Gastroesophageal Varices

Amreen M. Dinani MD, FRCPCVTSGNA Fall Conference

October 24, 2015

Objectives

• Understand the pathophysiology of portal hypertension and development of gastroesophageal varices

• Recognize and identify risk factors for developing gastroesophageal varices

• Understand the major principles in the management of gastroesophageal varices

Case 1

AST 56 ALT 42 Tbil 1.0 ALP 76 GGT 60INR 1.4Lipid Panel: Chol 230, TG 200, LDL 151, HDL 32

6.0

15.6 110135

4.0

109

23

12

1.0136

• 45M referred to your clinic for Hepatitis C treatment. Asymptomatic

Case 1

• In addition to starting treatment for HCV, he undergoes an upper endoscopy as you believe he has cirrhosis

• Upper endoscopy reveals:

Question 1

• What is the next step?1. Start a beta blocker2. Do nothing 3. Repeat upper endoscopy in 1 year4. Repeat upper endoscopy in 3 years5. Recommend endoscopic band ligation

(EBL)6. Recommend TIPS

Question 2

• What are risk factors for development of GEV?1. Presence of ascites 2. Cirrhosis secondary to alcohol3. Cirrhosis secondary to Hepatitis C4. Child’s Pugh Score B/C5. Presence of red wale signs

Cirrhosis

Resistance to portal flow

Varices

Portal PressurePortal blood

inflow

Splanchnic arteriolar resistance

Variceal GrowthRupture

Natural History Of Varices

No varices Small varices Large varices

7-8%/yr 7-8%/yrPredictors of development

HPVG >10mmHg AST

Groszmann et al. NEJM 2005

Predictors of progression Childs B/C

Red wale signs EtOH cirrhosis

Merli et al. Hepatology. 2003

Variceal hemorrhage Varices with red signs Predictors of hemorrhage

Size of varices Childs B/C

Red wale signs

Groszmann et al. NEJM 2005

Bleeding risk of pts with small varices and Childs C or red wale

signs is same as moderate/large size varicesMerli et al. J Hepatology 2003

Clinical Risk Factors For Variceal Hemorrhage

• Large esophageal varices • Appearance:

– Red wale marks– Cherry red spots – Diffuse erythema

• Childs-Pugh Class C cirrhosis• Presence of tense ascites- sign of portal

hypertension

High Risk Stigmata

Red wale sign

Cherry red spot

Nipple sign

Prevention of Varices/Variceal Bleeding

No varices

Small varicesNo hemorrhage

Large or high-risk small varices No hemorrhage

Variceal hemorrhage

Prevention of varices

Prevention of growth

Prevention of 1st growth

Prevention of recurrence

Pre-primary prophylaxis

Secondary prophylaxis

Primary prophylaxis

Non-Selective Beta-Blockers DO NOT Prevent Development Of Varices

More severe side effects (18% vs 6%)

n= 108n= 105

Groszmann RJ, Garcia-Tsao et al. NEJM 2005

HVPG Was Not Significantly Different Between Study Groups

Groszmann RJ, Garcia-Tsao et al. NEJM 2005

Baseline HVPG is the STRONGEST Predictor for Development of Varices

Groszmann RJ, Garcia-Tsao et al. NEJM 2005

Development Of Large Varices In Patients With No Or Small Varices At Baseline

2 years 3 years Small varices0

10

20

30

40

50

60

PlaceboPropanolol

% pts with large varices

- One third of patients lost to follow up- High risk small varices?

