What are the treatment recommendations for hepatic encephalopathy?

Treatment Recommendations for Hepatic Encephalopathy

Lactulose is the first-line treatment for hepatic encephalopathy, titrated to achieve 2-3 soft bowel movements per day, with rifaximin 550 mg twice daily added as secondary prophylaxis after recurrent episodes (more than one additional episode within 6 months of the first). 1

Initial Management: The Four-Pronged Approach

1. Identify and Correct Precipitating Factors (Resolves ~90% of Cases)

The most critical step is identifying triggers, which include 1, 2:

• Infections (most common precipitant)
• Gastrointestinal bleeding
• Constipation
• Dehydration and electrolyte disturbances (especially hyponatremia)
• Sedative medications (particularly benzodiazepines)
• Acute kidney injury
• Alkalosis

2. Rule Out Alternative Causes of Altered Mental Status

Do not automatically attribute confusion to hepatic encephalopathy 2, 3:

• Obtain brain imaging (CT or MRI) if diagnostic doubts exist, non-response to treatment, focal neurological signs, or first episode 1
• Check ammonia level: a normal ammonia level argues strongly against hepatic encephalopathy 1, 3
• Consider substance intoxication/withdrawal, drug toxicity, intracranial bleeding, seizures, and primary psychiatric disorders 3

3. Provide Appropriate Supportive Care

• Grades 3-4 hepatic encephalopathy require ICU admission due to aspiration risk and inability to protect airway 1, 2
• Grades 1-2 can typically be managed on a medicine ward 2
• Avoid sedatives when possible; if needed, use short-acting agents like propofol or dexmedetomidine 3
• Benzodiazepines are absolutely contraindicated as they precipitate and worsen hepatic encephalopathy 3

4. Start Empirical Treatment Without Delay

First-Line Treatment: Lactulose

Dosing and Administration 1, 2, 4:

• Start 25 mL orally every 12 hours (or 15-30 mL three times daily)
• Titrate to achieve 2-3 soft bowel movements per day (not diarrhea)
• If unable to take orally, administer via nasogastric tube 2
• For grades 3-4 or patients with ileus: use lactulose enema (300 mL lactulose in 700 mL water) 3
• Clinical response occurs in approximately 75% of patients, with 25-50% reduction in blood ammonia levels 4, 5

Mechanism: Lactulose acidifies the gastrointestinal tract, reducing ammonia production by coliform bacteria and increasing bacterial incorporation of nitrogen 6

Common Pitfall: Overuse of lactulose can cause dehydration, hypernatremia, aspiration, and perianal skin irritation 7. The goal is soft stools, not diarrhea.

Secondary Prophylaxis After First Episode

After the first episode of overt hepatic encephalopathy, continue lactulose indefinitely as secondary prophylaxis 1, 2:

• This prevents recurrence and should be maintained long-term
• Lactulose reduces recurrence from 46.8% to 19.6% over 14 months 8

Add-On Therapy: Rifaximin

Add rifaximin 550 mg twice daily when 1, 9:

• Patient experiences more than one additional episode within 6 months of the first episode despite lactulose therapy
• Lactulose alone fails to prevent recurrence

Evidence for Rifaximin 1, 7, 9:

• Reduces risk of hepatic encephalopathy recurrence by 58% when added to lactulose
• Improves recovery within 10 days and shortens hospital stays
• In clinical trials, 91% of patients were using lactulose concomitantly
• Nearly completely excreted unchanged in feces with minimal systemic absorption

Important Caveat: Rifaximin has not been adequately studied in patients with MELD scores >25, and only 8.6% of trial patients had MELD scores over 19 9

Special Clinical Scenarios

Gastrointestinal Bleeding

Rapid removal of blood from the gastrointestinal tract using lactulose or mannitol by nasogastric tube, or lactulose enemas, prevents hepatic encephalopathy 1

Post-TIPS Hepatic Encephalopathy

Neither rifaximin nor lactulose prevents post-TIPS hepatic encephalopathy better than placebo 1, 7:

• Routine prophylactic therapy is not recommended for post-TIPS patients
• If severe hepatic encephalopathy develops post-TIPS, consider shunt diameter reduction 1
• Rifaximin can be considered for prophylaxis prior to non-urgent TIPS placement 1

Recurrent/Persistent Hepatic Encephalopathy Despite Treatment

Consider the following interventions 1, 7:

• Evaluate for large spontaneous portosystemic shunts that may be amenable to embolization (in patients with MELD <11)
• Replace animal protein with vegetable and dairy protein (without compromising total protein intake)
• Assess for liver transplantation - recurrent intractable hepatic encephalopathy is an indication for transplant evaluation 1, 2

Covert (Minimal) Hepatic Encephalopathy

Treatment should be considered to prevent progression to overt hepatic encephalopathy 1:

• Use lactulose as first-line therapy 1
• Screen using the Animal Naming Test where available 1

Alternative and Adjunctive Therapies

IV L-ornithine L-aspartate can be used as alternative or additional therapy for patients nonresponsive to conventional treatment (oral form is ineffective) 7

Oral branched-chain amino acids improve manifestations and can be used as alternative or additional therapy (IV form is ineffective for acute episodes) 7

Nutritional Management

Do not restrict protein 7:

• Protein restriction worsens malnutrition and sarcopenia, which are risk factors for hepatic encephalopathy
• Encourage small, frequent meals throughout the day with a late-night snack
• Address malnutrition present in approximately 75% of patients 2
• Provide multivitamin supplementation 2
• Avoid prolonged fasting periods 7

When to Discontinue Prophylactic Therapy

Discontinuation may be considered only when 1, 2:

• Precipitating factors are well-controlled (infections treated, variceal bleeding resolved)
• Liver function has significantly improved
• Nutritional status has substantially improved
• Decision should be made on an individual basis with close monitoring

Important: Patients with positive tests for covert hepatic encephalopathy before stopping therapy are at higher risk for recurrence 1

Medications to Avoid

Zinc supplementation is not routinely recommended 1

Routine prophylactic antibiotics (other than rifaximin for secondary prophylaxis) are not indicated 1

Liver Transplantation Considerations

Refer for transplant evaluation 1, 2:

• After the first episode of overt hepatic encephalopathy (for evaluation)
• Recurrent or persistent hepatic encephalopathy not responding to treatment (urgent evaluation)
• Hepatic myelopathy (consider transplant as soon as possible - no other therapeutic option) 1