Hepatic Encephalopathy

Overview

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of liver disease characterized by a spectrum of cognitive, psychiatric, and motor abnormalities. It occurs when the liver cannot adequately remove toxins from the blood, leading to their accumulation in the brain. This condition represents one of the most debilitating complications of cirrhosis and significantly impacts quality of life and survival.

The syndrome encompasses a wide range of manifestations, from subtle cognitive changes detectable only through specialized testing (minimal hepatic encephalopathy) to profound alterations in consciousness including coma. HE affects 30-45% of patients with cirrhosis and 10-50% of patients with transjugular intrahepatic portosystemic shunt (TIPS). The condition can be episodic, recurrent, or persistent, with each pattern having different implications for management and prognosis.

Understanding hepatic encephalopathy is crucial because it is both a marker of disease severity and a treatable complication. While the pathophysiology is complex and not fully understood, ammonia plays a central role, though other factors including inflammation, oxidative stress, and alterations in neurotransmission contribute. With appropriate management, many patients experience significant improvement in symptoms, though the underlying liver disease must also be addressed for optimal outcomes.

Symptoms

Hepatic encephalopathy presents with a wide spectrum of neuropsychiatric symptoms that can be classified by severity using the West Haven Criteria. Symptoms can develop gradually or appear suddenly, and their recognition is crucial for timely intervention.

Grade 0: Minimal Hepatic Encephalopathy

• No clinically evident symptoms
• Subtle cognitive deficits detectable only by psychometric testing
• Impaired driving ability
• Reduced work performance
• Increased risk of falls

Grade I: Mild HE

Grade II: Moderate HE

• Asterixis: Characteristic "flapping tremor" when arms extended
• Disorientation: To time, occasionally to place
• Inappropriate behavior: Loss of inhibition
• Slurred speech: Dysarthria
• Obvious personality change: Marked irritability or apathy
• Dyspraxia: Difficulty with purposeful movements

Grade III: Severe HE

• Marked somnolence but arousable
• Gross disorientation to time and place
• Bizarre behavior and agitation
• Semi-stupor with response to verbal stimuli
• Muscular rigidity and hyperreflexia
• Clonus and positive Babinski sign

Grade IV: Coma

• Complete unresponsiveness (coma)
• May or may not respond to painful stimuli
• Decerebrate or decorticate posturing
• Loss of reflexes as coma deepens
• Pupillary reactions usually preserved

Additional Clinical Features

• Fetor hepaticus: Sweet, musty breath odor
• Constructional apraxia: Inability to draw simple figures
• Hyperventilation: Due to respiratory alkalosis
• Hypothermia: In advanced stages
• Seizures: Rare but possible in severe cases

Covert vs. Overt HE

Covert HE (Grades 0-I)

• Affects 20-80% of cirrhotic patients
• Impacts quality of life and daily functioning
• Increased risk of progression to overt HE
• Associated with poor driving performance

Overt HE (Grades II-IV)

• Clinically apparent symptoms
• Requires hospitalization in most cases
• Associated with poor prognosis
• High risk of recurrence

Causes

Hepatic encephalopathy results from the liver's inability to detoxify substances that are harmful to the brain. While the exact pathophysiology is complex and multifactorial, several key mechanisms and precipitating factors have been identified.

Primary Pathophysiologic Mechanisms

Ammonia Hypothesis

• Production: Gut bacteria produce ammonia from dietary protein and urea
• Impaired clearance: Failing liver cannot convert ammonia to urea
• Portosystemic shunting: Ammonia bypasses liver detoxification
• Brain effects: Ammonia causes astrocyte swelling and dysfunction
• Glutamine accumulation: Leads to cerebral edema

Other Neurotoxins

• Mercaptans: Contribute to fetor hepaticus
• Short-chain fatty acids: Affect neurotransmission
• Phenols: Synergistic effect with ammonia
• False neurotransmitters: Aromatic amino acids
• Manganese: Accumulates in basal ganglia

Precipitating Factors

Increased Nitrogen Load

• GI bleeding: Most common precipitant
  • Variceal bleeding
  • Peptic ulcer disease
  • Portal hypertensive gastropathy
• Excessive dietary protein: Especially red meat
• Constipation: Increased ammonia production/absorption
• Azotemia: Renal dysfunction

