BASICSMaximos Attia, MD, FAAFP • Marcelle Meseeha, MD
BASICS
DESCRIPTION
• Dilated submucosal distal esophageal veins connecting the portal and systemic circulations
• Results from portal hypertension (most commonly a result of cirrhosis), resistance to portal blood flow, and increased portal venous blood inflow
• Variceal rupture: most common fatal complication of cirrhosis; severity of liver disease correlates with presence of varices and risk of bleeding.
EPIDEMIOLOGY
Incidence
• At diagnosis, 30% of cirrhotic patients have varices; increases to 90% at 10 years
• 1-year rate of first variceal bleeding is 5% for small varices, 15% for large varices.
Pediatric Considerations
Portal hypertension is common in chronic liver disease (CLD) in children. No clear guidelines for screening; pharmacologic or endoscopic treatment are equivalent.
Prevalence
• 50% of patients with esophageal varices will experience bleeding at some point.
• Variceal bleeding: 10–20% mortality in the 6 weeks following the episode
• Gender: male > female
ETIOLOGY AND PATHOPHYSIOLOGY
• Portal hypertension causes portacaval anastomosis to develop to decompress 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
Sinusoidal remodeling causing 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.
Genetics
Cirrhosis is rarely hereditary.
RISK FACTORS
• Cirrhosis due to any cause
• In cirrhotic patients, thrombocytopenia and splenomegaly are independent predictors of esophageal varices.
• Noncirrhotic portal hypertension
• Increased bleeding risk for known varices is associated with varix size; endoscopic signs (red wale marks, cherry-red spots); vessel wall thickness; abrupt increase in variceal pressure (i.e., Valsalva maneuver)
• MELD/Child-Pugh score; presence of portal vein thrombosis; high hepatic venous pressure gradient (HVPG)
GENERAL PREVENTION
• Prevent underlying causes: alcoholism, hepatitis B vaccine, needle hygiene, detox in IV drug use (IVDU) to avoid HCV exposure; specific screening and therapy for hepatitis B and C, hemochromatosis
COMMONLY ASSOCIATED CONDITIONS
• Portal hypertensive gastropathy; varices in stomach, duodenum, colon, rectum (causes massive bleeding, unlike hemorrhoids); rarely at umbilicus (caput medusa) or ostomy sites
• Isolated gastric varices can occur due to splenic vein thrombosis/stenosis from hypercoagulability/contiguous inflammation (most commonly, chronic pancreatitis).
• Other complications of cirrhosis: hepatic encephalopathy, ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, hepatocellular carcinoma
DIAGNOSIS
• First indication of varices is often the presence of a GI bleeding episode: hematemesis, hematochezia, and/or melena.
• Occult bleeding (anemia): uncommon
HISTORY
• Underlying history of cirrhosis/liver disease. Variceal bleed can be initial presentation of previously undiagnosed cirrhosis.
• Alcoholism, exposure to blood-borne viruses
• Hematemesis, melena, or hematochezia
• Rapid upper GI bleed can present as rectal bleeding.
PHYSICAL EXAM
• Assess hemodynamic stability: hypotension, tachycardia (active bleeding).
• Abdominal exam—liver palpation/percussion (often small and firm with cirrhosis)
• Splenomegaly, ascites (shifting dullness; puddle splash)
• Visible abdominal periumbilical collateral circulation (caput medusae)
• Peripheral stigmata of alcohol abuse: spider angiomata on chest/back, palmar erythema, testicular atrophy, gynecomastia
• Anal varices
• Hepatic encephalopathy; asterixis
• Blood on rectal exam
DIFFERENTIAL DIAGNOSIS
• Upper GI bleeding: 10–30% are due to varices.
– In patients with known varices, as many as 50% bleed from nonvariceal sources.
