Definition of disease

• HE is a chronically incapacitating syndrome of neuropsychiatric symptoms, which can develop in patients with both acute and chronic liver dysfunction once other known brain diseases have been excluded.
  
• HE leads to deterioration in mental status, psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration, disorientation and in severe forms coma.

Disease classification (Figure 21.1)

• HE can be classified based on the type of liver dysfunction:
  
  
  
  • Type A – acute liver failure.
    
  • Type B – porto-systemic bypass and no intrinsic hepatocellular disease.
    
  • Type C – cirrhosis and portal hypertension.
  
  
• Type C HE can be further classified based on the duration and neurological manifestations:
  
  
  
  • Episodic HE: these episodes develop over a short period of time and fluctuate in severity. Episodic HE can be:
    
    
    
    • precipitated by an event such as GI hemorrhage or uremia.
      
    • spontaneous, when there is no recognized precipitating factors.
      
    • recurrent encephalopathy, when two episodes of episodic HE occur within 1 year.
    
    
  • Persistent HE: this includes persistent cognitive deficits that impact negatively on social and occupational functioning of the patient:
    
    
    
    • mild (HE grade 1)
      
    • severe (HE grades 2–4)
    
    
  • MHE: patients with MHE have no recognizable clinical symptoms of HE but do have mild cognitive and psychomotor deficits that are manifested by impairment in specialized testing of cognitive functioning.

Figure 21.1 Classification of HE

Incidence/prevalence

• Cirrhosis affects about 5.5 million people in the USA and 30–45% of these patients will develop HE.
  
• HE also develops in 10–50% undergoing TIPS.

Economic impact

• Chronic HE is a common and expensive complication of liver failure, requiring more than 55 000 hospitalizations annually, and costing over $1.2 billion per year in 2003 in the USA alone.

Etiology

• The etiology of HE is primarily due to the accumulation of toxins in the serum due to liver dysfunction.
  
• The major factors leading to HE are the reduction in the hepatic function and mass accompanied by the development of porto-systemic collaterals which lead to the circulatory bypass of the liver.
  
• Ammonia is the toxin most frequently implicated in pathogenesis of HE.

Pathology/pathogenesis

• Nitrogenous substances derived from the gut adversely affect brain function. These compounds gain access to the systemic circulation as a result of decreased hepatic function or portal-systemic shunts. Once in brain tissue, they produce alterations of neurotransmission that affect consciousness and behavior, leading to motor dysfunction and extrapyramidal symptoms exhibited in HE.
  
• The principal neuro-inhibitory neurotransmitter GABA is also increased in the CSF of patients with encephalopathy. Other toxins identified in the CNS include increased levels of endogenous benzodiazepine-like compounds, manganese, oxygen free radicals, circulation opioid peptides and nitric oxide.

Predictive/risk factors

• Increased nitrogen load due GI bleeding, azotemia, infection especially SBP, electrolyte imbalance, blood transfusions, constipation, dehydration and non-compliance with lactulose.
  
• Decreased toxins clearance due to porto-systemic shunts, spontaneous, surgical, TIPS.
  
• Altered neurotransmission due to inadvertent use of benzodiazepines or psychoactive drugs.
  
• Hepatocellular damage with decrease in functional hepatic mass due to continued alcohol abuse, hepatocellular carcinoma or its treatment with TACE and acute portal vein thrombosis.

Screening

Primary prevention

• Pre-emptive use of lactulose after TIPS as one third of patients may develop HE.
  
• Avoidance of constipation, psychoactive drugs, excessive diuretics.
  
• Prophylaxis against variceal bleeding and spontaneous bacterial peritonitis that can precipi­tate HE.

Secondary prevention

• Compliance with lactulose to ensure two to three bowel movements a day.
  
• Avoidance of sedatives and hypnotics in a hospitalized patient.
  
• Avoidance of dehydration due to overzealous use of diuretics or lactulose.
  
• Prompt diagnosis and treatment of GI bleeding or infection.
  
• Prompt correction of any electrolyte abnormalities.

Differential diagnosis

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