Hepatic Encephalopathy

Aka: Hepatic Encephalopathy, Portosystemic Encephalopathy

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II. Definitions

  1. Hepatic Encephalopathy
    1. Brain dysfunction due to liver insufficiency or portosystemic shunting

III. Epidemiology

  1. Incidence: 30-40% of Cirrhosis patients within 5 years of Cirrhosis diagnosis
    1. Mild Impairment (Grade 1): 20-80% of cases
    2. Overt Hepatic Encephalopathy (Grades 2-4): 5-25% of cases

IV. Pathophysiology

  1. Severe liver disease resulting in liver failure
  2. Inability to eliminate Neurotoxins
    1. Ammonia
    2. Mercaptans
    3. Fatty Acids
    4. Gamma-Aminobutyric Acid (GABA)
  3. Other mechanisms
    1. Astrocyte dysfunction
    2. Cerebral cellular swelling
    3. Blood-brain barrier disruption

V. Risk Factors: Precipitating Events

  1. Gastrointestinal Bleeding (especially Variceal Bleeding)
    1. Blood loss of 100 ml absorbed as 14-20 g Protein
  2. Azotemia
  3. Constipation
  4. High Protein dietary intake
  5. Hypokalemic acidosis
  6. CNS Depressants (e.g. Benzodiazepines)
  7. Hypoxia
  8. Hypercarbia
  9. Sepsis or other acute infection
  10. Status-post Transjugular Intrahepatic portosystemic shunt (TIPS)

VI. Types

  1. Type A: Acute Liver Failure associated encephalopathy
  2. Type B: Portosystemic bypass and no intrinsic hepatocellular disease with encephalopathy
  3. Type C: Cirrhosis associated encephalopathy
    1. Minimal Hepatic Encephalopathy
    2. Episodic Hepatic Encephalopathy (precipitated, spontaneous, recurrent)
    3. Persistent Hepatic Encephalopathy (mild, severe, treatment dependent)
  4. Type D: Disorders of Urea Cycle with associated encephalopathy

VII. Findings: Symptoms and Signs

  1. Mild Disease (insidious onset)
    1. Day-night reversal
    2. Somnolence
    3. Confusion
    4. Personality change
    5. Asterixis (Flapping Tremor)
    6. Hypersalivation
  2. Severe Disease
    1. Stupor
    2. Coma
    3. Dementia
    4. Extrapyramidal signs
    5. Fetor hepaticus (Odor of breath from mercaptans)

VIII. Labs

  1. Markers correlated with Hepatic Encephalopathy
    1. International Normalized Ratio (INR)
    2. Venous total ammonia
    3. Ong (2003) Am J Med 114:188-93 [PubMed]
  2. Blood Ammonia Level (on ice)
    1. Not correlated with prognosis
    2. Normal ammonia level should prompt evaluation for other encephalopathy cause
      1. See Altered Mental Status
  3. Consider Altered Mental Status Differential Diagnosis
    1. Comprehensive metabolic panel
    2. Blood Alcohol Level
    3. Urine Toxicology Screening
    4. Serum Ketones
    5. Lactic Acid

IX. Grading: West Haven Criteria Grading System

  1. Background
    1. Overt Hepatic Encephalopathy (OHE) seen in decompensated Cirrhosis refers to grades 2-4
  2. Grade 1
    1. Trivial lack of awareness
    2. Euphoria or anxiety
    3. Shortened attention span
    4. Impaired performance of addition or subtraction
  3. Grade 2
    1. Drowsiness
    2. Apathy
    3. Subtle personality change
    4. Inappropriate behavior
    5. Gross Disorientation for time or place
  4. Grade 3
    1. Somnolence to semi-stupor
    2. Arousable to verbal stimuli
    3. Significant confusion
    4. Incoherent speech
  5. Grade 4
    1. Coma (unresponsive to verbal or noxious stimuli)
    2. Decorticate Posturing or Decerebrate Posturing
  6. References
    1. Ferenci (2002) Hepatology 335(3): 716-21 [PubMed]

X. Evaluation: Encephalopathy

  1. Consider Altered Mental Status Differential Diagnosis
    1. See Altered Mental Status
    2. Hyponatremia
    3. Hypoglycemia
    4. Ketoacidosis
    5. Systemic infections
    6. Cerebrovascular Accident
    7. Closed Head Injury (e.g. Intracranial Hemorrhage)
    8. Intoxication or Toxin Ingestion
  2. Evaluate for underlying cause in new Hepatic Encephalopathy
    1. Gastrointestinal Bleeding (e.g. Variceal Bleeding)
    2. Portal Vein Thrombosis
      1. Obtain RUQ with Doppler Ultrasound
    3. Infection (e.g. subacute Bacterial peritonitis)
      1. Tailored history and exam for underlying infection
      2. Obtain blood and Urine Cultures, serum lactate, and Paracentesis
      3. Consider Lumbar Puncture

XI. Diagnostics

  1. CT Head
  2. Electroencephalogram (EEG)

XII. Management

  1. Initial Measures (effective in up to 90% of cases)
    1. ABC Management (especially airway)
    2. ICU admission for Grade 3 to 4 Hepatic Encephalopathy
    3. Avoid and correct precipitating factors listed above
    4. Reduce Blood Ammonia
      1. Lactulose (key management)
        1. Lactulose 30-45 ml syrup orally titrated to four times daily with goal of 2-3 soft stools daily
        2. Lactulose 25 ml every 1-2 hours until 2-3 soft stools daily
        3. Retention enema 300 ml until >1 stool/day
      2. Decrease Protein intake
        1. Limit to 20-30 g/day
        2. Protein restriction may not be needed
          1. Cordoba (2004) J Hepatol 41:38-43 [PubMed]
  2. Severe Hepatic Encephalopathy (hospital admission, ICU)
    1. Use Polyethylene Glycol with Electrolytes (GoLytely) via nasogastric or Orogastric Tube
    2. Administer 8 oz (240 ml) per 15 minutes (continuously 1 liter/hour) for 4 hours (Golytely supplied in 4 Liter containers)
    3. Rectal tube or rectal pouch devices
    4. Rahimi (2014) JAMA Intern Med 174(11):1727-33 +PMID: 25243839 [PubMed]
    5. Li (2022) J Clin Gastroenterol 56(1):41-8 +PMID: 34739404 [PubMed]
  3. Refractory cases
    1. First-line agents
      1. Rifamaxin (Xifaxan)
    2. Alternative short-term alternative agents
      1. Neomycin 4-12 grams orally divided q6-8 hours
      2. Metronidazole (Flagyl)
    3. Other measures
      1. IV or oral branched chain Amino Acids (L-Ornithine, L-Aspartate)
    4. Unproven or experimental methods
      1. Bromocriptine (may improve extrapyramidal symptoms)
      2. Flumazenil (may improve mental status)
      3. Lactilol (alternative to Lactulose)

XIII. References

  1. Swencki (2015) Crit Dec Emerg Med 29(11):2-10
  2. Abou-Assi (2001) Postgrad Med 109(2):52-65 [PubMed]
  3. Biel (2001) Am J Gastroenterol 96:1968-76 [PubMed]
  4. Keating (2022) Am Fam Physician 105(4): 412-20 [PubMed]

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