Key Facts

Hepatic encephalopathy (HE) is a common and serious complication of cirrhosis that significantly impacts quality of life and prognosis. It is potentially reversible with treatment of precipitants and appropriate therapy.

Epidemiology

Minimal HE is present in ~50-70% of cirrhosis patients. Overt HE affects 30-45% of cirrhotics. It is the second most common cause of hospital admission in decompensated cirrhosis (after ascites). HE after TIPSS occurs in ~30%.

Aetiology

HE occurs in three clinical settings:

• Type A: associated with acute liver failure
• Type B: associated with portosystemic bypass without intrinsic liver disease (rare)
• Type C: associated with cirrhosis and portal hypertension (most common)

Pathophysiology

Ammonia is the central neurotoxin. In health, ammonia from gut bacterial urease activity and amino acid deamination is metabolised to urea by the liver (urea cycle). In cirrhosis:

1. Hepatocyte dysfunction reduces ammonia clearance
2. Portosystemic shunts bypass the liver
3. Elevated arterial ammonia crosses the blood-brain barrier
4. Astrocytes metabolise ammonia via glutamine synthetase → glutamine accumulation → osmotic astrocyte swelling → low-grade cerebral oedema
5. Neuroinflammation (activated microglia, increased BBB permeability) synergises with ammonia
6. GABA-ergic tone increases (endogenous benzodiazepine-like compounds)

Minimal HE (Subclinical)

• No clinically obvious symptoms
• Impaired psychometric testing (number connection test, Stroop test)
• Impaired driving ability
• Reduced quality of life

Overt HE (West Haven Classification)

• Grade I: altered sleep-wake cycle, short attention span, mild confusion, irritability
• Grade II: lethargy, inappropriate behaviour, disorientation to time, asterixis (flapping tremor)
• Grade III: somnolent but rousable, grossly confused, bizarre behaviour, marked asterixis
• Grade IV: coma, unresponsive to painful stimuli

Episodic vs Persistent

• Episodic: precipitated events, resolves with treatment
• Recurrent: ≥2 episodes within 6 months
• Persistent: continuous cognitive impairment despite treatment

Red Flags

• Grade III-IV encephalopathy (risk of aspiration, airway compromise)
• No identifiable precipitant (consider HCC, PVT, TIPSS dysfunction)
• Failure to respond to treatment within 48-72 hours
• Focal neurological signs (exclude structural intracranial pathology — HE is diffuse/global)

Bedside

• GCS and West Haven grading: serial assessment
• Blood glucose: exclude hypoglycaemia
• Asterixis assessment: ask patient to dorsiflex wrists with arms extended — positive = flapping tremor
• Number connection test (NCT-A): for minimal HE screening

Bloods

• Ammonia (venous): usually raised in HE but level does not correlate well with severity; useful if diagnosis uncertain; must be transported on ice and analysed rapidly
• FBC: infection screen
• U&Es: electrolytes, renal function (precipitant)
• LFTs: liver function assessment
• CRP: infection marker
• Blood cultures: if infection suspected
• Blood glucose: exclude hypoglycaemia

Imaging

• CT head: if first presentation, focal neurology, or failure to improve (exclude subdural haematoma, intracerebral bleed, abscess)

Special Tests

• Ascitic tap: if ascites present — exclude SBP (common precipitant)
• CXR, urine MC&S: infection screening
• Psychometric testing (PHES): gold standard for minimal HE diagnosis
• Critical flicker frequency (CFF): quantitative test for minimal HE

Non-pharmacological

• Identify and treat precipitants (most important step): infection, GI bleeding, constipation, dehydration, electrolyte imbalance (hyponatraemia, hypokalaemia), sedatives/opioids, excess protein
• Nutritional support: do NOT restrict protein (increases muscle wasting and worsens HE long-term); 1.2-1.5 g/kg/day protein; small frequent meals; late-evening snack
• Avoid sedatives: benzodiazepines, opioids (use with extreme caution if needed)

Pharmacological

• Lactulose: 15-30 mL BD-QDS; titrate to 2-3 soft stools/day; for both treatment and prophylaxis
  • Enema: lactulose 300 mL in 700 mL water if unable to take orally (grade III-IV)
• Rifaximin 550 mg BD: non-absorbable antibiotic; add to lactulose for secondary prophylaxis after first episode of overt HE — reduces recurrence by 50% (NICE TA613; Bass et al. NEJM 2010)
• IV antibiotics: for concurrent infection
• Flumazenil: may produce transient improvement in HE (GABA receptor antagonist) but not routinely recommended; consider if benzodiazepine use suspected
• L-ornithine L-aspartate (LOLA): promotes ammonia metabolism; some evidence for IV use in overt HE; limited availability in UK

Surgical/Interventional

• TIPSS reduction/occlusion: if HE is clearly precipitated by TIPSS
• Liver transplantation: definitive cure; HE is an indication for transplant assessment

Referral Criteria

• All overt HE to hepatology
• Transplant assessment after first episode of overt HE (poor prognostic marker)
• ICU if grade III-IV with airway compromise
• Consider minimal HE screening in cirrhotics with impaired QoL or driving concerns

Development of overt HE is a major prognostic event in cirrhosis — 1-year survival ~40%. Recurrence is common (~40% within 6 months) — rifaximin prophylaxis reduces this. Minimal HE impairs driving ability and quality of life. HE after TIPSS is common (~30%) but usually manageable. Persistent/refractory HE has very poor prognosis without transplant. Post-transplant, cognitive function usually improves significantly.

Common Precipitants of HE

West Haven Classification