertensive gastropathy Normal duodenal bulb

11. CT Images Insert magical slide show here�

12. CT Results (1/3/2006) Compared with 11/1/2005 study Large heterogeneous enhancing lobulated liver mass occupying the entire R lobe of the liver, and medial segment of L lobe of the liver: increased in size by 50% Tumor invasion of right and main portal veins Cirrhosis with multiple collaterals, Portal HTN R inguinal hernia, fluid filled

13. Hospital Course Pt was subsequently transferred to USC University Hospital on 1/26/2006 TIPS considered for decompression of gastric varices, but not advised due to large tumor burden, portal vein invasion, and overall poor prognosis Hospice care discussed with patient, and patient discharged on 2/2/2006

14. Gastric Varices

15. Outline Overview of Gastric Varices Vascular Anatomy Classification Diagnostic Modalities Endoscopic CT/MRI Therapeutic options Endoscopic Interventional Radiology Surgery

16. Overview of Gastric Varices Gastric varices (GV) are a well known complication of both non-cirrhotic and cirrhotic portal hypertension In general, gastric varices bleed less frequently than esophageal varices However, when they bleed, bleeding is usually severe

17. Epidemiology Gastric varices can be found in 15-20% of patients with portal hypertension Lifetime bleeding rate of roughly 25% Overall mortality rate of 30-52% Kim T et al. Hepatology 1997. In a prospective study of 568 patients with portal hypertension, Sarin et al found that GVs formed at an annual incidence rate of 9% Sarin SK et al. Hepatology 1992.

18. Risk Factors for Bleeding Risk factors for bleeding may include Specific caliber and length Source of venous collaterals involved Advanced liver disease Kim et al. Hepatology 1997. Degree of portal hypertension appears to be less of a factor, with GVs often bleeding at portal pressure gradients of <12 mmHg Tripathi et al. Gut 2002.

19. Vasculature Involved Afferent Veins Left gastric vein (LGV) Posterior gastric vein (PGV) Short gastric vein (SGV) Efferent Veins Esophageal veins (EV) Gastrorenal shunt (GRS: 85% of IGV) Left inferior phrenic vein (LIPV: 10% of IGV) Left pericardiacophrenic vein (LPCPV: 5% of IGV) Chikamori et al. Abdominal Imaging 2005.

20. Formation of Varices in Portal HTN LGV to EV to azygous v. Traditional model for esophageal varices, can also result in the formation of gastric varices SV to GRS to LRV to IVC Significant portal HTN can also lead to reversal of flow in the splenic vein, resulting in transgastric shunts (usually GRS)

21. Splenic Vein Thrombosis Sinistral (left-sided) portal HTN due to splenic vein thrombsis (SVT) is an often cited but less common cause of gastric varices Incidence of gastric varices in patients with isolated SVT ranges from 17% to 55% SVT should be suspected in patients with History of pancreatitis with newly diagnosed GI bleeding splenomegaly in the absence of cirrhosis Isolated gastric varices Weber and Rikkers. Word J. Surg. 2003.

22. Splenic Vein Thrombosis Risk factors for SVT include Chronic pancreatitis (48-65%) Pancreatic carcinoma (9-29%) Other causes: adenopathy from metastatic carcinoma, lymphoma and iatrogenic (following surgery such as splenectomy and gastrectomy) Pathophysiology The splenic vein is posterior to and in direct contact with the pancreas Pancreatic inflammation is believed to trigger clot formation in the splenic vein Weber and Rikkers. Word J. Surg. 2003.

23. Splenic Vein Thrombosis Prevalence of SVT In patient with chronic pancreatitis, the prevalence of SVT by ultrasonography ranges from 4% to 45% Incidence of SVT In a prospective study of 266 patients with chronic pancreatitis, Bernard et al found the overall incidence rate of major splanchnic vein thrombosis to be 13% Splenic vein 8% Portal vein 4% Superior mesenteric vein 1% Bernades et al. Dig Dis Sci. 1992.

24. Formation of Varices in SVT

25. Histologic Findings Fundamentally, GVs differ from EVs by location EVs form in both the lamina propria and submucosa In contrast, GVs form in the submucosa This difference make rupture of GVs less frequent than EVs However, when do GVs rupture, they penetrate the muscularis mucosa and lamina propria, leading to more massive bleeding Hashizume M. JGH 2004.