<0.05 NSNS

Cales et al. Eur J Gastroenterol Hepatol 1999;11:741-747

Nadolol vs. Placebo In Patients With Small (not high-risk) Varices

Variceal Hemorrhage Survival

Merkel et al. Gastroenterology 2004

Recommendations- Pre-primary prophylaxis

No varices

Small varicesNo hemorrhage

Large or high-risk small varices No hemorrhage

Variceal hemorrhage

No β-blockersRepeat EGD in 2-3yrs

Consider β-blockers- ββ-> no repeat EGD

- No -> repeat endoscopy in 1-2yrs

Prevention of 1st growth

Prevention of recurrence

Primary Prophylaxis

• Prevention of variceal bleeding in a patient who has never bled previously

• 1st line of treatment– Non-selective beta blockers (nadolol,

propranol, carvedilol) OR– Endoscopic Band Ligation (EBL)

Primary Prophylaxis- Beta Blockers

• Mechanism of action: Blocks vasodilatory β-adrenergic receptors permitting unopposed α-adrenergic vasoconstriction in the mesenteric arterioles-> reducing portal venous inflow and pressure

• Reduce risk of bleeding from 25% to 15% compared to placebo

• Best predictor of response to ββ is sustained reduction in HVPG < 12mmHg

• Clinically- 25% reduction in HR, but not less than 55 beats/min– Only 20-30% of subjects achieve the goal HR– 15-20% of subjects cannot tolerate ββ

Primary Prophylaxis- Band Ligation

Meta-Analysis Of Trials of EBL vs ββ For Primary Prophylaxis

Best Prac Res Clin Gastroenterol 2007;21:31-42

Cirrhosis

Resistance to portal flow

VaricesVariceal growthVariceal rupture

Portal PressurePortal blood

inflow

Splanchnic arteriolar resistance

Non-selective β-blockers

Β-2 blockade

Β-1 blockade

Cardiac output

PropanololNadolol

Coreg-- nonselective beta blocker/alpha-1 blocker

Unable to tolerate BB-> EBL

Recommendations- Primary Prophylaxis

No varices

Small varicesNo hemorrhage

Large or high-risk small varices No hemorrhage

Variceal hemorrhage

No β-blockersRepeat EGD in 2-3yrs

Consider β-blockers- ββ-> no repeat EGD

- No -> repeat endoscopy in 1-2yrs

High risk stigmata- nonselective β-blockers OR EVL

No high risk stigmata- Non-selective β-blockers preferred

Combination of nonselective β-blockers plus EVL

Case 2

• 45M presents with a several hour history of hematemesis. His history is significant for long standing alcoholism

• PE: Tachycardia of 110 and SBP of 90• Labs on admission: Hgb of 10, plt 100,000 and

INR of 2.0

Question 3

• What would you do next?1. Call GI for an urgent upper endoscopy 2. Start Nexium ggt, 2 units PRBC 3. Call IR for urgent TIPS 4. Intubate the patient and stabilize 5. Start Nexium ggt, Octreotide ggt, 2 unit PRBC

Active Variceal HemorrhageGeneral Measures

• Airway protection• Gastric aspiration• Hemodynamic resuscitation

– Blood, crystalloid (avoid over-transfusion)– FFP, platelets are usually not necessary

• Antibiotics • Metabolic support

– Thiamine, DT’s monitoring, glucose/lytes

45-day mortality with Hgb goal >7 g/dl

Villanueva C et al. N Engl J Med 2013;368:11-21

Death by 6 weeks

Villanueva C et al. N Engl J Med 2013;368:11-21

Thresholds For Transfusion

• 9.0 g/dl for SBP <100, HR>100 – NO DATA

• 10 g/dl with concomitant cardiac sx’s– SOME DATA

• 7.0 g/dl or less for everyone else– International Consensus Recommendation– RECENT GOOD DATA

Barkun AN et al. Annals Intern Med 2010;152:101-113

Antibiotic Prophylaxis Improves Mortality

Overall Mortality Mortality due to Bacterial Infections

Chavez-Tapia NC et al. Aliment Pharmacol Ther. 2011;34(5):509-18

Pharmacologic Therapy in Active Variceal Hemorrhage

• Vasopressin– Causes splanchnic vasoconstriction reducing portal

venous inflow and reducing portal pressure– Has severe toxicity (cardiac, bowel ischemia)

