Endoscopic Variceal Ligation: A to Z

Division of Gastroenterology and Hepatology, Liver Clinic Department of Internal Medicine Soon Chun Hyang University School of Medicine, Soon Chun Hyang University Bucheon Hospital, Bucheon, Korea

김 상 균

Agenda

1. Endoscopic classification of 2. Endoscopic ultrasound for the management of esophageal varices 3. Endoscopic treatment of esophageal varices 1) Endoscopic injection sclerotherapy (EIS) vs. Endoscopic variceal ligation (EVL) 2) Primary prophylaxis for esophageal varices 3) Acute esophageal bleeding 4) Secondary prophylaxis after variceal bleeding 4. Procedure of endoscopic band ligation 5. Recurrence of esophageal varices after band ligation 6. Conclusions

Case • 52/M, Chronic alcoholism • C/C : Abdominal distension, 1 month ago • MELD score:22, Child-Pugh class C with ascites •  What should be recorded?

1. F2, Lm, Cb, red wale marking, hematocystic spots 2. F3, Lm, Cb, RC (++), 3. F2, Lm, RC (++) 4. F3, RC (++) 5. F1, RC Endoscopic Classification According to Form

F0: No varicose appearance F1: Straight, small-caliber varices F2: Moderately enlarged, beady varices F3: Markedly enlarged, nodular or tumor-shaped varices

The Japanese Research Society for Portal Hypertension. Dig Endosc 2010;22:1-229 Endoscopic Classification According to Color

• Cw: White varices Cb: Blue varices

• Cw-Th: Thrombosed white varices • Cb-Th: Thrombosed blue varices Endoscopic Classification According to Location

• Ls: Locus superior • Lm: Locus medialis • Li: Locus inferior • Lg-c: Adjacent to the cardiac orifice • Lg-cf: Extension from the cardiac orifice to the fornix • Lg-f: Isolated in the fornix • Lg-b: Located in the gastric body • Lg-a: Located in the gastric antrum

Modified from Sohendra N, et al. Therapeutic Endoscopy Endoscopic Classification According to Red Color Sign • Red wale markings, Cherry red spots, Hematocystic spots,

• RC0: absent, RC1: small in No & localized, RC2: RC1 - RC 3, RC3: large in No and circurmferential Endoscopic findings and scoring system predicting variceal bleeding • By Japansese Research Society for Portal Hypertension; • Validated by North Italian Endoscopic Club

Rate of Bleeding(%) Risk Beppu’s No.Who Class Score Bled/Total Expected Observed

1yr 2yr 1 >+1.14 7/61 0.0 3.4 9.2 2 0.38 to 1.14 35/146 20.6 14.9 22.1 3 <0.38 to 0.0 6/12 40.0 25.1 33.3 4 0.0 to >-0.38 13/50 64.5 16.7 29.0 5 -0.38 to >-1.14 11/25 90.2 36.8 41.0 6 <-1.14 13/23 100.0 42.9 51.7

NIEC, N Engl J Med 1988;319:983-9 Beppu K, Gastrointest Endoscopy, 1981;27:213-8 Agreement of endoscopic findings

Agreement (%) Kappa indexb Endoscopic Frequency features (%) Overall Single class p valueª Overall Single class

Esophageal varices Size 82±18 0.59 0 19 79±18 0.59 1 36 75±20 <0.01 0.45 2 38 86±16 [1-3] 0.60 3 7 100±0 0.84 Extent 75±19 0.37 1/3 24 66±22 0.28 2/3 67 78±17 <0.05 0.30 3/3 9 82±24 0.58 color 77±19 0.28 white 28 78±18 NS Blue 72 75±18 Red sign 88±17 0.58 Yes 32c 86±19 NS No 68 89±17

Gastroenterology 1990;98:156-162 Valuable findings to be noted

Factors related to bleeding of esophageal varices Transmural Pressure x Radius Variceal Wall Tension = Variceal Wall Thickness

