DESCRIPTION

Hepatic encephalopathy (HE) is characterized by changes in behavior, consciousness, and motor disturbances, associated with hepatic insufficiency and the accumulation of substances normally metabolized by the liver. HE may result from a combination of:

• Accumulation of ammonia (NH₃) from:
  • Protein degradation by colonic bacteria
  • Deamination of glutamine in small bowel, kidney, and muscle.
  • Accumulated NH₃ crosses the blood–brain barrier. Astrocytes uptake NH₃ and metabolize it into glutamine which causes cellular swelling. Ultimately leads to cerebral edema and cerebral mitochondrial dysfunction.
• Accumulation of other neurotoxins:
  • Short-chain fatty acids
  • Manganese toxicity
  • Neurosteroids
  • Phenols
  • Mercaptans
  • Amino acids such as tryptophan
• Increased levels of inhibitory neurotransmitters:
  • Benzodiazepines
  • γ-aminobutyric acid (GABA)
  • Serotonin
• Decreased levels of excitatory neurotransmitters:
  • Glutamate
  • Dopamine
  • Aspartate
  • Catecholamines
• Other contributing factors to HE:
  • Decreased cerebral blood flow and oxygen
  • Increased glucose consumption and possible hypoglycemia
  • Zinc deficiency
• Genetics:
  • Inherited errors of the urea cycle

ETIOLOGY

• Classification based on the 11th World Congress of Gastroenterology:
  • Type A: HE associated with acute liver injury and fulminant hepatic failure (FHF).
  • Type B: HE associated with portosystemic bypass and no intrinsic liver disease.
  • Type C: HE associated with cirrhosis and portal hypertension.
• Precipitating events:
  • GI bleeding (more common in elderly)
  • Hypokalemia and hyponatremia.
  • Alkalosis decreases renal NH₄ excretion.
  • Sepsis (e.g., spontaneous bacterial peritonitis [SBP])
  • Constipation
  • Noncompliance with treatment regimen in chronic liver failure
  • High-protein diet
  • Hypoglycemia
  • Hypovolemia (e.g., post large-volume paracentesis)
  • Azotemia (e.g., diuretic or diarrhea induced)
  • Narcotics or sedatives, including alcohol
  • Zinc deficiency as multiple urea cycle enzymes are zinc dependent
  • Hepatocellular injury
  • Viral- or drug-induced hepatitis
  • Post portosystemic shunt placement
  • Recurrent encephalopathy can occur without precipitating factors

[Outline]

• DESCRIPTION
• ETIOLOGY

SIGNS AND SYMPTOMS

• Type A: Rapidly progresses to seizures, decerebrate rigidity, coma, and frequently death from cerebral edema.
• Type B and C are chronic conditions that may manifest as minimal or overt HE. Overt HE may be classified as episodic or persistent:
  • Minimal HE: Characterized by impaired psychomotor speed, visual perception, and attention and concentration; slow mental processing; and memory loss. Only detected by psychometric testing.
  • Overt HE: Slow monotonous speech pattern, loss of fine motor skills, hyperreflexia, clonus, hyperventilation, extrapyramidal type movement disorder, seizures, confusion, coma, decerebrate/decorticate posturing.
  • Overt HE episodic: Characterized by short period of changes in consciousness over hours to days that usually return to a normal mental state with treatment. In persistent HE, patients do not return to a normal mental state.
• Grading (West Haven criteria):
  • Stage 0:
    • No apparent clinical changes
    • Abnormal neurophysiologic and neuropsychological tests
    • No asterixis
  • Stage I:
    • Personality changes, irritability, depression, or euphoria
    • Reversal of normal sleep pattern
    • Impairment of writing, drawing, addition, subtraction
    • Asterixis may be present
  • Stage II:
    • Significant behavioral changes, often inappropriate
    • Lethargy
    • Slow responses
    • Asterixis
    • Slurred speech
    • Ataxia
  • Stage III:
    • Disorientation to time and place
    • Amnesia
    • Paranoia
    • Nystagmus
    • Hypoactive reflexes
    • Positive Babinski reflex
    • Semistupor to stupor
  • Stage IV:
    • Dilated pupils
    • Stupor or coma

ESSENTIAL WORKUP

• Elicit history of liver disease and prior episodes of HE.
• Search for precipitating cause (particularly GI bleeding and infection).
• Check for electrolyte abnormalities:
  • Even minimal abnormalities may manifest as significant clinical changes.