26. Classification of Gastric Varices Gastro-oesophageal varices (GOV) Usually develop from the left gastric vein GOV1: extend from esophageal varices across the gastroesophageal junction, extending 5 cm or less GOV2: extend from esophageal varices into the fundus Fundic varices (IGV) Usually develop from the short gastric and posterior gastric veins or via direct anastomoses with retroperitoneal veins IGV1: varices found only in the fundus IGV2: isolated non-fundic varices GOV1 represents 75% of gastric varices IGV1 result in the most serious bleeding Sarin SK et al. Hepatology 1992.

27. Diagnostic Modalities Endoscopy Gastric varices can appear as �grape-like� clusters or �serpiginous� varices that resemble gastric folds The bluish color that is characteristic of esophageal varices is usually absent However, conventional endoscopy frequently misses submucosal lesions gastric varices: sensitivity of 48% and a specificity of 50% esophageal varices: sensitivity of 94% and a specificity of 17% (in a series of 23 patients, using EUS as a gold standard) Liu JB et al. Radiology 1993.

28. Non-invasive Imaging Multi-detector row CT (MDCT) is an emerging minimally invasive technique for detective GVs Allows for visualization of small visceral vessels by offering faster acquisition times with less motion artifact In a series of 22 patients by Willmann et all, MDCT was compared against the present old standard of EUS with comprable detection rates Willmann et all. Gut 2003

29. MDCT 3D Reconstruction

30. Treatment Options Endoscopic Therapy TIPS B-TRO Surgery Plan B

31. Endoscopic Therapy Endoscopic therapeutic options for gastric varices remains limited in the United States While band ligation is moderately effective in GOV1, rebleeding rates still approach 50% Endoscopic injection sclerotherapy (EIS) is largely ineffective, as the high flow rates in gastric varices �wash-out� the sclerosant Sarin SK. Gastro Endo 1997.

32. Does Treating EVs worsen GVs? Theoretically, obliteration of esophageal varices should lead to increased pressure elsewhere in the portal system Indeed, sclerotherapy of EVs has been shown to transiently worsen portal hypertensive gastropathy (PHG) Sarin et al. Am J Gastroenterol 2000. Furthermore, secondary GV�s following both EVL/EIS appeared at a rate of 8.8% However, overall sclerotherapy of EVs improves GVs post EVL: resolution of GOV1 in 50% post EIS: resolution of GOV1 in 61.5% Sarin et al. J Hepatol 1997.

33. Endoscopic Sclerosants Ethanolamine Oleate Agglutinating platelets Destroying the endothelial cells of shunts and varices Promotes clot formation N-butyl-2-cyanoacrylate (Histoacryl) Adhesive similar to super glue (which is made of ethyl-2-cyanoacrylate) Polymerize on contact with basic substances such as water or blood to form a strong bond Histoacryl is typically mixed 1:1 with Lipiodol to prevent premature solidification in the endoscope

34. Sclerotherapy Sarin studied 71 patients with gastric variceal sclerotherapy over an 11 year period Outcomes Primary hemostasis in acute bleeding: 66.7% Variceal obliteration: 71.6% (with repeated elective sclerotherapy) Variceal obliteration by GV type GOV1: 94.4% GOV2: 70.4% IGV1: 41% Rebleeding rates GOV1: 5.5% GOV2: 19% IGV1: 53% Sarin SK. Gastrointest Endosc 1997.

35. Combination EVL and EIS In a study by Arakai et al, 56 patients with gastric varices were treated with combination band ligation and polidocanol injection Extremely favorable results were obtained 100% control of acute bleeding 12.5% variceal recurrence rate 3.6% rebleeding rate However, most cases were GOV1, and applicability to all types of gastric varices remains questionable Arakai et al. Endoscopy 2003.

36. Combination EVL and EIS

37. Histoacryl Injections Endoscopic tissue adhesive injection was first applied in the treatment of bleeding gastric varices by Gotlib and Zimmermann, and Ramond et al. in 1986. The rapid rate of activation of the adhesive appears to overcome the high flow rates within the large varices Overall, Histroacryl is effective in controlling bleeding Primary hemostasis achieved in 94-97% Rebleeding rates of roughly 20-30% Long term survival is difficult to assess Mahadeva et al. Am J of Gastro 2003.

