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BASICS

Description

  • Reversible altered mental and neuromotor dysfunction associated with acute or chronic liver disease and/or portosystemic shunting.
  • Neurologic/psychiatric symptoms range from subtle cognitive changes to coma.
  • Classic findings: confusion, impaired arousal, asterixis (flapping tremor).

Epidemiology

  • Equal sex distribution (reflects liver disease prevalence).
  • Risk of first overt HE episode: 5-25% within 5 years after cirrhosis diagnosis.
  • Post-TIPS procedure: 10-50% incidence of overt HE within 1 year.
  • Occurs in all fulminant hepatic failure; overt HE in ~30-45% of cirrhotic patients.
  • Present in ~50% of patients undergoing liver transplantation.

ETIOLOGY AND PATHOPHYSIOLOGY

  • No definitive pathophysiology, but ammonia neurotoxicity central.
  • Classification:
  • By disease: Type A (acute liver failure), Type B (portosystemic bypass without liver disease), Type C (cirrhosis).
  • Severity: West Haven grades I–IV.
  • Time course: episodic, recurrent (>1 episode within 6 months), persistent.
  • Precipitating factors: precipitated vs nonprecipitated.
  • Other implicated toxins: mercaptans, octopamine, tyramine, fatty acids, lactate, manganese.
  • Neurotransmitter imbalance: increased aromatic amino acids, reduced branched chain amino acids, GABA receptor interactions.
  • Asterixis due to diencephalic dysfunction.
  • Genetic predisposition unclear; glutaminase gene variants may increase susceptibility.
  • Predisposing liver diseases: cystic fibrosis, α1-antitrypsin deficiency, hemochromatosis, Wilson disease.

RISK FACTORS

  • Electrolyte disturbances (Na+, K+, Mg2+).
  • Infection including spontaneous bacterial peritonitis.
  • GI hemorrhage.
  • Sedatives/opioids use.
  • Diuretic overuse causing fluid imbalance.
  • TIPS placement—higher risk in elderly and severe liver dysfunction.

DIAGNOSIS

History

  • Known liver disease.
  • Altered mental status: confusion, impaired arousal.
  • Constipation common.

Physical Exam

  • Signs of liver disease: jaundice, ascites, spider telangiectasias, muscle wasting.
  • West Haven grading of HE severity:
  • Minimal (covert): subtle psychometric abnormalities.
  • Grade I: lack of awareness, anxiety, impaired attention.
  • Grade II: asterixis, lethargy, disorientation.
  • Grade III: somnolence, confusion.
  • Grade IV: coma.
  • CNS exam: asterixis ("liver flap").
  • Glasgow Coma Scale for grade III–IV.

Differential Diagnosis

  • Other metabolic encephalopathies (anoxia, hypoglycemia, electrolyte abnormalities).
  • CNS insults (trauma, stroke, hemorrhage).
  • Alcohol intoxication or withdrawal.
  • Infection (meningitis, encephalitis).
  • Wilson disease without cirrhosis.
  • Wernicke-Korsakoff syndrome.

DIAGNOSTIC TESTS & INTERPRETATION

  • Clinical diagnosis in ~80% of cases.
  • EEG: symmetric slowing (nonspecific).
  • Psychometric tests for minimal HE: number connection, line drawing, critical flicker frequency.
  • Serum ammonia elevated in 90%, correlates with severity but not diagnostic.
  • Liver function tests, coagulation studies often abnormal.
  • CBC, metabolic panel to assess electrolytes, dehydration, infection.
  • Blood, urine, sputum cultures if infection suspected.
  • Imaging: CT/MRI brain to exclude other causes; MRI more sensitive.
  • Paracentesis if ascites present to exclude spontaneous bacterial peritonitis.

TREATMENT

General Measures

  • Identify and correct precipitating factors: infections, electrolyte imbalances, GI bleeding.
  • Avoid sedatives, benzodiazepines, opiates.
  • Ensure adequate nutrition and hydration.

Medications

First Line

  • Lactulose: nonabsorbable disaccharide reducing ammonia absorption.
  • Oral: 30-45 mL every hour until 3-6 bowel movements/day, then taper to 15-30 mL BID.
  • Enema: 300 mL lactulose + 700 mL water for those unable to take orally.
  • Add rifaximin if no improvement or worsening after 2 days.
  • Dosage: 400 mg PO TID or 550 mg PO BID.
  • Nonabsorbable antibiotic targeting gut flora.

Second Line

  • Neomycin 1-2 g/day PO if renal function normal.
  • Polyethylene glycol as lactulose alternative.
  • Metronidazole, vancomycin (limited use due to side effects).
  • Flumazenil in select patients.

ISSUES FOR REFERRAL

  • Early referral to transplant center if refractory to treatment.
  • Consider liver transplantation for grades II–IV HE or fulminant hepatic failure.

ADDITIONAL THERAPIES

  • Branched-chain amino acids, probiotics, IV L-ornithine L-aspartate (controversial evidence).
  • Artificial liver support devices in fulminant hepatic failure.

INPATIENT CARE

  • Monitor clinical status closely.
  • Airway protection and hemodynamic support as needed.

ONGOING CARE

Follow-Up

  • Secondary prophylaxis with lactulose or lactitol to maintain 2-3 soft stools daily.
  • Add rifaximin if HE recurs within 6 months.
  • Monitor cognitive function using asterixis and psychometric tests.
  • Assess MELD score in cirrhotics.

Diet

  • Regular protein intake (1.2–1.5 g/kg/day); avoid protein restriction.
  • Prefer vegetable proteins over animal in advanced cirrhosis.
  • Nutritional support for severe HE.

PATIENT EDUCATION

  • American Association for the Study of Liver Diseases (AASLD): https://www.aasld.org/

PROGNOSIS

  • Acute HE often reversible with treatment.
  • Recurrences worsen prognosis; mortality approaches 80% with repeated episodes.
  • Complications include permanent basal ganglia injury and hepatorenal syndrome.

REFERENCES

  1. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of hepatic encephalopathy. J Hepatol. 2022;77(3):807-824.

  2. Shalimar, Sheikh MF, Mookerjee RP, et al. Prognostic Role of Ammonia in Patients With Cirrhosis. Hepatology. 2019;70(3):982-994.

ADDITIONAL READING

  • Acharya C, Bajaj JS. Current management of hepatic encephalopathy. Am J Gastroenterol. 2018;113(11):1600-1612.