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Hepatic Encephalopathy
Walter M. Kim, MD, PhD
Jyoti Ramakrishna, MD
image BASICS
  • Reversible altered mental and neuromotor functioning occurring in association with acute or chronic liver disease and/or portal systemic shunting
  • The prominent features are confusion, impaired arousability, and a “flapping tremor” (asterixis).
  • System(s) affected: gastrointestinal; nervous
  • Synonym(s): portosystemic encephalopathy; hepatic coma; liver coma
Predominant sex: male = female (reflecting underlying liver disease)
  • Overt HE occurs in 30-45% of cirrhotic patients.
  • Occurs in all cases of fulminant hepatic failure
  • Present in nearly 1/2 of patients who require liver transplantation.
  • Parallels the age predominance of fulminant liver disease: peaks in the 40s; cirrhosis peaks in the late 50s; may occur at any age
  • There is no defined pathophysiology for the development of HE. Three classifications have been proposed (1):
    • Type A: resulting from acute liver failure
    • Type B: resulting from portosystemic bypass or shunting
    • Type C: resulting from cirrhosis
  • Several metabolic factors have been implicated in HE based on the failure of the liver to detoxify agents noxious to the CNS (e.g., ammonia, mercaptan, fatty acids).
  • Increased aromatic and reduced branched chain amino acids in blood may act as false neurotransmitters, possibly interacting with the &ggr;-aminobutyric acid (GABA) receptor and causing clinical symptoms.
  • HE presents most commonly in long-standing cirrhosis with spontaneous shunting of intestinal blood through collateral vessels or surgically constructed portacaval shunts.
  • Transjugular intrahepatic portosystemic shunt (TIPS), a widely used radiologically inserted shunt to lower portal pressure, is associated with HE in some cases.
  • Asterixis is the inability to maintain a particular posture due to metabolic encephalopathy. Abnormal diencephalic function leads to the characteristic liver flap noted when the arms and wrists are held in extension. Asterixis is also present in patients with uremia, barbiturate toxicity, and some cases of pulmonary disease. As such, asterixis is not pathognomonic for HE.
  • Unknown
  • Conditions such as cystic fibrosis, &agr;-1-antitrypsin deficiency, and Wilson disease can contribute to HE.
In patients with underlying liver disease, precipitating factors include the following:
  • Infection (overt or occult, including spontaneous bacterial peritonitis)
  • GI hemorrhage
  • Use of sedative or opiate drugs.
  • Fluid or electrolyte disturbance (Na+, K+, Mg2+, or other electrolyte depletion)
  • TIPS
  • Constipation
  • Recognize early signs and seek prompt treatment.
  • Avoid nonessential medications, particularly opiates, benzodiazepines, and sedatives.
  • May occur as a complication of acute fatty liver of pregnancy
  • Occurs rarely in patients with a portacaval shunt but normal liver function
  • Age 10 to 60 years
    • Prominent signs of underlying liver disease (50%); jaundice most common, ascites second most common
    • GI hemorrhage with hematemesis or melena (20%)
    • Systemic infection, urinary tract infection, or pulmonary infection (20%)
    • Five grades (West Haven classification) of confusion and degree of obtundation (1):
      • Minimal: psychometric or neuropsychological alterations without mental status changes
      • Grade I: lack of awareness, anxiety, shortened attention span, impairment of arithmetic, altered sleep rhythm
      • Grade II: asterixis, lethargy, disorientation to time, personality change, inappropriate behavior
      • Grade III: somnolence, confusion, gross disorientation, bizarre behavior
      • Grade IV: coma
  • Age >60 years
    • Signs of underlying liver disease diminish (25%)
    • Confusion more prominent
    • Precipitating GI hemorrhage or infection is less often identified.
    • Progression is slower.
  • Age <10 years
    • Signs of underlying liver disease prominent; usually fulminant hepatic failure or advanced cirrhosis
    • Progression is very rapid, often 6 to 12 hours.
    • Wilson disease can imitate HE.
  • Vital signs:
    • Bradycardia
    • Increased blood pressure suggestive of increased intracranial pressure
  • Jaundice, ascites, and other correlates of liver disease
  • CNS exam pertaining to stage of HE: Assess short-term memory and presence of asterixis (“liver flap”—a flapping of the wrist when arms are held in extension with the wrist fully extended)
  • Metabolic encephalopathy related to anoxia, hypoglycemia, hypokalemia, hypo- or hypercalcemia, or uremia
  • Head trauma, concussion, subdural hematoma
  • Transient ischemic attack (TIA), ischemic stroke
  • Alcohol intoxication
  • Alcohol withdrawal syndrome
  • Confusion due to medications or illicit drugs
  • Meningitis, encephalitis
  • Wilson disease
  • Reye syndrome
  • Clinical findings yield diagnosis in 80% of cases.
  • Response to treatment often confirms the diagnosis.
  • EEG: symmetric slowing of basic (&agr;) rhythm (common with other metabolic encephalopathies-limited utility) (2)
  • Visual evoked potential: specific in grades II to IV
  • Number connection test, line drawing test, clicker flicker frequency (CFF) test, continuous reaction time (CRT) test, inhibitory control test (ICT), and other psychometric tests may be used to assess for minimal HE.
Initial Tests (lab, imaging)
  • Liver tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum albumin to evaluate severity of liver disease
  • Prothrombin time (PT) and international normalized ratio (INR) are elevated in liver failure due to impaired hepatic synthesis of coagulation factors.
  • Serum ammonia level is elevated in 90% of patients with HE; levels affected by infusion of amino acid solutions, opiate administration (constipation), uremia, tissue breakdown, burns, trauma, or infection
  • CBC-anemia and leukocytosis
  • Complete metabolic profile to identify hypokalemia, hyperbilirubinemia, altered calcium concentration, hypomagnesemia, and hypoglycemia
  • BUN: Creatinine >20 suggests dehydration or GI bleeding.