38. Histoacryl: Complications The most severe complication is the occurrence of systemic embolization Risk factors for systemic embolization Large volume injection Shunt between the portal system and the pulmonary vein (rare) Major complications include Cerebral infarct in 2 patients Splenic infarction Pulmonary embolism Inflammatory tumor in pancreatic tail See A. Gastroenterol Clin Biol 1986. / Yu et al. Gastro Endo 2005. / Witthoft et al. Z Gastroenterol 2004. / Sato et al. J Gastroenterol. 2004.

39. Ethanolamine and Gastric Varices A novel approach has been proposed by Kojima et al., using Ethanolamine Oleate and Iopamidol (EOI) concurrently with vasopressin Vasopressin is infused at 0.4 u/min continuously from 30 minutes before to 6 hours after sclerotherapy To counteract systemic vasoconstriction, a nitroglycerin patch is also applied to the patient Under both endoscopic and fluroscopic guidance, using iopamidol as the contrast agent, EOI is injected to fill the varices (15 � 10.5 mL) As the injection needle is removed, the site is sprayed with thrombin glue to seal the puncture site Kojima et al. J Gastro Hepato 2005.

40. Ethanolamine/Fibrin Dual Needle

41. Ethanolamine: Outcomes Vasopressin presumably reduces portal pressure and blood flow, resulting in improved retention of the sclerosant (EOI) In a series of 30 patients by Kojima et al., favorable results were obtained Primary hemostasis achieved in 28/30 patients (93.3%) Cumulative rebleeding rate at 1, 3, and 5 years: 13%, 19%, 19% Mortality at 1, 3, and 5 years: 31%, 54%, 59% Average number of EIS sessions: 2.3 � 1.1 Side effects were minimal 8 patients with mild fevers 6 patients developed ulcerations at the injection site Kojima et al. J Gastro Hepato 2005.

42. Gastric Varices with Endoclip

43. TIPS Transjugular Intrahepatic Portosystemic Shunt (TIPS) in a human was first created in Germany in 1988 Since, TIPS has become the standard therapy for secondary prevention of bleeding esophageal varices Boyer T. Gastro 2003. TIPS is also used to treat gastric varices in Europe and the United States, however the clinical utility of TIPS in this setting is debatable

44. TIPS: Contraindications

45. TIPS: Technique A needle catheter is introduced into the hepatic vein typically via the right transjugular vein The catheter is thenwedged in a peripheral branch of the right hepatic vein Wedged hepatic venography is then performed with carbon dioxide gas, demonstrating the location of the main, left and right PVs Colapinto needle is advanced through the wall of the right hepatic vein and into the right PV After an elevated pressure gradient is confirmed, intrahepatic parenchymal tract is dilated with an 8- or 10-mm high-pressure balloon. Finally a self-expanding metallic stent, such as the Wallstent, is deployed Novelli et al. http://www.emedicine.com/radio/topic764.htm

46. TIPS: Procedure

47. TIPS: Outcomes TIPS has shown great success in achieving immediate short-term control of gastric variceal bleeding, with hemostasis in 90-96% of cases Barange. Hepatology 1999. Chau et al. Gastro 1998. However, long term outcomes are poor Rebleeding in 31% after 1 year Stenosis of TIPS in 95% after 2 years Mortality rate of 41% after 1 year Treatment may worsen encephalopathy Barange. Hepatology 1999. Arai et al. J Gastroenterol 2005.

48. TIPS: The Problem Central to the problem is the fact that gastric varices can form at portal pressures of <12 mmHg TIPS must compete with large gastro-renal shunts, reducing its efficacy Response can be predicted by the type of gastric varix GOV1 respond more favorably (>80% hemostasis) GOV2 respond less favorable (26% to 70% hemostasis) IGV1 and IGV2 are usually associated with larger gastro-renal shunts Barange et al. Hepatology 1999.

49. TIPS: Competing with SR Shunt

50. IVC Filter + Coil Embolization

51. B-TRO Balloon-occluded Retrograde Transvenous Obliteration (B-TRO) is an interventional radiolgy technique for embolizing gastric varices through a gastrorenal shunt. First introduced by Kanagawa et al. in 1991, it is increasingly used in Japan but has seen limited use in Europe and the United States

52. B-TRO: Technique B-TRO uses a 6.5 Fr occlusive balloon catheter placed through either the femoral or internal jugular vein, to the left renal vein and into the gastro-renal shunt (GRS) The balloon is inflated, and contrast is injected retrograde into the GRS Any collateral drainage (usually via the inferior phrenic vein) is embolized Patients also usually receive 4000 U of haptoglobin IV to reduce risk of hemolysis and renal failure

