What is the treatment for hepatic encephalopathy?

Treatment of Hepatic Encephalopathy

Lactulose is the first-line treatment for overt hepatic encephalopathy, dosed at 25 mL orally every 12 hours and titrated to achieve 2-3 soft bowel movements per day, with rifaximin 550 mg twice daily added for secondary prophylaxis after an episode or when lactulose alone is insufficient. 1, 2, 3, 4

Four-Pronged Management Approach

Every patient with overt hepatic encephalopathy requires simultaneous attention to four critical elements 1, 2:

1. Airway Protection and Intensive Monitoring

• Patients with grade III/IV hepatic encephalopathy or those unable to protect their airway require intensive care unit admission and possible intubation 2, 5
• Position the head elevated at 30 degrees to reduce intracranial pressure 5
• Avoid sedatives as they interfere with neurological assessment and have delayed clearance in liver failure 5

2. Rule Out Alternative Causes of Altered Mental Status

• Alternative causes of encephalopathy are not infrequent in patients with advanced cirrhosis 1
• Obtain brain imaging to exclude structural lesions, particularly in atypical presentations 5
• Check for hypoglycemia, electrolyte disturbances, and other metabolic derangements 2

3. Identify and Correct Precipitating Factors

• This is of paramount importance because nearly 90% of patients can be treated with just correction of the precipitating factor 1, 2
• Common precipitating factors include:
  • Infections (obtain blood cultures, urinalysis, diagnostic paracentesis if ascites present) 2, 5
  • Gastrointestinal bleeding (check hemoglobin, perform nasogastric lavage if indicated) 2
  • Electrolyte disturbances (particularly hypokalemia and hyponatremia) 2
  • Medication non-compliance with lactulose 2
  • Dehydration and hypotension 6
  • Use of benzodiazepines, psychoactive drugs, or alcohol 6
  • Hepatocellular carcinoma 6

4. Commence Empirical Hepatic Encephalopathy Treatment

Pharmacological Management

First-Line: Lactulose

• Start lactulose 25 mL (or 20 grams) orally every 12 hours 2, 3
• Titrate to achieve 2-3 soft bowel movements per day 1, 2
• For patients unable to take oral medications, administer via nasogastric tube or use lactulose enemas (300 mL lactulose in 700 mL water, retained for 30-60 minutes) 1, 7
• Lactulose reduces blood ammonia levels by 25-50% through acidification of the gastrointestinal tract, which inhibits ammonia production by coliform bacteria and traps ammonia as non-absorbable NH4+ 3, 8, 7
• Clinical response is observed in about 75% of patients 3
• Critical pitfall: Overuse of lactulose can paradoxically precipitate hepatic encephalopathy through excessive diarrhea leading to dehydration and electrolyte disturbances 2

Add-On Therapy: Rifaximin

• Add rifaximin 550 mg orally twice daily if lactulose alone is insufficient or for secondary prophylaxis after an episode 2, 4
• In the pivotal trials for hepatic encephalopathy, 91% of patients were using lactulose concomitantly with rifaximin 4
• Rifaximin decreases intestinal production and absorption of ammonia by altering gastrointestinal flora and is almost completely excreted unchanged in feces 8
• Do not use rifaximin as monotherapy for acute overt hepatic encephalopathy—always combine with lactulose initially 5
• Rifaximin has fewer side effects than older antibiotics like neomycin (which causes ototoxicity and nephrotoxicity) or metronidazole (which causes neurotoxicity with long-term use) 2, 8, 6

Alternative or Additional Therapies

• Oral branched-chain amino acids (BCAAs) can be used for patients not responding to conventional therapy, with meta-analyses showing improvement in manifestations of episodic hepatic encephalopathy 2
• IV L-ornithine L-aspartate (LOLA) is an alternative for refractory cases, improving psychometric testing and reducing postprandial venous ammonia levels 2
• Older antibiotics (neomycin, metronidazole) are alternative choices but long-term use is limited by toxicity 2, 6

Prevention Strategies

Secondary Prophylaxis (After an Episode)

• Secondary prophylaxis after an episode of overt hepatic encephalopathy is strongly recommended 1, 2
• Continue lactulose indefinitely at the dose that maintains 2-3 bowel movements daily 2, 5
• Add rifaximin 550 mg twice daily for long-term prevention if hepatic encephalopathy recurs despite lactulose 2, 5
• Critical pitfall: Do not discharge patients without secondary prophylaxis—recurrence risk is high without maintenance lactulose 5

Primary Prophylaxis

• Primary prophylaxis is not required except in patients with cirrhosis at high risk for developing hepatic encephalopathy (such as those with prior TIPS placement or large spontaneous portosystemic shunts) 1, 2
• Neither rifaximin nor lactulose has been shown to prevent post-TIPS hepatic encephalopathy better than placebo 2

Special Considerations

Liver Transplantation

• Recurrent intractable overt hepatic encephalopathy, together with liver failure, is an indication for liver transplantation 1, 2
• For patients with preserved liver function but recurrent hepatic encephalopathy, evaluate for large spontaneous portosystemic shunts that may be amenable to closure 2

Severe Liver Disease

• Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19 4
• There is increased systemic exposure to rifaximin in patients with more severe hepatic dysfunction 4

Nutritional Support

• Provide adequate protein and energy to maintain positive nitrogen balance and prevent sarcopenia, which worsens hepatic encephalopathy 5
• Protein restriction is no longer recommended in modern hepatic encephalopathy management 5

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting diagnostic confirmation—start empirical therapy immediately 2
• Do not assume all altered mental status is hepatic encephalopathy—failure to identify precipitating factors may lead to poor treatment response 2, 5
• Do not forget that controlling the precipitating factor (especially infection) is paramount—the encephalopathy will not fully resolve until the underlying trigger is adequately treated 5
• Monitor for lactulose-induced dehydration and electrolyte abnormalities, which can worsen encephalopathy 2
• Regularly assess for medication side effects, particularly with long-term use of antibiotics 2