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PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS
Large
60
Medium
Small
Overall
n=494
Child A
n=346
Child B
n=114
Child C
n=34
Pathophysiology
Portal Venous Anatomy
Portal venous blood flow averages 1500 cc/min Normal portal venous pressure is 4-8 mmHg
Pathophysiology
Gastroesophageal varices are a direct consequence of portal hypertension that, in cirrhosis, results from Increased resistance to portal flow
Structural (distortion of liver vascular architecture by fibrosis and regenerative nodules) and Dynamic (increased hepatic vascular tone due to endothelial dysfunction and decreased nitric oxide bioavailability).
Intracellular Spaces (of Disse) in the Portal Sinusoids Large Enough for Chylomicroms to Pass
A Threshold Portal Pressure of ~12 mmHg is Necessary for Esophageal Varices to Form
Varices Present
(n=72) 35 30
Varices Absent
(n=15)
25 20 P<0.01
15
12
10 5
No varices
Small varices
7-8%/year 7-8%/year
Large varices
Grade II Varices
No Varices
Small Varices
75
p<0.01 *
%
Patients without bleeding
50
25
Large Varices * *
2-year probability of first bleed: Small varices: 7% Large varices: 30%
0 12 24 12 Time (months) 36 24 36
*Merli et al., Hepatol 2003; 38:266, **Conn et al., Hepatology 1991; 13:902
Punctum
Variceal hemorrhage
Secondary Prophylaxis
Pharmcologic Endoscopic TIPS
Primary Prophylaxis
In view of the relatively high rate of bleeding from esophageal varices and the high associated mortality, an important goal of management of patients with cirrhosis is the primary prevention of variceal hemorrhage. As a result, all patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk for variceal hemorrhage.
Beta-blockers did not prevent the development of varices and were associated with a higher rate of serious adverse events
Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage * Sooner with cirrhosis decompensation
Endoscopic Therapies
Band Ligation Sclerotherapy (historican interest only)
DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDING
Decrease In Hepatic Venous Pressure Gradient (HVPG) Reduces Risk of Variceal Bleeding
100
80 46-65% 60
Rebleeding 40
20 0% 0 HVPG decrease to < 12 mmHg HVPG decrease > 20% from baseline No change in HVPG 7-13%
Goal of therapy to reduce portal pressure by 20% or below 12 mm Hg Dose titrated to a resting HR of 55, or a 25% reduction in baseline Initial dose propranolol 40 mg bid, Average dose 160 mg/day Up to 1/3 intolerant to side effects resulting in discontinuation
Control 25%
(n=600)
Beta-blocker 15%
(n=590)
All varices
(11 trials)
Large varices
(8 trials)
30%
(n=411)
14%
(n=400)
-16%
(-24 to -8)
Small varices
(3 trials)
7%
(n=100)
2%
(n=91)
-5%
(-11 to 2)
THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERS
The Risk of First Bleeding is Not Reduced by Adding Isosorbide Mononitrate (ISMN) to b-blockers
Free of a first variceal bleeding
100 100
Survival
75
ns
ns 75
50
25 0
Years
Years
Garca-Pagn et al., Hepatology 2003; 37:1260
VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGE
Variceal Band Ligation (VBL) vs. Beta-Blockers (BB) in the Prevention of First Variceal Bleed
First hemorrhage
Chen 1998 Sarin 1999 De 1999 Jutabha 2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total
Relative risk
Survival
10
10 40
Favors VBL
Favors BB
Favors VBL
Favors BB
Small Varices
Follow-up EGD in 1-2 years*
*EGD every year in decompensated cirrhosis Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No role for repeated endoscopy!!