Decreased Ammonia Clearance

• Worsening liver function: Progressive cirrhosis
• Portosystemic shunts:
  • TIPS placement
  • Spontaneous shunts
  • Surgical shunts
• Acute liver failure: Fulminant hepatitis
• Hepatocellular carcinoma: Reduced functional mass

Electrolyte and Metabolic Disturbances

• Hypokalemia: Increases renal ammonia production
• Alkalosis: Favors NH3 over NH4+, crosses blood-brain barrier
• Hyponatremia: Worsens cerebral edema
• Hypoglycemia: Impaired gluconeogenesis
• Hypoxia: Respiratory compromise

Infections

• Spontaneous bacterial peritonitis: Common in cirrhosis
• Urinary tract infections: Especially with urease-producing bacteria
• Pneumonia: Increased metabolic demands
• Cellulitis: Any systemic infection
• COVID-19: Associated with HE decompensation

Medications

• Benzodiazepines: Enhance GABA effects
• Opioids: Central nervous system depression
• Diuretics: Hypokalemia, dehydration
• Proton pump inhibitors: Alter gut microbiome
• Sedatives: Any CNS depressant

Underlying Liver Diseases

• Cirrhosis: Most common cause (any etiology)
• Acute liver failure: Rapid onset, cerebral edema
• Portosystemic shunts without cirrhosis: Congenital or acquired
• Severe acute alcoholic hepatitis: Even without cirrhosis
• Hepatocellular carcinoma: Reduced liver mass

Risk Factors

Understanding risk factors for hepatic encephalopathy helps identify high-risk patients and implement preventive strategies. These factors relate to both the development of HE and its recurrence.

Liver Disease Severity

• Child-Pugh class:
  • Class A: 5-10% risk
  • Class B: 25% risk
  • Class C: 50% risk
• MELD score: Higher scores correlate with HE risk
• Duration of cirrhosis: Risk increases over time
• Portal hypertension severity: Higher gradients increase risk

Previous HE Episodes

• Recurrence rate: 40% within 1 year
• Multiple episodes: Progressively higher risk
• Persistent cognitive impairment: Between episodes
• Non-compliance with therapy: Major risk factor

Portosystemic Shunting

• TIPS: 10-50% develop HE post-procedure
• Large spontaneous shunts: Splenorenal, paraumbilical
• Surgical shunts: Historical procedures
• Congenital shunts: Rare but significant

Comorbid Conditions

• Diabetes mellitus: Impaired ammonia metabolism
• Renal dysfunction: Reduced ammonia clearance
• Hyponatremia: Common in cirrhosis
• Sarcopenia: Reduced muscle ammonia metabolism
• Malnutrition: Protein-energy deficiency

Age and Demographics

• Advanced age: >65 years higher risk
• Male gender: Slightly higher incidence
• Cognitive reserve: Lower education associated with earlier detection
• Genetic factors: Glutaminase gene polymorphisms

Lifestyle Factors

• Poor medication adherence: Lactulose, rifaximin
• Irregular follow-up: Missed appointments
• Dietary indiscretion: High protein intake
• Constipation: Irregular bowel habits
• Alcohol use: Continued drinking with liver disease

Precipitant Exposure

• Infection risk: Immunocompromised state
• Bleeding risk: Varices, coagulopathy
• Medication exposure: Sedatives, analgesics
• Dehydration risk: Diuretic use, poor intake

Diagnosis

Diagnosing hepatic encephalopathy requires clinical assessment, exclusion of other causes of altered mental status, and often supportive testing. The diagnosis is primarily clinical, as no single test is diagnostic.