– Peptic ulcer; gastritis
– Gastric/esophageal malignancy
– Congestive gastropathy of portal hypertension
– Arteriovenous malformation
– Mallory-Weiss tears
– Aortoenteric fistula
– Hemoptysis; nosebleed
• Lower GI bleeding
– Rectal varices; hemorrhoids
– Colonic neoplasia
– Diverticulosis/arteriovenous malformation
– Rapidly bleeding upper GI site
• Continued/recurrent bleeding risk: actively bleeding/large varix, high Childs-Pugh severity score, infection, renal failure
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
• 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 lab 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 (1)[A]
• Esophagogastroduodenoscopy (1)[A]
– 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)
Diagnostic Procedures/Other
• Transient elastography (TE) for identifying CLD patients at risk of developing clinically significant portal hypertension (CSPH) (1)[A]
• Hepatic vein pressure gradient (HVPG) >10 mm Hg: gold standard to diagnose CSPH (normal: 1 to 5 mm Hg) (1)[A]
• HVPG response of ≥10% or to ≤12 mm Hg to intravenous propranolol may identify responders to nonselective β-blocker (NSBB) and is linked to a significant decrease in risk of variceal bleeding (1,2)[A].
• Video capsule endoscopy screening may be an alternative to traditional endoscopy.
• Doppler sonography (second line): demonstrates patency, diameter, and flow in portal and splenic veins, and collaterals; sensitive for gastric varices; documents patency after ligation or transjugular intrahepatic portosystemic shunt (TIPS)
• CT- or MRI-angiography (second line, not routine): demonstrates large vascular channels in abdomen, mediastinum; demonstrates patency of intrahepatic portal and splenic vein
– Venous-phase celiac arteriography: demonstrates portal vein and collaterals; diagnoses hepatic vein occlusion
– Portal pressure measurement using retrograde catheter in hepatic vein
GENERAL MEASURES
• Treat underlying cirrhotic comorbidities.
• Variceal bleeding is often complicated by hepatic encephalopathy and infection.
• Active bleeding (3)[A]
– IV access, hemodynamic resuscitation
– Type and crossmatch packed RBCs. Overtransfusion increases portal pressure and increases rebleeding risk.
– Treat coagulopathy as necessary. Fresh frozen plasma may increase blood volume and increase rebleeding risk.
– Avoid sedation, monitor mental status, avoid nephrotoxic drugs and β-blockers acutely.
– IV octreotide to lower portal venous pressure as adjuvant to endoscopic management. IV bolus of 50 μg followed by drip of 50 μg/hr.
– Terlipressin (alternative): 2 mg q4h IV for 24 to 48 hours, then 1 mg q4h
– Erythromycin 250 mg IV 30 to 120 minutes before endoscopy (1)[A]
– Urgent upper GI endoscopy for diagnosis and treatment
Variceal band ligation preferred to sclerotherapy for bleeding varices. Also for nonbleeding medium-to-large varices to decrease bleeding risk
Ligation: lower rates of rebleeding, fewer complications, more rapid cessation of bleeding, higher rate of variceal eradication.
• Repeat ligation/sclerosant for rebleeding.
• If endoscopic treatment fails, consider self-expanding esophageal metal stents or per oral placement of Sengstaken-Blakemore-type tube up to 24 hours to stabilize patient for TIPS (1)[C].
• As many as 2/3 of patients with variceal bleeding develop an infection, most commonly spontaneous bacterial peritonitis, UTI, or pneumonia. Antibiotic prophylaxis with oral norfloxacin 400 mg or IV ceftriaxone 1 g q24h for up to a week.
• In active bleeding, avoid β-blockers, which decrease BP and blunt the physiologic increase in heart rate during acute hemorrhage.
• Prevent recurrence of acute bleeding
– Vasoconstrictors: terlipressin, octreotide (reduce portal pressure)
– Endoscopic band ligation (EBL): if bleeding recurs/portal pressure measurement shows portal pressure remains >12 mm Hg
– TIPS: Second-line therapy if above methods fail; TIPS decreases portal pressure by creating communication between hepatic vein and an intrahepatic portal vein branch.
MEDICATION
Primary prevention of variceal bleeding (4)[A]
• Endoscopy: assesses variceal size, presence of red wale sign (longitudinal variceal reddish streak that suggests either a recent bleed or a pending bleed) to determine risk stratification
– Endoscopy every 2 to 3 years if cirrhosis but no varices; every 1 to 2 years if small varices and not receiving β-blockers (2)[A]
First Line
• (Not actively bleeding). NSBB reduce portal pressure and decrease risk of first bleed from 25% to 15% in primary prophylaxis. Used in cirrhosis with small varices and increased hemorrhage risk as well as cirrhosis + medium-to-large varices (2,4)[A]
• Carvedilol: 6.25 mg daily (2)[A] is more effective than NSBB in dropping HVPG (1)[A].