DIAGNOSIS TESTS & INTERPRETATION

Lab

• Blood NH₃ level:
  • Level correlates poorly with the degree of HE or the presence of cerebral edema.
  • Helpful in detecting HE in cases of altered mental status (AMS) of unknown cause
  • Normal NH₃ level with suspected HE warrants search for other causes of AMS.
  • Must be kept on ice and assayed within 30 min.
• Consider hemoccult testing and nasogastric (NG) lavage to rule out GI bleeding
• CBC to search for anemia
• Electrolytes, BUN, creatinine, glucose
• PT/INR with elevations suggesting significant liver failure
• Liver profile/liver enzymes
• Urinalysis for possible infection
• Culture urine and ascitic fluid to search for infectious cause
• Toxicology screen for alternate cause of altered level of consciousness:
  • Acetaminophen and alcohol level as necessary
• Additional labs as clinical scenario dictates:
  • TSH
  • Blood gases
  • Magnesium
  • Viral serology

Imaging

• CXR for pneumonia and signs of CHF
• Head CT scan: For new-onset AMS, focal neurologic deficit, suspected cerebral edema, or trauma.
• MRI of the brain is especially helpful in diagnosing HE in patients with portosystemic shunts but no intrinsic liver disease.

Diagnostic Procedures/Surgery

• ECG for arrhythmia and electrolyte imbalance
• CSF exam:
  • For new-onset or unexplained worsening of HE
  • CSF glutamine level correlates with severity of HE.
• Paracentesis for SBP workup and culture of ascitic fluid
• EEG is usually abnormal, most commonly with generalized slowing and other nonspecific changes.

DIFFERENTIAL DIAGNOSIS

• Alcohol withdrawal syndromes including delirium tremens
• Cerebrovascular accident
• Congestive heart failure
• CO₂ narcosis
• Head trauma with concussion or intracranial hemorrhage
• Hypocalcemia and hypercalcemia
• Hypoglycemia
• Hypokalemia
• Meningitis or encephalitis
• Metabolic encephalopathy
• Neuropsychiatric disorders
• Toxic confusional states secondary to:
  • Sedative overdose
  • Alcohol intoxication
  • Illicit drugs
  • Medications
• Uremia

Pediatric Considerations

• Consider Reye syndrome early (most common cause of fulminate hepatic failure in children) even if PT is only mildly prolonged.
• Consider fatty acid β-oxidation disorder:
  • Freeze serum and urine sample for subsequent testing

[Outline]

• SIGNS AND SYMPTOMS
• ESSENTIAL WORKUP
• DIAGNOSIS TESTS & INTERPRETATION
• DIFFERENTIAL DIAGNOSIS

INITIAL STABILIZATION/THERAPY

• Oxygen
• Airway protection:
  • Patients with grade 3 or 4 HE may require intubation for airway protection. Propofol is the preferred agent for sedation.
• Cardiac monitor
• Fluid resuscitation
• Initial AMS treatment:
  • Naloxone
  • D₅₀W (or bedside glucose)
  • Thiamine

ED TREATMENT/PROCEDURES

Identification and removal of precipitating factors is key and may improve clinical picture alone.