Clinical Assessment

History

• Known liver disease or risk factors
• Previous HE episodes
• Recent precipitating events
• Medication history
• Dietary protein intake
• Bowel movement frequency
• Sleep pattern changes

Physical Examination

• Mental status: Orientation, attention, memory
• Asterixis: "Flapping tremor" with arms extended
• Psychomotor tests:
  • Number connection test
  • Serial sevens
  • Signature comparison
• Constructional ability: Draw a star or clock
• Signs of liver disease: Jaundice, ascites, spider angiomas
• Fetor hepaticus: Sweet breath odor

Grading Systems

West Haven Criteria

• Grade 0: No detectable changes
• Grade I: Mild confusion, anxiety, shortened attention
• Grade II: Lethargy, disorientation to time
• Grade III: Somnolence, gross disorientation
• Grade IV: Coma

ISHEN Classification

• Type A: Acute liver failure
• Type B: Bypass without liver disease
• Type C: Cirrhosis
  • Episodic HE
  • Recurrent HE (>2 episodes in 6 months)
  • Persistent HE

Laboratory Tests

Ammonia Level

• Elevated in 90% of HE cases
• Normal level doesn't exclude HE
• Poor correlation with severity
• Useful for monitoring treatment response
• Must be processed immediately (on ice)

Other Blood Tests

• Liver function tests: Assess severity
• Electrolytes: Hypokalemia, hyponatremia
• Renal function: BUN, creatinine
• Complete blood count: Anemia, infection
• Coagulation studies: PT/INR
• Blood glucose: Exclude hypoglycemia
• Blood cultures: If infection suspected

Neurophysiological Tests

Psychometric Testing

• PHES: Psychometric Hepatic Encephalopathy Score
• Stroop test: Cognitive flexibility
• Critical flicker frequency: Visual discrimination
• Continuous reaction time: Sustained attention

Electroencephalography (EEG)

• Triphasic waves in advanced HE
• Diffuse slowing of background rhythm
• Not specific for HE
• Useful to exclude seizures

Neuroimaging

CT Scan

• Usually normal or shows cerebral edema
• Excludes intracranial hemorrhage
• May show signs of chronic liver disease

MRI Brain

• T1 hyperintensity in basal ganglia (manganese)
• T2/FLAIR hyperintensity (cerebral edema)
• MR spectroscopy shows increased glutamine
• Excludes other pathology

Differential Diagnosis

Must exclude other causes of altered mental status:

• Hypoglycemia
• Electrolyte imbalances
• Alcohol withdrawal or intoxication
• Wernicke encephalopathy
• Subdural hematoma
• Meningitis or encephalitis
• Uremia
• Drug intoxication
• Cerebrovascular accident
• Post-ictal state

Treatment Options

Treatment of hepatic encephalopathy focuses on reducing ammonia production and absorption, identifying and treating precipitating factors, and providing supportive care. Management strategies vary based on severity and whether HE is overt or covert.

Acute Management of Overt HE

Initial Stabilization

• Airway protection: Consider intubation for Grade III-IV
• IV access: For medications and fluids
• Monitor vitals: Blood pressure, oxygen saturation
• Glucose correction: If hypoglycemic
• Thiamine: 100mg IV before glucose

Identify and Treat Precipitants

• GI bleeding: Endoscopy, blood products, octreotide
• Infections: Cultures, empiric antibiotics
• Electrolyte correction:
  • Potassium replacement
  • Careful sodium correction
  • Avoid rapid shifts
• Stop offending medications: Benzodiazepines, opioids
• Treat constipation: Enemas, laxatives

Pharmacological Therapy

Lactulose (First-line)

• Mechanism: Acidifies colon, traps ammonia, cathartic effect
• Acute dosing: 30-45 mL orally every 1-2 hours until bowel movement
• Maintenance: 15-30 mL 2-4 times daily
• Goal: 2-3 soft bowel movements daily
• Enema: 300 mL in 700 mL water if unable to take orally
• Side effects: Bloating, flatulence, diarrhea

Rifaximin

• Mechanism: Non-absorbable antibiotic, alters gut flora
• Dose: 550 mg twice daily
• Use: Add-on to lactulose for recurrent HE
• Benefits: Reduces recurrence by 58%
• Well tolerated: Minimal side effects
• Cost: Expensive but cost-effective

Other Ammonia-Lowering Agents

• Polyethylene glycol:
  • Alternative to lactulose
  • 4 liters over 4 hours
  • Faster resolution in some studies
• L-ornithine L-aspartate:
  • Promotes ammonia metabolism
  • IV or oral formulations
  • More commonly used in Europe/Asia
• Sodium benzoate:
  • Alternative ammonia scavenger
  • 5-10 g daily
  • Limited availability