Transmural P = (Variceal P – Luminal P) High HVPG Transmural pressure

Luminal Variceal size RadiusPressure of the varix Variceal Variceal Pressure Wall Red color signs R Wall thickness Size of varix and RC sign are most important risk factors • To assess the risk of bleeding-NIEC index Size of varices Points to add NIEC index Rate of Bleeding (%) Small 8.7 6 months 12 months Medium 13.0 <20 0 1.6 Large 17.4 ~25 5.4 11.0 Red wale markings ~30 8.0 14.8 Absent 3.2 ~35 13.1 23.3 Mild 6.4 ~40 21.8 37.8 Moderate 9.6 >40 58.5 68.9 Severe 12.8 N Engl J Med 1988;319:983-9 Child-Pugh class A 6.5 This multicenter Italian prospective study showed the Beppu score significantly B 13.0 overestimated the probability of first C 19.5 esophageal varix hemorrhage. How to measure the varix size?

1. Naked-eye 2. Specific size marker 3. Computed tomography 4. Balloon assisted endoscopic ultrasound 5. Endoscopic ultrasound with mini-probe The issue for measuring the varix size

F1: small-caliber varices, not disappear with insufflation. F2: Moderately enlarged, beady varices, less than 1/3 of the esophageal lumen F3: Markedly enlarged, nodular or tumor-shaped varices, more than 1/3 of the esophageal lumen

World J. Surg 1995;19:420-423

 On EGD, esophageal varices should be graded as small or large (>5 mm) with the latter classification encompassing medium-sized varices when 3 grades are used (small, medium, large). (Class IIa, Level C).

AASLD practice guideline Hepatology 2007;46:922-938 How to measure the varix size

 Esophageal varices were graded from 1 to 4 grade 1 : ≤3 mm in diameter; grade 2 : 4-6 mm, grade 3, 7-10 mm, grade 4, ≥11 mm

Gastrointest Endosc 2005;61:58-66 Baveno III consensus workshop J Hepatology 1992;15:256-261

GASTROENTEROLOGY 1997;113:1640–1646 Varix size: Sum of Esophageal Variceal Cross-Sectional Surface Area?

• Risk of Esophageal Variceal Bleeding Based on Endoscopic Ultrasound evaluation of the Sum of Esophageal Variceal CSA

The grade of the esophageal varices by endoscopy was not a significant predictor of future variceal bleeding in this study.

Using a cutoff value for the CSA of 0.45 cm2, the sensitivity and specificity for future variceal bleeding above and below this point is 83% and 75%.

Am J Gastroenterol 2003;98:454–459. The objectiveness of EUS measurement

 The intraobserver and interobserver correlations reflecting the objectiveness of the EUS measurement were excellent.

Intraobserver Interobserver correlations correlations Variceal radius 0.98 0.97 Wall thickness 0.92 0.91

 Variceal radius was not correlated with wall thickness (r=-0.08)

Gastrointest Endosc 1996;44:425-8 Measurement of varix size with endoscopic ultrasound

6.5mm

0% 30% 60% 100%

• Measure the radius of varix by 20MHz IVUS • Grade I~V • Interobserver correlation r=0.88

Miller LS et al. HEPATOLOGY 1996;24:552-555 Endoscopic ultrasound for the management of esophageal varices Peri-, Para-EV & Perforating vein

Muscularis externa Muscular Peri-esophageal layer collateral veins Mucosa & (peri-ECVs) Submucosal layer

Lumen

Perforating vein (connected with Perforating vein para-ECVs) (connectedLarge Paraesophageal with collateral vein and perforating vein are peri-ECVs) Para-esophageal considered as an important risk factor for varicealcollateral recurrence veins Gastrointest(para Endosc-ECVs) 2001;53:77 -84 Modified from El-Saadany, M. et al. Endoscopy 2008;40:690-696 How to deal with it?