• Terlipressin– Semisynthetic analog of vasopressin– Less side effects than vasopressin– Evaluated in at least 20 clinical trials– Shown to increase survival in variceal bleeding– Not available in US

Pharmacologic Therapy in Active Variceal Hemorrhage

• Somatostatin– Decreases portal pressure and collateral blood

flow by inhibiting release of glucagon– Also reduces post prandial mesenteric blood flow– Not available in the US– Half life in circulation of 1-3 minutes

• Octreotide– Somatostatin analog– Half life of 80-120 minutes– Effect on portal pressure is not prolonged– Several studies have shown it to be superior to

placebo in controlling variceal hemorrhage

Endoscopic Therapy for Acute Variceal Hemorrhage

• EVL- Preferred endoscopic modality for control of acute esophageal variceal bleeding and for prevention of rebleeding

• Varices at the GE junction are banded initially, and then more proximal varices are banded in a spiral manner about every 2 cms

• 80-90% of patients will stop bleeding with EVL and octreotide

Endoscopic Variceal Ligation

Factors Associated With Failure To Control Acute Hemorrhage• Spurting varices• High Child-Pugh score• High HVPG• Infection• Portal Vein Thrombosis

Factors Associated with Early Rebleeding

• Severe initial bleeding• Overly aggressive

volume resuscitation• Infection• High HVPG• Complications of

endoscopic therapy• Renal failure

Secondary Prophylaxis

• Preventing hemorrhage in patients with a history of variceal hemorrhage

• After an index bleed, 70% of patients experience recurrent variceal hemorrhage within one year

• 1st line of treatment: EVL and ββ

EVL + Nadolol vs. EVL

0

5

10

15

20

25

30

Rebleeding Survival

EVL + N

EVL

** p<.006

Hepatology 2005;41(3):572-8

Secondary Prophylaxis Summary

• EVL and ββ • EVL every 2-3 weeks until varices eradicated• Once eradicated -> Upper endoscopy + EVL

every 3 to 6 months for treatment of recurrent varices

• TIPS if pharmacologic and endoscopic therapy fail

• Liver transplant referral- 60% mortality at 1 yr

Recommendations- Primary and Secondary Prophylaxis

No varices

Small varicesNo hemorrhage

Large or high-risk small varices No hemorrhage

Variceal hemorrhage

No β-blockersRepeat EGD in 2-3yrs

Consider β-blockers- ββ-> no repeat EGD

- No -> repeat endoscopy in 1-2yrs

High risk stigmata- nonselective β-blockers OR EVL

No high risk stigmata- Non-selective β-blockers preferred

Combination of nonselective β-blockers plus EVL

Case 3• 43F with alcoholic liver disease presents with

hematemesis• VS 90/50 HR 110• Somnolent, somewhat confused• Spider angiomas on chest• Hgb 10, plt 64, INR 2.3, Alb 2.1, TB 3.2, AST 85,

ALT 26• Childs Pugh Class C on admission

What worrisome features does this patient have that puts her at high risk of rebleeding or difficult to control?

Treatment of Early Rebleeding or Uncontrolled Active Bleeding

Early Use Of TIPS In Patients With Cirrhosis and Variceal Bleeding

Inclusion Criteria• Cirrhosis with acute variceal hemorrhage• Treated with vasoactive drugs, endoscopic

therapy and antibiotics.• Child-Pugh class C (10-13) or Child Pugh class B

(7-9) with active bleeding• More than 10 Child-Pugh points excluded

Garcia-Pagan, et al. NEJM 2010;362:2370-2378

Probability of Remaining Free of Bleeding and of Survival

Garcia-Pagan, et al. NEJM 2010;362:2370-2378

Conclusion

• First priority: Hemodynamic stability and resuscitation • No role for pharmacological therapy to prevent

varices • Non-selective beta blockers preferred over EVL for

primary prophylaxis • Treat infections aggressively • Presence of ascites- indicative of portal hypertension • Rescue measures: Blakemore/Minnesota Tube and

TIPS +/- liver transplant referral