Hepatic Encephalopathy (HE)

Definition

• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 1815

Pathophysiology

1. Ammonia Toxicity

• The best-described neurotoxin is ammonia, produced primarily in the colon by bacterial metabolism of proteins/nitrogen-based products, and by enterocyte synthesis from glutamine
• Under normal conditions, hepatocytes metabolize and clear portal ammonia; in cirrhosis, reduced hepatocyte function plus portosystemic shunting causes hyperammonemia
• Arterial hyperammonemia occurs in up to 90% of HE patients
• Increased blood-brain barrier permeability leads to enhanced uptake by the cerebellum and basal ganglia
• Ammonia directly causes brain edema, astrocyte swelling, and disrupts transport of neuroactive compounds (e.g., myoinositol)
• In ALF, ammonia increases astrocyte glutamine production (via glutamine synthetase), raising glutamine/glutamate levels - contributing to cytotoxic edema

2. GABA-Benzodiazepine System

• Increased sensitivity of the astrocyte peripheral-type benzodiazepine receptor enhances GABA-benzodiazepine activation
• A feed-forward loop: astrocytes produce neurosteroids (allopregnanolone, tetrahydrodeoxycorticosterone) that further activate GABA-A receptors

3. Other Neurotransmitter Changes

• Serotonin (5-HT), nitric oxide (NO), circulating opioid peptides, manganese, and excess oxygen free radicals also contribute
• Manganese causes dopaminergic dysfunction
• Other implicated agents: mercaptans, beta-phenylethylamine, tyramine, octopamine

4. Gut Microbiota

• Differences in colonic mucosal microbiota in cirrhotic patients with vs. without HE influence production of ammoniagenic substances
• Distinct allelic mutations in the glutaminase gene increase overt HE risk, potentially by increasing ammonia and glutamate levels
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease, p. 1815-1816

Classification

By Underlying Disease (Type)

By Severity - West Haven Criteria & SONIC Classification

• Covert/Minimal HE affects ~50% of all cirrhotic patients and is commonly overlooked
• Disorientation to time is the key feature distinguishing Grade 1 from Grade 2 (covert from overt HE)

By Time Course

1. Episodic - recurrent HE (multiple episodes within 6 months)
2. Persistent - altered behavior always present, with relapses

By Precipitating Factors

• Spontaneous (no identifiable trigger)
• Precipitated - by GI bleeding, electrolyte abnormalities (especially hypokalemia), infections, sedating medications (benzodiazepines, narcotics), dehydration, constipation
• Sleisenger and Fordtran's, p. 1815-1816; Bradley and Daroff's Neurology in Clinical Practice, p. 3520-3525

Clinical Features

• Early/covert: Forgetfulness, altered handwriting, difficulty driving, reversal of sleep-wake cycle
• Progressive (overt): Asterixis (flapping tremor - characteristic sign), agitation, disinhibited behavior, disorientation, ataxia, slurred speech
• Severe: Stupor, seizures (10-30% of patients), coma, decerebrate/decorticate posturing
• ALF-specific: Cerebral edema and intracranial hypertension are invariably present in Stage 4, with brainstem herniation being the most common cause of death

Asterixis is pathognomonic but not exclusive to HE - it also occurs in other metabolic encephalopathies (uremia, CO2 narcosis, etc.)

Diagnosis

No Gold Standard Laboratory Test

• Blood ammonia levels are not sensitive or specific for HE
• False elevations: GI bleeding, tourniquet use during blood draw, delayed lab processing, diuretics, alcohol, narcotics, valproic acid
• Arterial ammonia offers no advantage over venous ammonia in chronic liver disease

Neuropsychometric Testing

• Portosystemic encephalopathy (PSE) syndrome test and Stroop test - evaluate attention, concentration, fine motor skills, orientation
• EncephalApp (smartphone-based Stroop test) - validated for covert/minimal HE detection
• Critical flicker frequency (CFF) test - reliable marker for minimal HE

Neurophysiological

• EEG: Early slowing of alpha rhythm progressing to delta frequencies; triphasic waves in later stages (poor prognosis)
• MR spectroscopy and T1 TAPIR mapping - research tools to quantify HE parameters

Differential Diagnosis of Hyperammonemia (Box 94.1)

• Sleisenger and Fordtran's, p. 1816-1817

Treatment

1. Correct/Eliminate Precipitating Factors

2. Dietary Management

• Protein restriction is no longer recommended - it is harmful and does not benefit HE
• Vegetable and dairy proteins are preferable to animal proteins (more favorable calorie-to-nitrogen ratio)
• Branched-chain amino acid (BCAA) supplementation may benefit HE, but does not clearly reduce mortality

3. Reduce Intestinal Ammonia - First-Line

• Non-absorbable disaccharide metabolized by colonic bacteria
• Mechanism: causes catharsis, acidifies the colon (inhibits ammonia absorption), and decreases transit time
• Effective for acute and chronic HE vs. placebo
• Dose: titrate to 2-3 soft stools/day
• Side effects: abdominal cramping, flatulence, diarrhea, electrolyte imbalance
• Can be given per rectum as an enema in patients at aspiration risk

4. Oral Antibiotics - Second-Line or Add-On

• Used for chronic HE and prevention of recurrence of overt HE
• Superior tolerability vs. lactulose; main limitation is cost
• Other antibiotics studied (neomycin, metronidazole, vancomycin) - not clearly established for chronic HE

5. Other Agents

6. Liver Transplant (LT)

• Definitive treatment - generally reverses HE
• Should be considered before permanent neurologic damage
• Sleisenger and Fordtran's, p. 1817-1818

Acute vs. Chronic HE - Key Distinguishing Features

Special Considerations: Pediatric HE

• In children, irritability and lethargy are the most common initial signs
• Neurological findings: pyramidal signs → hypotonia → focal signs → early parkinsonism, ataxia, tremor, dysarthria
• Asterixis is present but less prominent as a discriminating feature
• Clinically evident HE is less common in children with chronic liver disease than in adults, but 50% of children with chronic liver disease have minimal HE on neuropsychological testing
• Seizures occur in 10-30% of pediatric patients
• Common pediatric causes: fulminant viral/autoimmune hepatitis, drug ingestion (acetaminophen, salicylates, valproate), Reye syndrome, Wilson disease, mitochondrial diseases
• Bradley and Daroff's Neurology, p. 1252-1253

Prognosis

• Overt HE: 1-year survival 20-40%, 3-year survival ~15% without transplant
• Cerebral edema (Stage 4) - brainstem herniation is the leading cause of death
• Minimal HE predicts progression to overt HE and negatively impacts driving ability and quality of life

Recent Evidence Update (PubMed 2025-2026)