What causes hepatic encephalopathy?

Causes of Hepatic Encephalopathy

Hepatic encephalopathy is primarily caused by the synergistic action of hyperammonemia and systemic inflammation in the setting of liver insufficiency and/or portosystemic shunting. 1, 2

Primary Pathophysiological Mechanisms

Liver Dysfunction and Ammonia

• Liver insufficiency: The liver's reduced ability to eliminate ammonia leads to hyperammonemia 2
• Portosystemic shunting (PSS): Allows ammonia-rich blood to bypass the liver and enter systemic circulation 2

Inflammatory Factors

• Systemic inflammation acts synergistically with hyperammonemia 1, 2
• Sepsis is associated with neurological symptoms in 21-33% of cirrhotic patients 2

Common Precipitating Factors

Metabolic Disturbances

• Hyponatremia: Independent risk factor for hepatic encephalopathy 2
• Renal dysfunction: Increases risk independent of cirrhosis severity 2
• Diabetes mellitus: Particularly increases risk in patients with HCV-related cirrhosis 2

Nutritional Factors

• Thiamine deficiency: Predominantly occurs in alcoholic liver disease but can occur in end-stage cirrhosis of any cause 1
  • Can present with symptoms indistinguishable from hyperammonemia (disorientation, altered consciousness, ataxia, dysarthria) 1
  • Thiamine should be given IV before glucose-containing solutions in suspected cases 1

Infections and Inflammation

• Sepsis/infections: Major precipitating factors 2
• Systemic inflammatory response: Alters blood-brain barrier function 3

Medication-Related

• Certain medications can worsen hepatic encephalopathy, particularly sedatives and diuretics
• Caution with medications metabolized by the liver, such as rifaximin in severe hepatic impairment 4

Underlying Liver Conditions

• Cirrhosis: Most common underlying condition
  • 30-40% of cirrhotic patients will develop overt HE during their clinical course 1, 5
  • 10-14% have HE at time of cirrhosis diagnosis, 16-21% in decompensated cirrhosis 1
• Portosystemic shunts: Including TIPS (10-50% develop HE within 1 year) 1
• Acute liver failure: Can cause HE without portal-systemic shunting 6

Diagnostic Considerations

• Normal blood ammonia level in a patient suspected of HE requires consideration of other diagnoses 1
• Brain imaging should be performed in patients with unexplained alteration of brain function to exclude structural lesions 1
• The temporal evolution and response to therapy may be the best support for diagnosis 1

Clinical Pitfalls to Avoid

1. Failing to identify precipitating factors: Always search systematically for infections, electrolyte disturbances, renal dysfunction, and medication effects
2. Missing thiamine deficiency: Particularly in alcoholic patients, symptoms can mimic HE
3. Overlooking mild forms: Minimal HE reduces quality of life and is a risk factor for overt HE 1
4. Ignoring the underlying liver disease: Treatment of the liver condition is essential for long-term management
5. Attributing all neurological symptoms to HE: Other neurological conditions can coexist with liver disease

The management of hepatic encephalopathy should focus on identifying and treating precipitating factors while addressing the underlying mechanisms of hyperammonemia and inflammation.