53. B-TRO: Technique Once isolation of the shunt is confirmed, a 5-10% mixture of ethanolamine oleate with iopamidol (EOI) is injected to fill the GRS (up to 50 cc may be required) The EOI and balloon are left in place for at least 1 hour (even over-night in some protocols) The balloon is deflated after cessation of blood flow within the shunt is confirmed by angiography A contrast-enhance CT is performed 1 week after the procedure; if recanalization is seen, B-TRO is repeated

54. B-TRO: Diagram

55. B-TRO: Images

56. B-TRO: Results Prophylactic B-TRO shows excellent results 5-year recurrence rate of GVs: 2.7% 5-year rebleeding rate from GVs: 1.5% (78 patients with a median follow-up of 700 days) Ninoi et al. AJR 2005. Prophylactic B-TRO increases survival Cummulative survival at 1, 3 and 5 years B-RTO (17 patients): 94%, 85%, 39% Control (17 patients): 71%, 41%, 22% (p=0.04 34 patients, prospective, non-randomized study) Takuma et al. Clin Gastro Hepato 2005.

57. B-TRO: Results B-TRO has been applied in patients presenting with acute bleeding In a series of 11 patients by Arai et al, after either spontaneous of endoscopic hemostasis was achieved, B-TRO was performed within 24 hours Obliteration of GVs was achieved in 10 out of 11 patients (90.9%) Arai et al. J Gastroenterol 2005. Other benefits include Improvement in both Child-Pugh score, possibly due to increased hepatic blood flow Reduction of hepatic encephalopathy by occluding a major shunt Takuma et al. Clin Gastro Hepato 2005.

58. B-TRO: Worsening Varices Obliteration of the gastro-renal shunt results in elevation of pressures elsewhere in the portal system Worsening of esophageal varices is seen in roughly 50% of patients post-B-TRO Presence of esophageal varices prior to B-TRO is a significant risk factor Post B-TRO Rates of EVs at 1, 2 and 3 years Patients with prior EVs: 35%, 66% and 91% Patients without EVs: 21%, 21% and 29% (p < 0.01) Ninoi et al. AJR 2005.

59. Surgical Management Indications Failure of endoscopic therapy and salvage of for TIPS Noncirrhotic portal hypertension, in particular with extrahepatic portal vein thrombosis

60. Surgical: Shunt Procedures Non-selective Decompresses the entire portal tree by diverting all flow away from the portal system i.e. Portacaval shunt Selective decompressed variceal system, but maintains sinusoidal perfusion via a hypertensive superior mesenteric-portal compartment i.e. Distal splenorenal shunt (Warren) Partial Partial portocaval small diameter interposition shunt (Sarfeh) Wolff M and Hirner Arch Surg 2003.

61. Surgical: Obliteration Gastrectomy IGV1 (Fundic): fundic portion of the stomach is resected with mechanical stapling to eradicate intramural varices. IGV2 (Cardiac): proximal gastrectomy Devascularization Gastric devascularization and splenectomy (Hassab�s procedure) Gastroesophageal devascularization and splenectomy (Hassab-Paquet procedure) Hassab MA. Surgery 1967.

62. When All Else Fails� This Fails Too Primary hemostasis in 30 to 90 percent Complications Esophageal rupture High risk of rebleeding following balloon deflation Aspiration pneumonia secondary to inbaility to clear oral secretions Chojkier and Conn. Dig Dis Sci 1980. Hunt et al. Dig Dis Sci 1982.

63. Name the Tube

64. Types of Tamponade Balloons Sengstaken-Blakemore tube 250 cc gastric balloon and an esophageal balloon single gastric suction port Minnesota tube 250 cc gastric balloon and an esophageal balloon esophageal suction port and gastric suction port Linton-Nachlas tube a single 600 cc gastric balloon