  • Blood, urine, and ascitic fluid cultures to identify infection, if clinically indicated
  • Consider arterial blood gas measurement.
  • Toxicology screen for illicit drugs.
  • Head CT to identify frontal cortical atrophy and mild general edema.
  • MRI may demonstrate increased T1 signal in globus pallidus.
Tests Interpretation
  • Brain edema in 100% of fatal cases
  • Glial hypertrophy in chronic encephalopathy
  • Identify and treat precipitating causes: GI bleeding, infection, electrolyte imbalance. Eliminate offending medications.
  • Grade I or higher: Ensure adequate fluid intake and at least 1,000 kcal (4.19 MJ) daily; avoid hypoglycemia.
  • Administer initial enema to all patients who don't have diarrhea.
  • If clumsiness and poor judgment are prominent, avoid falls and other accidents.
  • Avoid sedatives, opiates, diphenoxylate, and atropine.

First Line
  • Lactulose syrup (nonabsorbable disaccharide whose laxative action decreases colonic transit time while bacterial digestion acidifies the colon, thereby promoting excretion of ammonia): 30 to 45 mL PO up to every hour for goal of 3 to 6 bowel movements per day. Diminish to 15 to 30 mL BID when ≥3 bowel movements occur daily (3)[A].
  • Lactulose enema (for patients who cannot tolerate oral lactulose or have suspected ileus): 300 mL lactulose plus 700 mL tap water, retained for 1 hour
  • If worsening occurs acutely or there is no improvement in 2 days, add antibiotics:
    • Rifaximin: 400 mg PO TID or 550 mg PO BID (nonabsorbable antibiotic); highly effective in reversing minimal HE and preventing HE recurrence (4)[B]
  • Contraindications:
    • Total ileus
    • Hypersensitivity reaction
  • Precautions:
    • Hypokalemia
    • Electrolyte imbalance
    • Renal failure
Second Line
  • Neomycin: 1 to 2 g/day PO divided q6-8h, if renal function is within normal limits
  • Polyethylene glycol has recently been studied for acute hepatic encephalopathy and appears to be effective.
  • Metronidazole is an alternative antibiotic.
  • Flumazenil may be of benefit in select patients.
Refer early to a transplant center.
  • Artificial liver perfusion devices are useful in fulminant hepatic failure as a bridge until a donor liver is available for transplantation.
  • Consider liver transplant in grade II to IV patients.
Probiotics and prebiotics have been associated with improvement of HE through modulation of gut flora (5)[C].
Admission Criteria/Initial Stabilization
  • Monitor clinical status closely in grades I and II when diagnosis is clear, and watch for progression.
  • Evaluate patients with grade II to IV HE in fulminant hepatic failure for liver transplantation
Activity as tolerated once resolved
Patient Monitoring
  • Trail-making test (a pencil/paper connect-the-dots according to numbers) can help monitor HE patients. Period evaluation helps determine how much maintenance treatment is needed and what diet is appropriate. The test should be run daily at first and then at each visit when changes in drugs and diet are made.
  • Patients with changed findings on the trail-making test should be seen twice weekly.
  • Stable patients should be seen monthly.
  • Number connection test or line drawing test at each office visit also help with patient monitoring.
  • In cirrhosis, evaluate for transplantation and periodically monitor Model for End-stage Liver Disease (MELD) score.
  • Integrate with underlying disease.
  • Regular protein diet (1.2 to 1.5 g/kg/day) (6)[C]; vegetable protein diets are better tolerated than animal protein diets in patients with advanced cirrhosis; special IV/enteral formulations with increased branched chain amino acids are available.
  • Grades III to IV patients need parenteral nutrition or jejunal feeds.
American Association for the Study of Liver Diseases, 1729 King Street, Suite 200, Alexandria, VA 22314; 703-299-9766; www.aasld.org
  • With adequate aggressive treatment, HE resolves without residue or recurrence
  • Chronic disease
    • Coma returns.
    • With each recurrence, HE is more difficult to treat—the degree of improvement with treatment is less and the mortality rate approaches 80%.
1. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735.
2. Saxena N, Bhatia M, Joshi YK, et al. Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy. Liver. 2002;22(3):190-197.
3. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004; 328(7447):1046.
4. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081.
5. Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology. 2004; 39(5):1441-1449.
6. Córdoba J, López-Hellín J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004; 41(1):38-43.
Additional Reading
  • Agrawal A, Sharma BC, Sharma P, et al. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107(7):1043-1050.
  • Blei AT, Córdoba J; Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. Am J Gastroenterol. 2001;96(7):1968-1976.
  • Ellul MA, Gholkar SA, Cross TJ. Hepatic encephalopathy due to liver cirrhosis. BMJ. 2015;351:h4187.
  • McGee RG, Bakens A, Wiley K, et al. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2011;(11):CD008716.
  • Ong JP, Aggarwal A, Krieger D, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2003;114(3):188-193.
  • Quero Guillén JC, Herrerías Gutiérrez JM. Diagnostic methods in hepatic encephalopathy. Clin Chim Acta. 2006;365(1-2):1-8.
  • Sidhu SS, Goyal O, Mishra BP, et al. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol. 2011;106(2):307-316.
See Also
Algorithm: Delirium
  • K72.90 Hepatic failure, unspecified without coma
  • K72.91 Hepatic failure, unspecified with coma
Clinical Pearls
  • HE includes a spectrum of neuropsychiatric findings that occur in patients with significant alterations in hepatic function.
  • Lactulose is a cornerstone of therapy for HE.
  • Asterixis (“liver flap”) is the classic physical finding associated with HE.