Hepatic Encephalopathy

Neuropsychiatric syndrome characterized by cognitive and motor dysfunction, resulting from the liver’s inability to effectively clear ammonia and other toxins, and is classified by cause into:

Acute and chronic liver failure are covered in detail under Acute Liver Failure and Chronic Liver Disease.

Type 1
Secondary to acute liver failure. Encephalopathy secondary to acute liver failure is:
- Associated with cerebral oedema and ↑↑ ICP
- A severe and acute threat to life
  Responsible for most of the mortality burden of acute liver failure.
Type 2
Secondary to portosystemic shunting without liver disease.
Type 3
Secondary to cirrhosis. Typically:
- Encephalopathy without severe ↑ ICP
  Consequently has no:
  - Requirement for aggressive ICP control
  - Significant ↑ in mortality

Degree of hepatic encephalopathy is strongly associated with the degree of hyperammonaemia, and so is typically less severe in ACLF compared to ALF.

Epidemiology and Risk Factors

Pathophysiology

Aetiology

Clinical Features

Assessment

Hepatic encephalopathy has a wide variety of clinical appearances:

The Parson-Smith scale grades hepatic encephalopathy into:

Mild confusion/irritability, ↓ attention
Disorientation, drowsiness, inappropriate
Somnolent but rousable, incoherent
Coma

Asterixis
Delirium
- Inattention
- Psychomotor retardation
- Personality changes
- Agitation
- Somnolence
- Coma

History

Exam

Investigations

Bedside:

BSL
ABG
Primary respiratory alkalosis.

Laboratory:

Blood
- Electrolytes
- LFTs
- Ammonia
  Useful in Type A encephalopathy, not useful in Type C due to:
  - Fluctuating levels
  - Poorly correlated with degree of clinical encephalopathy
Other
- Paracentesis

Ammonia >200μmol/L associated with cerebral herniation.

Imaging:

Other:

Diagnostic Approach and DDx

Many patients with (or at risk for) hepatic encephalopathy are at risk for multifactorial delirium. However, the treatment for encephalopathy is also benign and can be initiated whilst conducting a search for other causes.

Diagnosis of encephalopathy should consider:

Triggers
- Infection
- GI bleeding
- ↑ Protein diet
- Non-compliance with rifaximin or lactulose
- AKI
- Portal vein thrombosis
- Intoxication
Features
- Delirium
  Typically hypoactive.
- Non-focal
- Stupor
- Respiratory alkalosis

Key differential diagnoses include:

Medication-induced delirium
- Opioids
- Alcohol intoxication
- Alcohol withdrawal
Infective delirium
Metabolic encephalopathy
- Wernicke’s
- ↓ BSL
- Uraemic
- Hyponatraemia

Management

Secure airway if high grade encephalopathy
Manage ICP with quad-H therapy in Type A disease
- Hyperventilation
- Haemodiafiltration
- Hypernatraemia
- Hypothermia
Correct ammonia with polyethylene glycol or lactulose
Identify and treat precipitants

Resuscitation:

Invasive intracranial pressure monitoring associated with ~10% intracranial haemorrhage rate.

A
- Secure if high grade (III/IV) encephalopathy
B
- Hyperventilation
  If required for ICP control.
C
- Defend cerebral perfusion
  MAP 65-70mmHg, or CPP >50mmHg if measuring ICP.
D
- ↑ ICP
  - General measures
    If grade 3/4 encephalopathy, recommend:
    - Intubation
    - Sedation
    - Avoid stimulation
    - Head-up positioning
  - Consider invasive ICP management if all of:
    - Grade 3-4 encephalopathy
    - Hyperacute liver failure
    - Ammonia >150mmolL
    - Young
E
- Hypothermia (35°C)
  In addition to ↓ in ICP, also ↓ proteolysis and ammonia production.
F
- Hypernatraemia
  If required for ICP control. Target 148-152mmol/L.

The combination of hyperventilation, haemodiafiltration, hypernatraemia, and hypothermia is referred to as quadruple-H or quad-H therapy.

Specific therapy:

Pharmacological
- Hyperammonaemia
  - Polyethylene glycol
    Preferred in severe encephalopathy. Results in rapid clearance of:
    - Stool
      And ammonia-producing bacteria.
    - Water
      Assists in ↑ Na⁺.
  - Lactulose
    May ↓ hepatic encephalopathy but lead to gaseous intestinal distension.
    - 15-45mL Q4-12H PO, adjusted to achieve >4 bowel actions/day
    - 300mL in 700mL of sterile water PR Q2H
      Nurse patient in the lateral position to optimise colonic spread.
  - Rifaximin 550mg PO BD
    Combination with lactulose more effective than lactulose alone.
Procedural
- Shunt ligation
  ↓ Porto-systemic shunting may improve encephalopathy, but ↑ portal hypertension and risk of variceal bleeding.
  - Closure of previous TIPS
  - Ligation
Physical

Lactulose, an osmotic diuretic, ↓ ammonia by several mechanisms:

Osmotic diuretic
↓ Intestinal transit time and ↓ absorption.
↑ Lactobacillus division
Non-ammonia producing gut flora.
Colonic acidification
- Lactulose is metabolised by gut bacteria into lactic and acetic acid
- The ↓ in colonic pH favours conversion of ammonia (NH₃) to ionised ammonium (NH₄⁺), which is trapped in the colon
  This is analogous to urinary alkalinisation for elimination of weak acids.
- Trapped ammonium is then cleared by the more mundane osmotic laxative effect

Rifaximin is a non-absorbed, broad-spectrum antibiotic that ↓ gut flora concentrations, ↓ ammonia production.

TIPS is covered under Transjugular Intrahepatic Portosystemic Shunt.

Supportive care:

G
- Feeding
  Enteral nutrition should be given.
- Thiamine supplementation

Disposition:

Preventative:

Rifaximin 550mg PO BD
Significant (~60%) in hepatic encephalopathy in patients with chronic liver disease.

Marginal and Ineffective Therapies

Anaesthetic Considerations

Complications

Prognosis

Death
- Type A
  High mortality if untreated.
- Type C
  - Favourable short-term prognosis
  - Poor long-term (1-3 year) prognosis in absence of transplantation
    - 1-year survival ~40%
    - 3-year survival ~20%