Hepatitis C Information Central

Outlook Not Bright for Patients With Bleeding Oesophageal Varices

Introduction

• accurate diagnosis

Treatment to arrest haemorrhage often involves vasoactive drug therapy to reduce portal hypertension and stop bleeding (see Differential features table ) in combination with an endoscopic procedure (see table 1). However, the risk of rebleeding after the index bleed is high and eradication of the varices in conjunction with long-term propranolol therapy to reduce portal hypertension is recommended. In addition, propranolol prophylaxis may be considered in patients with oesophageal varices who are at high risk of bleeding as propranolol appears to be well tolerated, effective and inexpensive in the prevention of variceal haemorrhage.

Varices a Complication of Cirrhosis...

In patients with cirrhosis, 30 and 60% of those with compensated and decompensated liver disease, respectively, will have varices. ^[14] Once varices occur, they tend to progressively increase in size, and the risk of bleeding has been shown to be related to varix size and appearance as well as the severity of the underlying liver disease. ^[2] About 30% of patients with varices will experience a bleed. ^[14]

...And a Leading Cause of Death

Variceal haemorrhage remains a leading cause of death in patients with liver cirrhosis, with mortality from the index bleed being reported as about 50%. ^[2,3] Without treatment, recurrent haemorrhage occurs in almost all patients who survive the initial bleeding episode, often within a year. In order to assess the risk of haemorrhage, an index combining Child's classification (indicating severity of liver disease), size of varices and the presence/absence of red wale markings seen on endoscopic examination was developed. Patients were then stratified into groups with a risk of bleeding ranging from 6 to 63%. ^[15]

Portal hypertension is a crucial factor affecting the risk of recurrent haemorrhage. It has been observed that patients with variceal bleeding have a hepatic vein pressure gradient of >12mm Hg. ^[16]

Stabilise Patient and Confirm Diagnosis

Haemodynamic stability is generally achieved using packed red blood cells to maintain the haematocrit at about 30% and fresh frozen plasma to manage coagulopathy. ^[3]

Drug Therapy to Reduce Portal Pressure

Immediately portal hypertensive haemorrhage is suspected, drug treatment to lower portal pressure should be commenced (see Differential features table ). ^[2] Nitroglycerin (glyceryl trinitrate) is often added to vasopressin or terlipressin therapy, because nitrates are powerful venodilators with a lesser arterial dilator effect. In addition, these agents further reduce portal pressure by venodilation. ^[2]

Endoscopy Essential

Once the patient is haemodynamically stable , urgent endoscopy should be performed. Endoscopy enables: ^[2]

• an accurate diagnosis to be made by excluding other causes of upper gastrointestinal tract blood loss

Stop the Bleeding

In clinical practice, most patients receive emergency sclerotherapy or band ligation, usually in conjunction with drug therapy (see Differential features table ), to control the haemorrhage. Vasoactive drugs contribute to control of bleeding and decrease portal pressure.

Sclerotherapy Successful for Many

The success rate of emergency sclerotherapy in stopping haemorrhage is about 90%. ^[2,3] The rate of early rebleeding may also be reduced following sclerotherapy. ^[2]

In sclerotherapy, a sclerosant is injected into the varix under direct vision. Injection techniques can be either intravariceal or paravariceal, or a combination of the two. Alternatively, adhesive agents can be used; however, as these agents harden quickly, they must be used quickly. Although, rebleeding does occur, it appears to be less common following sclerotherapy using adhesives than sclerosants. ^[2] Combined therapy with vasoactive drugs appears to be more effective than sclerotherapy alone in controlling haemorrhage. In addition, there appears to be a lower incidence of early rebleeding and reduced transfusion requirements using combined therapy. ^[2]

Band Ligation Better for Spurting Varices

Emergency band ligation is at least as effective as injection sclerotherapy in the control of bleeding from oozing varices and more effective in arresting haemorrhage from spurting varices. ^[17] However, endoscopic ligation may require more technical skill and the procedure may take longer than sclerotherapy. ^[3]

Prevent Further Bleeding

Obliterate the Varices

Eradication of varices can be achieved either by repeated injection sclerotherapy or by band ligation. Although both methods are equally effective, band ligation requires fewer treatments, and is associated with fewer complications (oesophageal and gastric ulcers occur in about 70% of patients after sclerotherapy) and rebleeding episodes per treatment course than sclerotherapy. ^[2] However, these procedures do not reduce the portal pressure, and prophylactic drug therapy is usually initiated.

Lower Portal Pressure

Propranolol is the agent most frequently used to decrease portal pressure and prevent further bleeds in patients with oesophageal varices. ^[2,3] Propranolol acts by: ^[2]

• decreasing cardiac output and hence decreasing portal venous and hepatic arterial blood flow (a beta1-antagonist effect)

The dosage of propranolol is adjusted until the heart rate is reduced by 25%, but not less than 55 beats/min. ^[2] Ideally, response to propranolol should be assessed by measuring the hepatic venous pressure gradient. In patients with a satisfactory reduction in hepatic venous pressure gradient with propranolol, there is a reduction in variceal bleeding episodes and a trend towards survival. ^[2]

In patients who cannot tolerate the adverse effects of propranolol, isosorbide dinitrate is a suitable alternative. ^[3] The dosage of isosorbide dinitrate should be titrated according to the change in blood pressure.