1. Nonselective β-blocker (NSBB) 2. Endoscopic injection sclerotherapy (EIS) 3. Endoscopic variceal ligation (EVL) 4. Combination of EIS+EVL 5. Combination of NSBB + EVL Nonselective β-blocker for the primary prevention of bleeding

• Small varices & Not bled – High risk of hemorrhage (Child B/C or red wale markings), • Nonselective ß-blockers should be used for (IIA) – No increased risk of hemorrhage • Nonselective ß-blockers can be used. • Medium/large varices & Not bled – High risk of hemorrhage (Child B/C or red wale markings) • Nonselective ß-blockers or EVL may be recommended (IA). – No high risk of hemorrhage • Nonselective ß-blockers are preferred • EVL: CIx, intolerance or non-compliance to ß-blockers (IA)

2005 ASGE guideline, Gastrointest Endosc 2005;62:651-655 2007 AASLD and ACG Practise guideline Beta-blockers in patients with end- stage cirrhosis needs to be cautioned.

 The use of beta-blockers may be associated with a high risk of paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites.

J Hepatol 2011;55:794-9  The use of beta-blockers is associated with poor survival in patients with refractory ascites.

patients not patients taking b-blocker taking b- blocker Median 20.2 months 5.0 months survival (4.8-35.2) (3.5-6.5)

HEPATOLOGY 2010;52:1017-1022 The effect of long-term use of non-selective beta-blocker on the development of acute kidney injury in patients with liver cirrhosis

 208 patients developed AKI from 2,250 liver transplantation waitlist registrants.  Median follow-up duration : 20.3 (range:3~201) months.

4.27

1.53

1.00 Hazard ratio AKI ofratio Hazard

Probability of being free of AKI of free beingof Probability

0.19 Ascites(-) & Ascites(-) & Ascites(+) & Ascites(+) & NSBB(-) NSBB(+) NSBB(-) NSBB(+)

Kim SG et al. 2014 KASL Endoscopic injection sclerotherapy (EIS)

 Injection of 5% ethanolamine oleate in the varix Endoscopic injection sclerotherapy (EIS) vs. Endoscopic variceal ligation (EVL)  Randomized trials showed that EVL is more effective than EIS in controlling esophageal variceal bleeding. 1. makes less complications 2. requires fewer treatment sessions to achieve eradication 3. improves the survival of patients

Authors Treatment N Complications, Eradication, Recurrence, Rebleed,% % % % Stiegmann et al. EIS 65 22 56 50 48 EVL 64 2 55 33 36 Gimson et al. EIS 49 57 71 - 53 EVL 54 67 82 - 30 Laine et al. EIS 39 56 69 - 44 EVL 38 24 59 - 26 Lo et al. EIS 59 19 63 - 51 EVL 61 3 74 - 33 Hou et al. EIS 67 22 79 30 33 EVL 67 5 87 48 18 Lo et al EIS 34 29 - - 33 EVL 37 5 - - 17 Baroncini et al. EIS 54 31 92 13 19 EVL 57 11 93 30 16 Avgerinos et al. EIS 40 60 97 - 47 EVL 37 35 93 - 27 Sarin et al. EIS 48 10 92 8 21 EVL 47 0 96 29 6 Hou et al. EIS 84 - 86 - 38 EVL 84 - 88 - 24 Ann Intern Med 1995;123:280-287 Combination treatment (EIS + EVL) vs. Endoscopic variceal ligation (EVL) alone  A meta-analysis showed that there is no additive effect of combination treatment. Combination EVL and sclerotherapy had more formation than EVL alone.

