What is the treatment for hepatic encephalopathy in a patient with a history of liver disease, particularly cirrhosis, presenting with symptoms such as confusion, altered mental status, or lethargy?

Treatment of Hepatic Encephalopathy

Start lactulose immediately at 25 mL orally every 12 hours, titrated to achieve 2-3 soft bowel movements daily, while simultaneously identifying and correcting precipitating factors—this four-pronged approach of stabilization, exclusion of alternative diagnoses, precipitating factor correction, and empirical lactulose therapy resolves HE in approximately 75% of patients. 1, 2

Immediate Management Priorities

Identify and Correct Precipitating Factors

• Precipitating factors cause HE in nearly 90% of cases and their correction alone resolves most episodes. 3, 1
• Systematically evaluate for:
  • Infections (spontaneous bacterial peritonitis, pneumonia, urinary tract infection): obtain complete blood count with differential, C-reactive protein, chest X-ray, urinalysis with culture, blood cultures, and diagnostic paracentesis if ascites present 3
  • Gastrointestinal bleeding: perform endoscopy, complete blood count, digital rectal examination, and stool blood test 3
  • Constipation: take detailed history and obtain abdominal X-ray 3
  • Electrolyte disturbances (hyponatremia, hypokalemia): check serum sodium and potassium 3, 4
  • Dehydration from diuretics or paracentesis: assess skin elasticity, blood pressure, pulse rate 3
  • Medication non-compliance with lactulose 4
  • Benzodiazepines or opioids: take medication history; these are contraindicated in decompensated cirrhosis 3, 4
  • Proton pump inhibitors: restrict to strict validated indications only 4

Exclude Alternative Causes of Altered Mental Status

• Obtain blood glucose, electrolytes, inflammatory markers, full blood count, blood alcohol level, ammonia (though not diagnostic), thyroid-stimulating hormone 4
• Consider brain imaging when structural lesions cannot be excluded clinically 3
• Do not rely on ammonia levels for diagnosis, staging, or prognosis—they lack clinical utility for these purposes 1

Grade-Specific Management

Grades I-II (Mild to Moderate)

• Manage on medicine ward with frequent mental status checks, though ICU is preferable 1
• Grade I: mild alterations in consciousness, subtle personality changes, decreased attention, sleep disturbances, irritability or apathy, difficulty with complex cognitive tasks 1
• Grade II: mild disorientation, pronounced lethargy, inappropriate behavior, asterixis, dysarthric or slow speech 1
• Transfer to ICU immediately if level of consciousness declines 1
• Avoid all sedatives as they worsen encephalopathy and have delayed clearance in liver failure 1

Grades III-IV (Severe)

• Require ICU admission with intensive monitoring 1, 5
• Intubate the trachea to protect airway 1, 5
• Elevate head of bed 1
• Minimize stimulation 1
• Cerebral edema occurs in 25-35% of grade III patients and 65-75% of grade IV patients 1

Pharmacologic Treatment

First-Line: Lactulose

• Start lactulose 25 mL (or 20-30 g) orally every 1-2 hours until patient has at least 2 bowel movements per day 3, 1
• After initial response, titrate to achieve 2-3 soft stools daily 3, 1, 2
• Equivalent daily dose of lactitol is 67-100 g 3
• Achieves clinical response in approximately 75% of patients 1, 2
• Reduces blood ammonia levels by 25-50% 2

Alternative Routes for Lactulose

• If unable to take orally: administer via nasogastric tube 3
• If severe HE (Grade 3 or higher) or unable to take orally/via nasogastric tube: give enema of 300 mL lactulose mixed with 700 mL water, 3-4 times per day 3
• Retain enema solution in intestine for at least 30 minutes 3

Second-Line: Add Rifaximin

• Add rifaximin 550 mg twice daily if patient has recurrent episodes despite lactulose 1, 6
• Reduces HE recurrence risk by 58% when added to lactulose 1
• In clinical trials, 91% of patients were using lactulose concomitantly with rifaximin 6
• Rifaximin has not been studied in patients with MELD scores >25; only 8.6% had MELD scores over 19 6

Alternative Antibiotics (When Rifaximin Unavailable)

• Neomycin 4-12 grams per day in divided doses for 5-6 days, though long-term use carries risks of ototoxicity, nephrotoxicity, and neurotoxicity 1, 7
• Metronidazole is another alternative with similar toxicity concerns 1

Additional Agents for Refractory Cases

• Oral branched-chain amino acids (BCAAs) can be used as alternative or additional agent for patients nonresponsive to conventional therapy 1
• IV L-ornithine L-aspartate (LOLA) can be used as alternative or additional agent for patients nonresponsive to conventional therapy 1

Secondary Prophylaxis (Prevention of Recurrence)

After First Episode

• Secondary prophylaxis with lactulose is mandatory after the first episode of overt HE 3, 1, 4
• Continue lactulose indefinitely, titrated to 2-3 soft stools daily 1, 5
• Evaluate for liver transplantation after the first episode of overt HE 1

After Second Episode or Recurrence Despite Lactulose

• Add rifaximin 550 mg twice daily 1, 4, 5
• Patients with previous bout of OHE have 40% cumulative risk of recurring OHE at 1 year 3
• Patients with recurrent OHE have 40% cumulative risk of another recurrence within 6 months, despite lactulose treatment 3

Nutritional Management

Protein Intake

• Do not restrict protein—this worsens malnutrition and sarcopenia, which are risk factors for HE 1, 4
• Provide moderate hyperalimentation with small, frequent meals throughout the day 1
• Include a late-night snack 1
• Avoid fasting periods which worsen HE 1
• Provide enough protein and energy to favor positive nitrogen balance and increase muscle mass 3, 4

Critical Pitfalls to Avoid

• Failing to systematically search for precipitating factors, which cause 90% of cases 1
• Not titrating lactulose adequately to achieve 2-3 stools per day 1
• Confusing HE with other causes of altered mental status 1
• Not initiating secondary prophylaxis after the first episode 1
• Relying exclusively on ammonia levels for diagnosis—they lack diagnostic, staging, or prognostic value 1
• Restricting protein intake, which worsens outcomes 1
• Using benzodiazepines in decompensated cirrhosis 4

Long-Term Follow-Up

Patient and Caregiver Education

• Effects of medication (lactulose, rifaximin) and potential side effects (diarrhea) 3, 4
• Importance of treatment adherence 3, 4
• Early signs of recurring HE 3, 4
• Actions to take if recurrence occurs (anticonstipation measures for mild recurrence, referral to physician if HE with fever) 3

Monitoring

• Monitor neurological manifestations to adjust treatment and investigate presence of covert HE or signs of recurring HE 3, 4
• Evaluate gait and walking to consider risk of falls 3, 4
• Treatment endpoints should cover cognitive performance (improvement in one accepted test as minimum) and daily life autonomy 3, 4

Liver Transplantation Consideration

• Recurrent intractable overt HE with liver failure is an indication for liver transplantation 1, 5
• Transplantation leads to significant improvement in most cognitive functions, though some mental deficits may persist 5