Shunts When Treatment Fails

Recurrent bleeding occurring after TIPS insertion is usually related to shunt insufficiency caused by thrombosis or stenosis of the stent. ^[2]

Because of the invasive nature of portacaval anastomosis and a high operative mortality rate of 5 to 15% in cirrhotic patients, this procedure is usually reserved for patients in whom other methods have failed to control the haemorrhage. ^[1]

Transplantation the Ideal?

The best survival rates in patients with oesophageal varices are achieved in those who receive a liver transplant (79% at 1 year and 71% at 5 years), with patients who are Child class C having the greatest survival advantage. ^[18]

Primary Prophylaxis for Those at Risk

Beta-Blocker therapy should be started if moderate- or large-sized varices are identified and the patient has no contraindications to treatment. ^[2] A meta-analysis of propranolol therapy showed that the incidence of first time variceal bleeding was reduced by 47%, deaths due to bleeding by 45% and overall mortality by 22%. ^[19]

table 1. Different types of procedure used in the treatment of bleeding oesophageal varices ^[1-3]

Feature	Endoscopic sclerotherapy	Endoscopic ligation of varices	Transjugular intrahepatic portosystemic shunt	Portacaval anastomosis
Abbreviation	EST	ELV	TIPS	PCA
Procedure	Thrombosis or necrosis of the varices is induced by injecting either a sclerosant (e.g. sodium tetradecyl-sulfate) or an adhesive [e.g. N-butyl-2-cyanoarylate (histoacryl)]	Thrombosis of the varices is caused by attachment of a tight rubber band around the varix and its surrounding mucosa	Placement of an expandable metal stent within the liver parenchyma to create a shunt between the portal and hepatic venous systems	Traditional surgical method of decompressing portal hypertension
Reduces portal hypertension?	No	No	Yes	Yes
Complications	Oesophageal strictures and ulcerations, pleural effusions and mediastinitis	Complications are those associated with the endoscopic procedure	Shunt insufficiency resulting in recurrent bleeds	Major surgical procedure with associated complications, including significant morbidity and mortality
	There may be a risk of stroke following adhesive injection sclerotherapy [4]		Encephalopathy (10-20% of patients a ) Transient worsening of liver function in [TM] 33% of patients Liver failure	Shunt occlusion and encephalopathy

Differential features

Feature	Vasopressin †	Terlipressin †	Somatostatin	Octreotide
Mechanism of action	Vasoconstrictor that reduces portal pressure by constricting the splanchnic bed and reducing inflow into the portal system	Similar to vasopressin as terilpressin is a prodrug of vasopressin with some intrinsic activity. However, as terlipressin is converted by a saturable enzyme system, this agent results in a controlled release of active vasopressin	Reduces splanchnic blood flow and has a modest effect on hepatic blood flow and wedged hepatic venous pressure with little effect on the systemic circulation	Similar effects to somatostatin
Route of administration	Intravenous infusion	Intravenous bolus	Intravenous infusion	Intravenous infusion
Dosage	20 units over 15 minutes, then 0.4 units/minute until bleeding has stopped for 12 hours	1-2mg every 4-6 hours for 48 hours	250 mg/hour for 5 days	50 mg/hour for 2-5 days
Adjunctive nitroglycerin (glyceryl trinitrate) a	Yes	Optional	No	No
Adverse effects	Myocardial, mesenteric and cutaneous ischaemia b	As for vasopressin, but vasoconstrictor effects are less than vasopressin		Occasionally causes altered liver function tests, hepatitis, pancreatitis and transient alopecia
Efficacy shown in clinical trials (control of haemorrhage; % of patients)	50% (meta-analysis) [6] 74% (vasopressin) vs 83% (vasopressin + nitrate) c[7]	77.7%c ( vs 41.9% with placebo) [8]	64% ( vs 41% with placebo) d[9]	84% ( vs 90% with sclerotherapy) [10] and 85% ( vs 82% with sclerotherapy) [11]

†	Vasopressin is not available in France and Spain; terlipressin is not available in Australia and Sweden.
a	A nitroglycerin patch 10mg is applied. Replace after 24 hours.
b	The incidence of adverse effects associated with vasopressin are reduced by the use of intravenous or transdermal nitrates.
c	A nitroglycerin patch was used in conjunction with the study drug.
d	An earlier study showed no benefit associated with somatostatin therapy; however, there was an unexpectedly high incidence of cessation of haemorrhage in the placebo group (83%). [12]

References

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5. British National Formulary. No. 376. London. The Pharmaceutical Press, 1999 Mar
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13. Hope RA, Longmore JM. Oxford handbook of clinical medicine. Oxford University Press, 1985: 440
14. D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995; 22 (1): 332-54
15. North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1988; 319: 983-9
16. Gross M, Zoller WG. Medical prophylaxis of haemorrhage from oesophageal varices in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 1997 Jun; 9: 603-12
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18. Millikan WJ Jr, Henderson JM, Galloway JR, et al. Surgical rescue for failures of cirrhotic sclerotherapy. Am J Surg 1990; 160: 117-21
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