Variceal rebleeding Mortality

Dig Dis Sci 2005;50:399-406 Endoscopic variceal ligation (EVL); Multi-band ligation

Six-shooter Saeed multi-band ligator® Speedband® Superview (Wilson-Cook) super7 (Microvasive)

FDA-MAUDE(manufacturer and user facility device experience) Visual Field Endoscopic variceal ligation EVL for Active EV Bleeding

Sohendra N, et al. Therapeutic Endoscopy EVL for Active EV Bleeding Advantage of EVL

• Easier to learn and require less experience • Complications are less operator-dependent • Fewer complications • Eradicating varices more rapidly with less recurrent bleeding • improve survival (compared to EIS)

• EVL is the recommended for acute esophageal variceal bleeding, primary prophylaxix and prevention of variceal rebleeding (1b;A) 2010 Baveno V Revising consensus

Complications of EVL

• 2-20% of patients treated by EVL • Chest pain and < 20% • Mediastinitis, perforation, esophageal stricture : extremely rare • Shallow ulcer, only a minority associated with bleeding. • 11/150 patients (7.3%) had post-EVL ulcer bleeding

Clin Gastroenterol Hepatol 2009;7:988-93 Follow-up after EVL Manangement of post-EVL ulcer

 Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled Trial Method: day 1 : IV pantoprazole 40mg, day 2-10 : PO pantoprazole 40mg

Control Pantoprazole P-value (n=20) (n=22) No. of ulcers, day 10, 2.25 (0.31) 2.18 (0.20) 0.85 mean (SE) Ulder size (mm2), 82 (22) 37 (9) 0.01 day 10, mean (SE) Dysphagia present, 1 (5) 3 (14) 0.61 day 10, n (%) Chest pain present, 0 (0) 1 (5) 1.0 day 10, n (%)

HEPATOLOGY 2005;41:588-594 Change of gastric varices after EVL

Obliteration of gastric varices Hemodynamics of varices and collateral vessels Non-dominant

Paraesophageal Perforating vein collateral vein

Post. branch short.gastric vein Ant. branch Lt.gastric vein Dominance was defined as lack of one branch, or a ratio of the smaller branch diameter to the larger branch diameter of less than 0.75 Hemodynamics of varices and collateral vessels

Anterior dominant

High risk of Esophageal varix recurrence Gastric varix can develop after esophageal band ligation. Hemodynamics of varices and collateral vessels

Posterior dominant

Gastriorenal shunt Low risk of Esophageal varix recurrence Gastric varix can disappear after esophageal band ligation. Recurrence of esophageal varices after EVL Anterior dominant : high risk of recurrence of esophageal varices

J Gastroenterol 2007; 42:219–224 Color-Doppler EUS Endoscopic Secondary Prophylaxis

• Ix : survivor from episode of active variceal hemorrhage. (I, A) • Best option: “ß-blockers plus EVL” (I, A). • Maximal tolerated dose of nonselective ß-blocker • Repeat EVL every 1-2 weeks (?) until obliteration. • EGD after obliteration. – 1-3 months ⇒ then every 6-12 months (I, C).

2005 ASGE guideline, Gastrointest Endosc 2005;62:651-655 2007 AASLD and ACG Practise guideline Bi-weekly vs. Bi-monthly EVL session

A Randomized Control Trial of Bi-monthly Versus Bi-weekly Endoscopic Variceal Ligation of Esophageal Varices.

Recurrence rate after complete Additional treatment for recurrent eradication varices after complete eradication

 The second treatment session after recanalization of variceal blood flow had a greater impact on the stimulation of shunt formation

Am J Gastroenterol 2005;100:2005–2009 Summary

• Esophageal varix size and red color sign are the most important findings to predict variceal bleeding.

• EVL is effective for control of active bleeding, primary and secondary prophylaxis in patients with EV.

• Endoscopic ultrasound is useful to assess the size of esophageal varices and predict variceal bleeding Conclusions

• Endoscopic variceal ligation is the most effective method to control active bleeding and prophylaxis of gastro-esophageal varices.

• To provide successful endoscopic treatment, you should know about complication of EVL and anatomy of varices.

Thank you for your attention

Greatly appreciation to Dr. Kim Young Seok, Dr. Jang Jae Young, Kim Yulhee for giving an advice and materials.