Management of esophageal varices

INTRODUCTION ㅡ Esophageal varices are dilated collateral blood vessels that develop as a complication of portal hypertension, usually in the setting of cirrhosis. They can be seen on endoscopy. The major cause of cirrhosis is alcoholic liver disease. Hepatitis B virus infection and hepatitis C virus infection are the major causes of cirrhosis. Once cirrhosis has developed, increasing hepatic vein pressure gradient and deteriorating liver function may result in the formation of oesophageal varices.

          Rupture of oesophageal varices can cause life-threatening bleeding. The most important predictor of variceal hemorrhage is the size of varices, with the highest risk of first hemorrhage occurring in patients with large varices (15% per year). Other important predictors of hemorrhage are decompensated cirrhosis (Child-Pugh B/C) and the endoscopic finding of red wale marks.

RISK FACTORS

PORTAL HYPERTENSION ㅡ Portal hypertension leading to the formation of porto-systemic collaterals is the underlying cause of oesophageal varices. Although a small proportion of patients may have varices when the hepatic venous pressure gradient (HVPG) is > 5 mmHg and < 10 mmHg (mild portal hypertension), varices mostly develop when the HVPG is > 10 mmHg. HVPG ≥ 10 mmHg has been defined as the threshold for clinically significant portal hypertension. In the majority of patients this is due to chronic liver disease (of any etiology) resulting in cirrhosis. In Western countries alcoholic liver disease is the most common cause of cirrhosis. However, non-alcoholic fatty liver disease is an increasingly common cause of cirrhosis, and chronic viral hepatitis (B and C) is also relevant. Direct antiviral agents are expected to reduce the burden of chronic hepatitis C.

AUTOIMMUNE LIVER DISEASE ㅡ Autoimmune liver disease, hemochromatosis, and Wilson's disease may also result in cirrhosis. Less commonly, other recognised causes of portal hypertension, such as Budd-Chiari syndrome, myeloproliferative disorders, and sarcoidosis, may also lead to oesophageal variceal development.

LARGE VARICES ㅡ Multiple studies have shown that large varices are more likely to bleed than small varices. Variceal size is the most important factor for prediction of variceal bleeding, with the greatest risk at 15% per year for large varices. Endoscopic red wale marks (defined as longitudinal dilated venules resembling whip marks on the variceal surface) have been shown to predict increased risk of variceal bleeding.

CHILD-PUGH CLASS ㅡ Decompensated cirrhosis (Child-Pugh class B/C) has been shown to predict increased risk of variceal bleeding.

ETIOLOGY

Portal hypertension causes the formation of portacaval anastomoses which decompress the portal circulation. This leads to a congested submucosal venous plexus with tortuous dilated veins in the distal esophagus. Variceal rupture results in hemorrhage.

          Pathophysiology of portal hypertension. Increased resistance to portal flow at the level of hepatic sinusoids caused by intrahepatic vasoconstriction due to decreased nitric oxide production and increased release of endothelin-1 (ET-1), angiotensinogen, and eicosanoids and sinusoidal remodeling causes disruption of blood flow. Increased portal flow caused by hyperdynamic circulation due to splanchnic arterial vasodilation through mediators such as nitric oxide, prostacyclin, and TNF.

Causes of portal hypertension. Prehepatic, extrahepatic portal vein obstruction (EHPVO) or massive splenomegaly with increased splenic vein blood flow. Posthepatic, severe right-sided heart failure, constrictive pericarditis, and hepatic vein obstruction (Budd-Chiari syndrome). Intrahepatic, cirrhosis (accounts for most cases of portal hypertension). Less frequent causes are schistosomiasis, massive fatty change, diseases affecting portal microcirculation as nodular regenerative hyperplasia, and diffuse fibrosing granulomatous disease as sarcoidosis.

GENERAL PREVENTION

Prevent underlying causes: Prevent alcohol abuse, administer hepatitis B vaccine, needle hygiene, IV drug use (needle exchange programs to reduce risk of hepatitis C); specific screening and therapy for hepatitis B and C, hemochromatosis.