Nutritional Management

Protein Intake

• No protein restriction: Old practice now discouraged
• Target: 1.2-1.5 g/kg/day
• Small frequent meals: Better tolerated
• Vegetable protein: Better tolerated than meat
• Branched-chain amino acids: May be beneficial

Other Nutritional Considerations

• Zinc supplementation: If deficient
• Multivitamins: Including B-complex
• Avoid fasting: Worsens muscle breakdown
• Late evening snack: Reduces morning ammonia

Management of Minimal HE

• Treatment controversial: Benefit vs. cost
• Consider in:
  • Impaired driving
  • Work performance issues
  • Falls or injuries
  • Poor quality of life
• Options: Lactulose or rifaximin
• Monitor response: Psychometric testing

Prevention of Recurrence

• Continuous lactulose therapy: Titrate to bowel movements
• Add rifaximin: For breakthrough episodes
• Avoid precipitants:
  • Prompt infection treatment
  • Prevent constipation
  • Medication vigilance
  • Regular follow-up
• Patient education: Recognition of early symptoms

Advanced Therapies

Molecular Adsorbent Recirculating System (MARS)

• Albumin dialysis system
• Removes protein-bound toxins
• Bridge to transplant
• Limited availability

Liver Transplantation

• Definitive treatment
• Consider for recurrent/persistent HE
• MELD exception points may apply
• Cognitive recovery usually complete

Investigational Therapies

• Fecal microbiota transplantation: Alters gut microbiome
• Probiotics: VSL#3, lactobacillus
• Ammonia scavengers: Glycerol phenylbutyrate
• Albumin infusions: Beyond volume expansion

Prevention

Preventing hepatic encephalopathy involves both primary prevention in at-risk patients and secondary prevention to avoid recurrence. A comprehensive approach addressing modifiable risk factors is essential.

Primary Prevention

In High-Risk Patients

• Prophylactic lactulose:
  • Post-TIPS procedure
  • After variceal bleeding
  • Advanced cirrhosis (Child-Pugh C)
• Rifaximin prophylaxis: Selected high-risk cases
• Regular monitoring: Psychometric testing

Management of Liver Disease

• Treat underlying cause:
  • Antiviral therapy for hepatitis
  • Alcohol cessation
  • Weight loss for NASH
  • Immunosuppression for autoimmune hepatitis
• Prevent progression: Regular monitoring, lifestyle changes
• Manage complications: Varices, ascites

Secondary Prevention

Medication Adherence

• Education on importance: Explain consequences
• Simplify regimen: When possible
• Address barriers: Cost, side effects
• Involve caregivers: Medication supervision
• Regular refills: Avoid gaps in therapy

Precipitant Avoidance

• Infection prevention:
  • Pneumococcal vaccination
  • Annual influenza vaccine
  • COVID-19 vaccination
  • SBP prophylaxis when indicated
• Bleeding prevention:
  • Beta-blockers for varices
  • Proton pump inhibitors
  • Avoid NSAIDs
• Constipation prevention:
  • Adequate fiber intake
  • Hydration
  • Regular lactulose
  • Physical activity

Lifestyle Modifications

Dietary Management

• Regular meals: Avoid prolonged fasting
• Adequate protein: 1.2-1.5 g/kg/day
• Complex carbohydrates: Steady energy
• Late evening snack: Reduces morning ammonia
• Sodium restriction: If ascites present

Activity and Exercise

• Regular physical activity: As tolerated
• Maintain muscle mass: Reduces ammonia
• Fall prevention: Home safety assessment
• Driving assessment: If minimal HE

Monitoring and Follow-up

• Regular clinic visits: Every 3-6 months
• Laboratory monitoring:
  • Liver function tests
  • Electrolytes
  • Renal function
  • Ammonia levels if indicated
• Cognitive assessment: Serial testing
• Caregiver involvement: Education and support

Patient and Family Education

• Recognize early symptoms:
  • Sleep disturbances
  • Confusion
  • Personality changes
• Medication importance: Never stop suddenly
• Emergency plan: When to seek help
• Support resources: Patient organizations

Special Considerations

• Pre-procedure prophylaxis:
  • Before surgery
  • Before TIPS
  • Before chemotherapy
• Travel precautions:
  • Medication supply
  • Medical alert bracelet
  • Written medical summary

When to See a Doctor

Recognizing when to seek medical attention for hepatic encephalopathy is crucial for patients and caregivers. Early intervention can prevent progression and reduce complications.

