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).

Epidemiology

Male = female (reflects prevalence of underlying liver disease)

Incidence

• The 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 30–45% of cirrhotic patients; present in ~50% of patients requiring liver transplantation

Etiology and Pathophysiology

• There is no defined pathophysiology for the development of HE. However, elevated serum levels of ammonia (hyperammonemia) correlate with the severity of HE, suggesting a central role of ammonia as a neurotoxin.
• Classifications based on four factors have been proposed:
  • According to the underlying disease:
    • Type A: resulting from ALF; type B: resulting from portosystemic bypass or shunting in absence of inherent liver disease; type C: resulting from cirrhosis
  • According to severity of manifestation:
    • West Haven classification: Convert to grades I to IV (see “Physical Exam” section).
  • According to time course:
    • Episodic HE; recurrent HE = >1 episode 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.

Genetics

• Unknown/unclear
• 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.
• A glutaminase gene variation that increases enzyme activity may predispose patients to develop HE.

Risk Factors

In patients with underlying liver disease, precipitating factors include the following:

• Electrolyte disturbance (Na⁺, K⁺, Mg²⁺ most common); infection (overt or occult, including spontaneous bacterial peritonitis [SBP]); GI hemorrhage
• Use of sedative (e.g., benzodiazepines) or opiate drugs; fluid abnormalities including from diuretic overuse
• TIPS—a radiologically inserted shunt to lower portal pressure—elderly patients and those with worse liver function are at increased risk of 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 overt HE.
• 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