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A. Definition and Symptoms navigator

  1. Fulminant Hepatitis implies Severe Hepatic Failure with Jaundice
  2. Hepatic Encephalopathy (HE)
    1. Fulminant (Acute) Hepatitis: HE within 2 weeks of jaundice
    2. Subfulminant Hepatitis: hepatic encephalopathy within 3 months of jaundice
  3. Absence of Pre-existing Liver Disease
  4. Hepatic Encephalopathy
    1. Neurological dysfunction due to severe liver insufficiency
    2. Affects consciousness, coordination, brain waves, etc.

B. Causes navigator

  1. Cirrhosis is most common cause overall, typically chronic progression
    1. In USA, cirrhosis due to alcoholism is most common
    2. Chronic hepatitis C virus > hepatitis B virus infections also contribute substantially
  2. Fulminant Liver Failure is most common acute cause
    1. In USA, acetaminophen overdose is responsible for about 10% of cases
    2. In United Kingdom, up to 50% of fulminant liver failure due to acetaminophen
    3. Hepatitis A virus, or superinfection of HBV with delta virus can causes acute failure
  3. Anything causing chronic hepatitis may eventually lead to HE

C. Pathophysiology [2]navigator

  1. A complete understanding is not yet available
  2. Multiple factors have been implicated
    1. Central GABA receptor activation (benzodiazepine receptor)
    2. Endogenous benzodiazepine effects most likely (reversed with flumazenil) [3]
    3. Ammonia (or other basic toxin) excess
    4. Failed Detoxification - due to bypassing portal system
    5. Presence of "false" neurotransmitters due to liver failure
    6. Accumulation of oxindole, a tryptophan metabolite; strongly sedative and hypotensive
    7. Overactivation of cerebral glutamate receptors
    8. Deposition of mangenese in cerebrum
  3. Factors which precipitate HE in chronic cirrhotic patients affect any of these mechanisms
  4. Causes of Ammonia Excess
    1. Increased dietary protein - questionable based on recent data [5]
    2. Gastrointestinal hemorrhage
    3. Infection - septic and/or bacterial peritonitis
    4. Blood transfusion
    5. Azotemia
  5. Increased Diffusion of Ammonia across Blood-Brain Barrier: alkalosis
  6. Reduced Liver Function
    1. Hypoxia - hepatic underperfusion, blood hypoxia, excessive paracentesis
    2. Diversion of Portal Blood Flow - portosystemic shunts (spontaneous, elective)
    3. Progressive Liver Damage - acetaminophen, liver hepatoma, alcoholism
  7. Other psychoactive drugs

D. Grading System for HE [1]navigator

GradeConsciousnessIntelectNeurologic SignsEEG Abnormalities
0normalnormalnonenone
1normalnormalon psychometric analysisnone
2abn sleep pattern restlessnessforgetful confusiontremor,apraxia,agraphia incoordinationtriphasic waves (5c/sec)
3somnolent, but arousabledisoreintedaggressive asterixis, dysarthria, ataxia, hypoactivitytriphasic waves (5c/sec)
4COMANONEDecerebrationDelta Activity

E. Evaluation and Diagnosis navigator
  1. Laboratory examination with history and physical should reveal cause of encephalopathy
  2. Multiple contributing factors may be present and add to level of encephalopathy
  3. Serum ammonia levels correlation moderately (r=0.5-0.6) with severity of encephalopathy [4]
  4. Rule out contributing metabolic causes
  5. Search for infection; all patients should have surveillence blood cultures
  6. Toxin screen (urine and blood) for drugs
  7. Neurologic examination to elucidate focal signs and symptoms
    1. Grade as above or using other systems
    2. Asterixis is classic sign, but only occurs with moderately severe HE

F. Treatment navigator

  1. Reduce Ammonia Production
    1. Restriction of dietary protein has not been beneficial in recent studies [5]
    2. Carbohydrate enemas
    3. Oral lactulose or lactitol (may use lactose in lactase deficiency)
    4. Lactulose and sorbitol of questionable benefit in recent studies [5]
    5. Oral antibiotics - metronidazole, neomycin
  2. Increase Ammonia Metabolism
    1. Ornithine aspartate supplementation
    2. Sodium benzoate
    3. Phenylacetate
    4. Zinc supplementation
  3. Flumazenil (Romazicon®) [3]
    1. Useful for temporary reversal of HE
    2. Only available parenterally
    3. Oral flumazenil may be useful for chronic treatment of severe HE
  4. Glucocorticoids may improve cirrhotic encephalopathy
  5. Correction of mangenese deposition in basal ganglia being evaluated
  6. Liver transplantation is often required

References navigator

  1. Riordan SM and Williams R. 1997. NEJM. 337(7):473 abstract
  2. Albrecht J and Jones EA. 1999. J Neurol Sci. 170(2):138 abstract
  3. Goulenok C, Bernard B, Cadranel JF, et al. 2002. Aliment Pharmacol Ther. 16:361 abstract
  4. Ong JP, Aggarwal A, Krieger D, et al. 2003. Am J Med. 114(3):188 abstract
  5. Shawcross D and Jalan R. 2005. Lancet. 365(9457):431 abstract