65. Questions� Comments?

67. References Arai et al. Emergency balloon-occluded retrograde transvenous obliteration for gastric varices. J Gastroenterol. 2005 Oct;40(10):964-71. Arantes and Albuquerque. Fundal variceal hemorrhage treated by endoscopic clip. Gastrointest Endosc. 2005 May;61(6):732. Cakmak et al. Sinistral portal hypertension; imaging findings and endovascular therapy. Abdom Imaging. 2005 Mar-Apr;30(2):208-13. Epub 2005 Dec 30. Cheng et al. Sclerosant extravasation as a complication of sclerosing endotherapy for bleeding gastric varices. Endoscopy. 2004 Mar;36(3):239-41. Chikamori et al. Percutaneous transhepatic obliteration for isolated gastric varices with gastropericardiac shunt: case report. Abdom Imaging. 2005 Oct 21. Chojkier M, Conn HO. Esophageal tamponade in the treatment of bleeding varices. A decadel progress report. Dig Dis Sci 1980 Apr;25(4):267-72. Ferral and Patel. Selection criteria for patients undergoing transjugular intrahepatic portosystemic shunt procedures: current status. J Vasc Interv Radiol. 2005 Apr;16(4):449-55. Ford et al. Embolization of large gastric varices using vena cava filter and coils. Cardiovasc Intervent Radiol. 2004 Jul-Aug;27(4):366-9. Epub 2004 Jun 23. Fukuda et al. Application of balloon-occluded retrograde transvenous obliteration to gastric varices complicating refractory ascites. Cardiovasc Intervent Radiol. 2004 Jan-Feb;27(1):64-7.

68. References Hassab MA. Gastroesophageal decongestion and splenectomy in the treatment of esophageal varices in bilhazial cirrhosis; further studies with a report of 355 operations. Surgery 16:169�176, 1967. Hsieh et al. Modified devascularization surgery for isolated gastric varices assessed by endoscopic ultrasonography. Surg Endosc. 2004 Apr;18(4):666-71. Epub 2004 Mar 19. JB Liu, LS Miller, RI Feld, CA Barbarevech, L Needleman and BB Goldberg. Gastric and esophageal varices: 20-MHz transnasal endoluminal US. Radiology. 1993 May;187(2):363-6. Kakutani et al. Use of the curved linear-array echo endoscope to identify gastrorenal shunts in patients with gastric fundal varices. Endoscopy. 2004 Aug;36(8):710-4. Kim T, et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology 1997;25:307-12. Kojima et al. Sclerotherapy for gastric fundal variceal bleeding: is complete obliteration possible without cyanoacrylate? J Gastroenterol Hepatol. 2005 Nov;20(11):1701-6. Komorizono et al. Successful balloon-occluded retrograde transvenous obliteration for ruptured gastric fundal varices in a patient with Child-Pugh C cirrhosis: case report and literature review. Dig Dis Sci. 2004 Feb;49(2):270-4. Mahadeva et al. 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 Dec;98(12):2688-93.

69. References Matsumoto et al. Limitations of transjugular intrahepatic portosystemic shunt for management of gastric varices. Gastroenterology. 2004 Jan;126(1):380-1. Ninoi 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 Apr;184(4):1340-6. Ninoi et al. TIPS versus transcatheter sclerotherapy for gastric varices. AJR Am J Roentgenol. 2004 Aug;183(2):369-76. Northup and Caldwell. Treatment of bleeding gastric varices. J Gastroenterol Hepatol. 2005 Nov;20(11):1631-3. Sarin SK, et al. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertensive patients. Hepatology 1992;16:1343-9. Sarin SK, Govil A, Jain AK, Guptan RC, Issar SK, Jain M, Murthy NS. Prospective randomized trial of endoscopic sclerotherapy versus variceal band ligation for esophageal varices: influence on gastropathy, gastric varices and variceal recurrence. J Hepatol. 1997 Apr;26(4):826-32. Sarin SK, Shahi HM, Jain M, Jain AK, Issar SK, Murthy NS. The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol. 2000 Oct;95(10):2888-93. Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven-year experience. Gastrointest Endosc. 1997 Jul;46(1):8-14.

70. References Takuma et al. Prophylactic balloon-occluded retrograde transvenous obliteration for gastric varices in compensated cirrhosis. Clin Gastroenterol Hepatol. 2005 Dec;3(12):1245-52. Taniai et al. The treatment of gastric fundal varices--endoscopic therapy versus interventional radiology. Hepatogastroenterology. 2005 May-Jun;52(63):949-53. Weber and Rikkers. Splenic vein thrombosis and gastrointestinal bleeding in chronic pancreatitis. World J Surg. 2003 Nov;27(11):1271-4. Epub 2003 Oct 13. Wolff M, Hirner A. Current state of portosystemic shunt surgery. Langenbecks Arch Surg. 2003 Jul;388(3):141-9. Yu et al. Splenic infarction complicated by splenic artery occlusion after N-butyl-2-cyanoacrylate injection for gastric varices: case report. Gastrointest Endosc. 2005 Feb;61(2):343-5.