Beta-blocker therapy
No Contraindications Contraindications or Beta-blocker intolerance
Secondary Prophylaxis
Pharmcologic Endoscopic TIPS
Specific therapy:
Pharmacological therapy: octreotide, vasopressin + nitroglycerin Early endoscopic therapy: band ligation Shunt therapy: TIPS, surgical shunt
P= 0.04
6-week survival in variceal bleeders who did not have therapeutic failure
The use of prophylactic antibiotics in cirrhotics with GI hemorrhage has been shown by metaanalysis to reduce infection, increase survival, and reduce recurrent hemorrhage (13 prospective trials) Recommended antibiotics include oral norfloxacin, ciprofloxin, ofloacin, and amoxicillin clavulanate, ceftriaxone IV
Scand J. Gastro 2003;38:193-200
Antibiotic
(n=264)
14% 8% 15%
-32%
(-42 to 23)
-18%
(-26 to 11)
-9%
(-15 to 3)
0.8
0.6
No antibiotics (n=61)
%
free of 0.4 variceal hemorrhage
0.2
0 0 1 2 3 12 18 24 30
Follow-up (months)
Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days
Vasopressin:
Lactulose 30 mL TID_QID until pts had non-melenic stools and then the dose was reduced so that patients had two to three semiformed stools per day
Combination Drug / Endoscopic Therapy is More Effective Than Endoscopic Therapy Alone in Achieving Five-Day Hemostasis
Sclero + Octreotide Ligation + Octreotide Sclero + Octreotide / ST Sclero + Octreotide Sclero + Octreotide Sclero + ST Sclero + Octreotide Sclero / ligation + Vapreotide TOTAL
0.8 1 1.2 1.4 1.6 1.8 2
Besson, 1995 Sung, 1995 Signorelli, 1996 Ceriani, 1997 Signorelli, 1997 Avgerinos, 1997 Zuberi, 2000 Cales, 2001
Relative Risk
No Mortality Difference
TIPS
Portal vein
TIPS is indicated in patients who rebleed on combination endoscopic plus pharmacologic therapy (10-20%) In patients with Child A/B cirrhosis, the distal spleno-renal shunt is as effective as TIPS
(dependent on local expertise)
Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival
116 cirrhotics with acute variceal bleed Urgent assessment of wedged hepatic vein pressure 64 HVPG < 20 mmHg: routine therapy 52 HVPG > 20 mmHg randomized to TIPS vs routine therapy Early TIPS in patients with HVPG>20 associated with reduced transfusion, rebleed, in-hospital and 1 year mortality
Monescillo et al., Hepatology 2004; 40:793
EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVAL
Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival
1
HVPG <20 0.8 0.6 HVPG >20 - TIPS
Probability of survival
0.2
0 0 3 6 9 12
Months
Monescillo et al., Hepatology 2004; 40:793
Actuarial Probability of the Primary Composite End Point and of Survival, According to Treatment Group.
No significant differences were observed between the two treatment groups with respect to serious adverse events.
Garca-Pagn JC et al. N Engl J Med 2010;362:2370-2379.
Balloon Tamponade
YES
Early rebleeding?
NO
2nd Endoscopy
Secondary Prophylaxis
Pharmcologic Endoscopic TIPS
LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERS
Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation + b-Blockers
80
60
%
Rebleeding
40
20
Untreated b-blockers
Sclerotherapy
Ligation
Initiate combination Rx
TIPS/Shunt Surgery
Further bleeding
Evolution of Varices
Cirrhosis with no varices
Small varices No hemorrhage
Level of Intervention
Management Recommendations
Repeat endoscopy in 2-3 years No specific therapy Small varices Repeat endoscopy in 1-2 years No specific therapy ? beta-blocker to prevent enlargement
Pre-primary prophylaxis
Primary prophylaxis
Medium/Large varices Non-selective beta-blockers EVL in those intolerant to drugs Endoscopic/pharmacologic therapy Antibiotics in all patients TIPS or shunt surgery as rescue therapy
Variceal hemorrhage
Beta-blockers + nitrates or EVL Beta-blockers + EVL ? TIPS or shunt surgery as rescue therapy
GASTRIC VARICES
Gastric Varices
10-15% of variceal bleeding episodes Limited data from controlled trials
GOV 1
IGV 1
IGV 2
Bleeding controlled?
NO YES
TIPS*
Gastric Varices
Pretreatment cyanoacrylate
Post-treatment cyanoacrylate
May be associated with chronic occult bleeding, anemia, and occasionally cause of acute UGI hemorrhage
SEVERE PORTAL HYPERTENSIVE GASTROPATHY MAY BE DIFFICULT TO DISTINGUISH FROM DIFFUSE GAVE
Severe Portal Hypertensive Gastropathy May be Difficult to Distinguish from Diffuse GAVE
Severe PHG
Diffuse GAVE
Diffuse GAVE
Radius (r)
Varix
Tension (T)
r T = tp x w
Groszmann, Gastroenterology 1984; 80:1611
Endoscopic Findings
Which is the best option? 1) Start atenolol 2) Start propranolol 3) Variceal band ligation 4) Propranol and isosorbide mononitrate 5) Band ligation and beta blockers
Bleeding controlled with band ligation, antibiotics an octreotide No bleeding for 5 days Child score 10. MELD 15 MAP 90 mmHg Which is the best discharge regiment? 1) Beta blockers and nitrates 2) Serial ligation alone 3) Ligation and beta blockers 4) TIPS 5) Portacaval shunt