ALERT

• Treatment of complicating conditions:
  • Acute GI bleeding
  • Sepsis
  • Electrolyte and pH abnormalities
  • Coagulopathy
  • Renal and electrolyte disturbances
• Avoid sedative/narcotics if possible:
  • If necessary, use agents not metabolized by the liver
• Increase NH₃ elimination:
  • Bowel cleansing with nonabsorbable sugars (i.e., lactulose is mainstay of treatment). Retention enema preferred in grade 3/4 HE
• Decrease NH₃-producing intestinal flora (in combination with lactulose):
  • Neomycin (nephrotoxic and ototoxic)
  • Metronidazole (PO)
  • Vancomycin (PO)
  • Rifaximin: Recommended for lactulose-resistant HE. Current data suggests it is as effective as lactulose and neomycin and has a favorable safety and tolerability profile, although more expensive
• Treat associated cerebral edema if present
• Correct zinc deficiency
• Short-term restriction of protein intake in diet
• Flumazenil in patients who have received benzodiazepines may provide moderate, short-term improvement.
  • Avoid flumazenil unless you are sure that the patient is not a chronic alcoholic or benzodiazepine user as resultant seizures may occur.
• Precautions to prevent bodily harm to the confused patient with HE
• Liver transplantation provides cure for severe, spontaneous, or recurrent HE
• Possibly of benefit:
  • L-carnitine
  • Albumin dialysis
  • Broad-spectrum antibiotic coverage
  • N-acetylcysteine
  • Lactobacillus acidophilus supplementation
  • Ornithine aspartate
  • Benzoate or Bromocriptine
  • Branched-chain amino acids
  • Chelation of manganese with edetate calcium disodium

MEDICATION

• Dextrose: 1–2 amps (25 g) of 50% dextrose (child: 2 mL/kg D₂₅W) IV
• Lactulose: 30 mL (peds: 0.3 mL/kg) PO/NG tube q6h titrated to produce 2 or 3 soft stools per day and stool pH < 5 or retention enema at 300 mL + 700 mL saline/tap water q4–6h
• Metronidazole: 250 mg PO/NG (peds: 10–30 mg/kg/d) q8h for 2 wk
• Narcan: 2 mg (peds: 0.1 mg/kg) IV/IM initial dose
• Neomycin: 1–3 g (peds: 50–100 mg/kg/d) PO q6h
• Rifaximin: 550 mg PO/NG q12h. (safety not established for children < 12 yr)
• Mannitol: 0.5 –1 g/kg IV
• Thiamine (vitamin B₁): 100 mg (peds: 50 mg) IV/IM
• Zinc acetate or sulfate: 220 mg PO/NG q8h

[Outline]

• INITIAL STABILIZATION/THERAPY
• ED TREATMENT/PROCEDURES
• MEDICATION

DISPOSITION

Admission Criteria

• HE grade 2, 3, or 4 or inadequate social support
• Type A HE (any grade) and type B or C (grade 2 or above) should be admitted to the ICU with urgent GI consult
• Associated complicating condition (GI bleeding and sepsis)
• Uncertainty about cause of AMS

Discharge Criteria

• Known chronic or intermittent HE
• Grade 0 or 1 with remediable cause
• Adequate supervision with close follow-up
• Those appropriate for discharge should go home with:
  • Low-protein diet
  • Lactulose prescription

Issues for Referral

• Refer to primary physician or GI for consideration of medication or diet changes if recurrent early stage HE episodes
• For any grade of type A HE, consider transfer to a liver transplant facility

FOLLOW-UP RECOMMENDATIONS

• Dietary consultation if possible cause of exacerbation
• Alcohol counseling if it is a concern

[Outline]

• DISPOSITION
• FOLLOW-UP RECOMMENDATIONS

• Consider rifaximin for lactulose-resistant HE
• Hypoglycemia is common in HE patients.
• Avoid sedatives and narcotics if possible in HE patients. If necessary, use medications not metabolized by liver.

ICD9

• 070.6 Unspecified viral hepatitis with hepatic coma
• 070.9 Unspecified viral hepatitis without mention of hepatic coma
• 572.2 Hepatic encephalopathy

ICD10

• B19.0 Unspecified viral hepatitis with hepatic coma
• K72.90 Hepatic failure, unspecified without coma
• K72.91 Hepatic failure, unspecified with coma

[Outline]

• ICD9
• ICD10

• Eroglu Y, Byrne WJ. Hepatic encephalopathy. Emerg Med Clin North Am. 2009;27(3):401–414.
• Khungar V, Poordad F. Hepatic Encephalopathy. Clin Liv Dis. 2012;16:301–320.
• Riordan SM, Williams R. Treatment of hepatic encephalopathy. New Engl J Med. 1997;337(7):473–479.

See Also (Topic, Algorithm, Electronic Media Element)

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Sidney James

Matthew N. Graber