LAB INVESTIGATIONS

• Anemia: Hemoglobin may be normal in active bleeding; may require 6 to 24 hours to equilibrate; other causes of anemia are common in cirrhotics.
• Thrombocytopenia: most sensitive and specific parameter, correlates with portal hypertension, large esophageal varices.
• Abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin; prolonged PT, low albumin suggest cirrhosis.
• BUN, creatinine (BUN often elevated in GI bleed).
• Sodium level: may drop in patients treated with terlipressin.
• Esophagogastroduodenoscopy 
• Can identify actively bleeding varices as well as large varices and stigmata of recent bleeding.
• Can be used to treat bleeding with esophageal band ligation (preferred to sclerotherapy); prevent rebleeding; detect gastric varices, portal hypertensive gastropathy; diagnose alternative bleeding sites.
• Can identify and treat nonbleeding varices (protruding submucosal veins in the distal third of the esophagus).

MANAGEMENT (COMPENSATED)

IN HCV COMPENSATED CIRRHOSIS ㅡ If liver stiffness < 20 kPa and platelet count > 150,000, could forego endoscopy (low likelihood of medium/large varices). If NO varices, repeat endoscopy in 3 years if etiology removed OR in 2 years if ongoing injury OR at the time of decompensation. If small varices (varices with red signs), nonselective beta-blockers (propranolol 20-160 mg BID or nadolol 20-160 mg QD; titrate to maximum tolerable dosage or a heart rate of 55-60 beats/min) or carvedilol, maximum 12.5 mg/day.

          If varices without red signs, nonselective beta-blockers optional. If NO beta-blockers given, repeat endoscopy in 2 years if etiology removed OR in 1 year if ongoing injury OR at the time of decompensation.

Medium/Large varices, Prevention of first variceal hemorrhage, use nonselective beta-blockers (propranolol, nadolol) or Carvedilol. No need to repeat endoscopy. OR endoscopic variceal ligation (choice depends on patient characteristics and preferences, local resources). Ligate every 1-2 weeks until variceal obliteration. First surveillance endoscopy 1-3 months after obliteration, then every 6-12 months indefinitely.

MANAGEMENT (DECOMPENSATED)

Patient has developed ascites, variceal hemorrhage, or encephalopathy. HCC surveillance (every 6 months), do ultrasound and AFP. If NO varices, repeat endoscopy every year. If small varices, in a CTP class C patient OR varices with red signs, use nonselective beta-blockers Propranolol (20-160 mg BID) or nadolol (20-160 mg QD) but not carvedilol. In patients with ascites cap dose to 80 mg (BID for propranolol, QD for nadolol). Titrate to maximum tolerable dosage or a heart rate of 55-60 beats/min. OR endoscopic variceal ligation. Ligate every 1-2 weeks until variceal obliteration. First surveillance endoscopy 1-3 months after obliteration, then every 6-12 months. In CTP class B patient, without red signs, nonselective beta-blockers optional, doses as above. If no beta-blockers given, repeat endoscopy in 1 year. If medium/Large varices, nonselective beta-blockers (propranolol, nadolol) but not carvedilol. OR endoscopic variceal ligation.

          Variceal hemorrhage (if no history, follow guidelines for varices surveillance in compensated cirrhosis), establish Child-Pugh score on admission. Cautious transfusion of fluids and PRBC with a goal hemoglobin of ~7-8 g/dL. Antibiotic prophylaxis (3-7 days) with ceftriaxone 1 g/day (IV). Pharmacologic therapy initiated as soon as diagnosis is suspected with octreotide 50 mcg IV bolus followed by continuous infusion 50 mcg/hour (3-5 days). Endoscopy within 12 hours of admission with ligation performed if variceal source is confirmed. In patients with CPS of 10-13, placement of TIPS must be considered within 24-48 hours of endoscopy (early TIPS). Rescue TIPS considered in patients with bleeding esophageal varices who are not candidates for early TIPS and who have failed pharmacologic + endoscopic therapy or in patients with bleeding gastric fundal varices who have failed one endoscopic therapy (cyanoacrylate).

REFERENCES

• Boregowda, U., Umapathy, C., Halim, N., Desai, M., Nanjappa, A., Arekapudi, S., Theethira, T., Wong, H., Roytman, M. and Saligram, S. (2019). Update on the management of gastrointestinal varices. World Journal of Gastrointestinal Pharmacology and Therapeutics, [online] 10(1), pp.1–21. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347650

  Wilkins, T., Naiman Khan, Akash Nabh and Schade, R.R. (2012). Diagnosis and Management of Upper Gastrointestinal Bleeding. American Family Physician, [online] 85(5), pp.469–476. Available at: https://www.aafp.org/afp/2012/0301/p469.html