Emergency Situations (Call 911)

• Severe confusion or disorientation: Unable to recognize people or place
• Unresponsiveness: Difficulty arousing patient
• Seizures: New onset in liver disease patient
• Violent or aggressive behavior: Risk to self or others
• Signs of GI bleeding:
  • Vomiting blood
  • Black, tarry stools
  • Severe abdominal pain
• Severe dehydration: Dizziness, rapid pulse, low blood pressure

Urgent Medical Evaluation (Within 24 Hours)

• New mental status changes:
  • Increased forgetfulness
  • Difficulty concentrating
  • Mood swings or irritability
  • Sleep pattern reversal
• Worsening tremor: New or progressive asterixis
• Speech changes: Slurring or difficulty finding words
• Suspected infection:
  • Fever or chills
  • Worsening abdominal pain
  • Urinary symptoms
  • Productive cough
• Medication issues:
  • Unable to take lactulose
  • Severe diarrhea from treatment
  • Missed multiple doses

Routine Medical Follow-up

• Stable patients: Every 3-6 months
• Recent HE episode: Within 1-2 weeks
• Medication adjustment: As directed
• Worsening liver function: More frequent visits

Contact Healthcare Provider For

• Subtle cognitive changes:
  • Family notices personality changes
  • Work performance decline
  • Driving difficulties
  • Frequent falls
• Treatment concerns:
  • Side effects from medications
  • Questions about diet
  • Need for dose adjustment
  • Cost or access issues
• New symptoms:
  • Increasing fatigue
  • Worsening jaundice
  • Swelling in legs or abdomen
  • Easy bruising

Caregiver Concerns

Caregivers should seek help when:

• Unable to manage patient at home
• Safety concerns (wandering, falls)
• Medication non-compliance
• Caregiver burnout or stress
• Need for additional support services

Pre-appointment Preparation

• Document symptoms:
  • Timeline of changes
  • Severity progression
  • Potential triggers
• Medication list: Including doses and adherence
• Recent events: Infections, dietary changes, new medications
• Questions: Write down concerns

Related Conditions

Hepatic encephalopathy is closely associated with various liver diseases and their complications. Understanding these relationships helps in comprehensive management.

Liver-Related Complications

• Portal hypertension: Drives portosystemic shunting
• Esophageal varices: Bleeding precipitates HE
• Ascites: Often coexists with HE
• Spontaneous bacterial peritonitis: Common precipitant
• Hepatorenal syndrome: Worsens ammonia clearance
• Hepatopulmonary syndrome: Hypoxia worsens HE

Metabolic Conditions

• Diabetes mellitus - impairs ammonia metabolism
• Hyponatremia - worsens cerebral edema
• Hypokalemia - increases ammonia production
• Metabolic alkalosis - increases NH3 crossing BBB

Neurological Differential Diagnoses

• Wernicke encephalopathy: Thiamine deficiency
• Alcohol withdrawal: Can mimic or coexist
• Uremic encephalopathy: From kidney failure
• Hypoglycemic encephalopathy: Check glucose
• Drug intoxication: Benzodiazepines, opioids

Conditions Affecting Prognosis

• Hepatocellular carcinoma: Reduces liver mass
• Sarcopenia: Muscle loss reduces ammonia metabolism
• Malnutrition: Common in advanced liver disease
• Depression: Affects compliance and outcomes
• Cognitive impairment: May persist after HE

References

1. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735.
2. Wijdicks EF. Hepatic Encephalopathy. N Engl J Med. 2016;375(17):1660-1670.
3. Rose CF, Amodio P, Bajaj JS, et al. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol. 2020;73(6):1526-1547.
4. Bajaj JS, Lauridsen M, Tapper EB, et al. Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus. Am J Gastroenterol. 2020;115(7):989-1002.
5. Butterworth RF. Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology. Drugs. 2019;79(Suppl 1):17-21.