What defines hepatic encephalopathy?

Definition of Hepatic Encephalopathy

Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or portosystemic shunting, manifesting as a spectrum of neurological or psychiatric abnormalities ranging from subtle cognitive impairment to coma. 1, 2

Core Diagnostic Criteria

The diagnosis fundamentally requires detecting signs suggestive of HE in a patient with severe liver insufficiency and/or portosystemic shunting who does not have obvious alternative causes of brain dysfunction. 1 This is a diagnosis of exclusion that demands ruling out other metabolic, toxic, and neurological causes before attribution to hepatic dysfunction. 3

Classification Framework

The 2014 EASL/AASLD guidelines mandate classification according to four essential factors to properly characterize each case: 1

1. By Underlying Disease (Type)

• Type A: Results from acute liver failure, with distinct features including risk of increased intracranial pressure and cerebral herniation 1
• Type B: Results predominantly from portosystemic bypass or shunting without intrinsic liver disease 1, 3
• Type C: Results from cirrhosis and portal hypertension 1, 3

Clinical caveat: Types B and C have similar manifestations, but Type A requires fundamentally different management focused on intracranial pressure control. 1

2. By Severity of Manifestations

The spectrum ranges from: 3

• Minimal (covert) HE: Cognitive impairment detectable only through psychometric testing
• Grade 1 (covert): Shortened attention span, altered sleep rhythm, mild cognitive or behavioral changes without disorientation
• Grades 2-4 (overt): Progressive disorientation, confusion, stupor, and coma

3. By Time Course

• Episodic HE: Discrete episodes 1
• Recurrent HE: Bouts occurring with intervals of 6 months or less 1
• Persistent HE: Continuous behavioral alterations interspersed with relapses of overt HE 1

4. By Precipitating Factors

• Non-precipitated or Precipitated (with specific factors identified) 1

Critical point: Precipitating factors can be identified in nearly all bouts of episodic HE type C and should be actively sought, as they include infection, bleeding, constipation, electrolyte disorders, and medications. 1, 3

Epidemiology and Clinical Impact

• Prevalence of overt HE at cirrhosis diagnosis is 10-14% overall, but increases to 16-21% in decompensated cirrhosis 2
• Risk of first overt HE episode is 5-25% within 5 years after cirrhosis diagnosis 2
• After the first overt episode, there is a 40% cumulative risk of recurrence at 1 year 2
• HE affects 30-45% of cirrhotic patients overall 4

Essential Differential Diagnoses

Common pitfall: Failing to exclude other causes of altered mental status before attributing symptoms to HE. The differential is extensive and includes: 1, 3

Metabolic Disorders

• Diabetic emergencies (hypoglycemia, ketoacidosis, hyperosmolar states)
• Electrolyte disorders (particularly hyponatremia and hypercalcemia)
• Uremic encephalopathy (which may overlap with HE in end-stage liver disease) 1

Substance-Related

• Alcohol (intoxication, withdrawal, Wernicke encephalopathy)
• Drugs (benzodiazepines, neuroleptics, opioids) 1

Neurological

• Neuroinfections
• Non-convulsive status epilepticus
• Intracranial bleeding and stroke
• Brain lesions (traumatic, neoplastic, normal pressure hydrocephalus) 1, 3

Other Critical Considerations

• Septic encephalopathy (found in 50-70% of septic patients and may present before sepsis criteria are met) 3
• Psychiatric disorders
• Severe medical stress and organ failure 1

Important nuance: Hyponatremia and sepsis can both produce encephalopathy independently AND precipitate HE through pathophysiological interactions, making diagnosis particularly challenging. 1

Pathophysiological Basis

While traditionally considered completely reversible, recent research challenges this assumption. 1 Episodes of overt HE may be associated with persistent cumulative deficits in white matter and learning, and some mental deficits may persist even after liver transplantation. 1 The condition is primarily considered a gliopathy with astrocyte dysfunction as the main neuropathological hallmark. 5