– Propranolol: 20 mg BID increase until heart rate decreased by 25% from baseline
– Nadolol 80 mg daily; increase as above
– Contraindications: severe asthma
• Chronic prevention of rebleeding (secondary prevention): NSBBs and EBL reduce rate of rebleeding to a similar extent, but β-blockers reduce mortality, whereas ligation does not (5)[A].
Second Line
Obliterate varices with esophageal banding for not tolerant of medication prophylaxis.
• During ligation: proton pump inhibitors, such as lansoprazole 30 mg/day, until varices obliterated
• Management of Budd-Chiari syndrome: anticoagulation, angioplasty/thrombolysis, TIPS, and orthotopic liver transplantation (1)[C]
• Management of extrahepatic portal vein obstruction: anticoagulation (1)[B]; mesenteric-left portal vein bypass (Meso-Rex procedure) (1)[C]
ISSUES FOR REFERRAL
Refer for endoscopy, liver transplant, and interventional radiology for TIPS.
ADDITIONAL THERAPIES
Pneumococcal and hepatitis A/B (HAV/HBV) vaccine
SURGERY/OTHER PROCEDURES
• Esophageal transection: in rare cases of uncontrollable, exsanguinating bleeding
• Liver transplantation
ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS
• Inpatient to stabilize acute bleeding and hemodynamic status, therapeutic endoscopy. ICU is typically the most appropriate initial setting.
• Discharge criteria: bleeding cessation; hemodynamic stability and appropriate plan for treating comorbidities
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
• Close monitoring of vital signs.
• Endoscopic variceal ligation, every 1 to 4 weeks, until varices eradicated
• If TIPS, repeat endoscopy to assess rebleeding.
• Endoscopic screening in patients with known cirrhosis every 2 to 3 years; yearly in patients with decompensated cirrhosis (1)[C]
• Patients with a liver stiffness <20 kPa and with a platelets >150,000 can avoid endoscopic screening (1)[A] and may follow up by annual TE and platelet count (1)[C].
PATIENT EDUCATION
National Digestive Information Clearinghouse (http://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/Pages/default.aspx) or American Liver Foundation (http://www.liverfoundation.org/)
PROGNOSIS
• Depends on underlying comorbidities
• In cirrhosis, 1-year survival is 50% for those surviving 2 weeks following a variceal bleed.
• In-hospital mortality remains high related to severity of underlying cirrhosis, ranging from 0% in Child A to 32% in Child C disease (3).
• Prognosis in noncirrhotic portal fibrosis is better than for cirrhotics.
COMPLICATIONS
• Formation of gastric varices after eradication of esophageal varices
• Esophageal varices can recur.
• Hepatic encephalopathy, renal dysfunction, hepatorenal syndrome
• Infections after banding/ligation of varices
REFERENCES
1. de Franchis R; and the Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743.
2. Tripathi D, Stanley AJ, Hayes PC, et al. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;64(11):1680.
3. Herrera JL. Management of acute variceal bleeding. Clin Liver Dis. 2014;18(2):347–357.
4. Simonetto DA, Shah VH, Kamath PS. Primary prophylaxis of variceal bleeding. Clin Liver Dis. 2014;18(2):335–345.
5. Albillos A, Tejedor M. Secondary prophylaxis for esophageal variceal bleeding. Clin Liver Dis. 2014;18(2):359–370.
ADDITIONAL READING
• Kochhar GS, Navaneethan U, Hartman J, et al. Comparative study of endoscopy vs. transjugular intrahepatic portosystemic shunt in management of gastric variceal bleeding. Gastroenterol Rep (Oxf). 2015;3(1):75–82.
• Zanetto A, Senzolo M, Ferrarese A, et al. Assessment of bleeding risk in patients with cirrhosis. Curr Hepatol Rep. 2015;14(1):9–18.
SEE ALSO
Cirrhosis of the Liver; Portal Hypertension
CODES
ICD10
• I85.00 Esophageal varices without bleeding
• I85.01 Esophageal varices with bleeding
• I85.10 Secondary esophageal varices without bleeding
CLINICAL PEARLS
• Thrombocytopenia is the most sensitive marker of increased portal pressure and large esophageal varices.
• In acute bleeding, avoid β-blockers.
• In acute bleeding, overtransfusion can elevate portal pressure and increase bleeding risk.
TREATMENT