Description

• Reversible altered mental and neuromotor functioning in association with acute or chronic liver disease and/or portosystemic shunting
• Wide spectrum of neurologic/psychiatric abnormalities ranging from subclinical alterations to coma: prominent features are confusion, impaired arousability, and a “flapping tremor” (asterixis)
• System(s) affected: gastrointestinal (GI); hepatic; nervous
• Synonym(s): portosystemic encephalopathy (PSE); hepatic coma; liver coma

Epidemiology

Male = female (reflects prevalence of underlying liver disease)

Incidence

• Risk of first episode of overt hepatic encephalopathy (HE) is 5–25% within 5 years of cirrhosis diagnosis.
• Posttransjugular intrahepatic portosystemic shunt (TIPS), median cumulative 1-year incidence of overt HE is 10–50%.

Prevalence

• May occur at any age
• Parallels the age predominance of fulminant liver disease: peaks in the 40s (Cirrhosis peaks in the late 50s.)
• Occurs in all cases of fulminant hepatic failure or acute liver failure (ALF)
• Overt HE occurs in 30–40% of cirrhotic patients.
• Present in ~50% of patients requiring liver transplantation

Etiology and Pathophysiology

• There is no defined pathophysiology for the development of HE. Classifications based on 4 factors have been proposed (1):
  • According to the underlying disease:
    • Type A: resulting from acute liver failure (ALF)
    • Type B: resulting from portosystemic bypass or shunting
    • Type C: resulting from cirrhosis
  • According to severity of manifestation:
    • West Haven classification:
      • Minimal: psychometric or neuropsychological alterations without mental status changes
      • Grade I: lack of awareness, anxiety, shortened attention span, impaired arithmetic, altered sleep rhythm
      • Grade II (overt): asterixis, lethargy, disorientation to time, personality change, inappropriate behavior
      • Grade III: somnolence to stupor, confusion, gross disorientation, bizarre behavior
      • Grade IV: coma
  • According to time course:
    • Episodic HE
    • Recurrent HE = bouts occurring within 6 months
    • Persistent HE = persistent behavioral alterations interspersed with relapses of overt HE
  • According to precipitating factors:
    • Nonprecipitated
    • Precipitated
• Several metabolic factors implicated in HE based on the failure of the liver to detoxify noxious CNS agents (e.g., ammonia, mercaptan, octopamine, tyramine, fatty acids, lactate, manganese)
• Increased aromatic and reduced branched chain amino acids in blood may act as false neurotransmitters, possibly interacting with the γ-aminobutyric acid (GABA) receptor to cause clinical symptoms.
• HE presents most commonly in patients with long-standing cirrhosis and spontaneous shunting of intestinal blood through collateral vessels or surgical portacaval shunts.
• 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.

Genetics

• Unknown
• Conditions that predispose an individual to developing chronic liver disease such as cystic fibrosis, α₁-antitrypsin deficiency, hemochromatosis, and Wilson disease can contribute to the development of HE.

Risk Factors

In patients with underlying liver disease, precipitating factors include:

• Infection (overt or occult, including spontaneous bacterial peritonitis [SBP])
• GI hemorrhage
• Use of sedative (e.g., benzodiazepines) or opiate drugs
• Electrolyte disturbance (Na⁺, K⁺, Mg²⁺ most common)

• Fluid abnormalities including from diuretic overdose
• Transjugular intrahepatic portosystemic shunt (TIPS—a radiologically inserted shunt to lower portal pressure): Elderly patients and those with worse liver function are at increased risk for developing HE following TIPS.

General Prevention

• Recognize early signs and seek prompt treatment.
• Avoid nonessential medications, particularly opiates, benzodiazepines, and sedatives.
• Consider lactulose therapy as secondary prophylaxis for recurrence of HE (2)[B].
• For patients who have already experienced bouts of overt HE while on lactulose, lactulose + rifaximin is the best-documented agent to maintain remission (1).

Commonly Associated Conditions

• Cirrhosis
• Portal hypertension
• May occur as a complication of acute fatty liver of pregnancy
• Occurs rarely in patients with a portacaval shunt accompanied by normal liver function