What are the causes of hepatic encephalopathy?

Causes of Hepatic Encephalopathy

Hepatic encephalopathy is primarily caused by liver insufficiency and/or portosystemic shunting, with hyperammonemia and systemic inflammation acting synergistically as the core pathophysiological mechanisms. 1, 2

Primary Causes

• Liver Insufficiency

  • Cirrhosis (30-40% of cirrhotic patients develop overt HE during their lifetime) 1, 3
  • Acute liver failure 4
  • Chronic liver disease with decompensation 1

• Portosystemic Shunting

  • Spontaneous portosystemic shunts 2, 5
  • Iatrogenic shunts (TIPS - associated with 10-50% risk of HE) 1
  • Non-cirrhotic portal hypertension with shunting 5

Precipitating Factors

1. Metabolic Derangements

   • Hyponatremia (independent risk factor with increasing incidence as sodium levels decrease) 2
   • Renal dysfunction (independent of cirrhosis severity) 2
   • Dehydration 4

2. Inflammatory Conditions

   • Systemic inflammation (acts synergistically with hyperammonemia) 1, 2
   • Infections and sepsis (associated with neurological symptoms in 21-33% of cirrhotic patients) 2
   • Gastrointestinal bleeding 6

3. Medication and Toxins

   • Sedatives and benzodiazepines 4
   • Diuretics (causing electrolyte imbalances) 4
   • Alcohol intoxication 1

4. Nutritional Factors

   • Thiamine deficiency (particularly in alcoholic liver disease and malnutrition) 1, 2
   • Excessive protein intake in susceptible patients 7

5. Comorbidities

   • Diabetes mellitus (especially in HCV-related cirrhosis) 1, 2
   • Constipation (increasing intestinal ammonia production) 4

Pathophysiological Mechanisms

1. Ammonia-Related Mechanisms

   • Impaired urea cycle function in liver disease 4
   • Increased ammonia production by intestinal bacteria 4
   • Astrocytic swelling due to glutamine accumulation 4

2. Inflammatory Mechanisms

   • Neuroinflammation from cytokines (TNF-α, IL-6, IL-17) 4
   • Blood-brain barrier disruption 4
   • Synergistic effects with hyperammonemia 1, 2

3. Other Mechanisms

   • Altered neurotransmission 4, 7
   • Manganese and zinc deposition 4
   • Disrupted enterohepatic circulation with bile acid elevation 4
   • Oxidative/nitrosative stress 4

Clinical Pearls

• A normal blood ammonia level in a patient with suspected HE should prompt consideration of alternative diagnoses 1
• Thiamine should be given intravenously before glucose-containing solutions in cases of suspected thiamine deficiency 1
• Brain imaging should be performed in patients with chronic liver disease and unexplained alteration of brain function to exclude structural lesions 1
• HE in non-cirrhotic portal hypertension allows for the study of portosystemic shunting effects without significant hepatic parenchymal injury 5

Diagnostic Approach

When evaluating a patient with liver disease and neurological alterations, systematically assess:

1. Renal function
2. Electrolyte levels (particularly sodium)
3. Blood glucose
4. Signs of infection
5. Nutritional status (particularly thiamine levels)
6. Presence of portosystemic shunts 2

By identifying and addressing these causes and precipitating factors, clinicians can effectively manage hepatic encephalopathy and improve patient outcomes.