What is the treatment for hepatic encephalopathy?

Treatment of Hepatic Encephalopathy

The treatment of hepatic encephalopathy requires a four-pronged approach: (1) supportive care for altered consciousness, (2) identification and correction of precipitating factors (which resolves ~90% of cases), (3) exclusion of alternative causes of altered mental status, and (4) empirical pharmacologic therapy with lactulose as first-line treatment, titrated to achieve 2-3 soft stools daily. 1

Initial Assessment and Stabilization

Airway Protection and Monitoring

• Patients with Grade III-IV hepatic encephalopathy (HE) require intensive care unit admission due to risk of airway compromise and need for intubation 2, 3
• Grade 0-II HE can typically be managed on a general medicine ward with frequent mental status checks 3
• Use the West Haven criteria for grading overt HE (Grades I-IV) and add Glasgow Coma Scale assessment for Grades III-IV 2

Exclude Alternative Diagnoses

• Obtain brain imaging (CT or MRI) to rule out other causes of altered mental status, particularly for first-time presentations, as intracranial hemorrhage risk is 5-fold increased in cirrhotic patients 1, 2
• Consider other causes: intracranial hemorrhage, stroke, metabolic encephalopathy (uremia, hypoglycemia), Wernicke-Korsakoff syndrome, infections (meningitis/encephalitis), and medication effects 1
• Blood ammonia levels do not add diagnostic, staging, or prognostic value for HE; however, a normal ammonia level should prompt reconsideration of the diagnosis 1, 2

Identify and Correct Precipitating Factors

This is the cornerstone of HE management, as nearly 90% of patients improve with correction of precipitating factors alone. 1, 3

Common Precipitating Factors and Their Management

Precipitating Factor	Diagnostic Approach	Treatment
Gastrointestinal bleeding	Endoscopy, CBC, digital rectal exam, stool blood test [1]	Transfusion, endoscopic therapy, vasoactive drugs [1]
Infection (most common)	CBC with differential, CRP, chest X-ray, urinalysis/culture, blood culture, diagnostic paracentesis [1]	Appropriate antibiotics [1,3]
Constipation	History, abdominal X-ray [1]	Enema or laxatives [1]
Dehydration	Skin turgor, blood pressure, pulse [1]	Stop/reduce diuretics, IV albumin infusion [1]
Hyponatremia (especially <130 mmol/L)	Serum sodium [1]	Stop/reduce diuretics, fluid restriction [1]
Hypokalemia	Serum potassium [1]	Potassium replacement, stop/reduce diuretics [1]
Benzodiazepines	Medication history [1]	Discontinue benzodiazepines, consider flumazenil [1]
Renal dysfunction	BUN, creatinine, electrolytes [1]	Stop/reduce diuretics, IV albumin [1]

Prevention of Precipitating Factors

• Monitor and correct hyponatremia in decompensated cirrhosis, as severe hyponatremia is a predisposing factor and associated with non-response to lactulose 1
• Limit proton pump inhibitors to strict validated indications (appropriate doses and durations) 1
• Contraindicate benzodiazepines in patients with decompensated cirrhosis 1

Pharmacologic Treatment

First-Line: Non-Absorbable Disaccharides (Lactulose)

Lactulose is the first-line treatment for overt HE and is FDA-approved for prevention and treatment of portal-systemic encephalopathy. 1, 4

Mechanism and Efficacy

• Reduces blood ammonia levels by 25-50% through intestinal acidification, converting ammonia to non-absorbable ammonium 4
• Produces osmotic laxative effect that flushes ammonia from the colon 1
• Clinical response observed in approximately 75% of patients 4

Dosing Strategy

• Initial dose: 25 mL (or 15-30 g) orally every 12 hours 1
• Titrate to achieve 2-3 soft or loose bowel movements per day 1, 2, 3
• For patients unable to swallow, administer via nasogastric tube 1
• Reduce dose once target stool frequency achieved—overuse can cause dehydration, hypernatremia, aspiration, and paradoxically worsen HE 1

Second-Line: Rifaximin

Rifaximin is FDA-approved for reduction in risk of overt HE recurrence in adults, with 91% of trial patients using concomitant lactulose. 5

When to Use Rifaximin

• Add rifaximin to lactulose for secondary prophylaxis after recurrent episodes of overt HE 1, 2, 3
• Rifaximin as monotherapy is not supported by solid data 1
• Not studied in patients with MELD scores >25; only 8.6% of trial patients had MELD >19 5

Dosing

• 550 mg orally twice daily for hepatic encephalopathy 5
• Can be taken with or without food 5

Alternative and Adjunctive Therapies

Branched-Chain Amino Acids (BCAAs)

• Oral BCAA-enriched formulations can be used as alternative or additional therapy in patients non-responsive to standard treatment 1
• Meta-analysis shows improvement in manifestations of episodic HE 1
• IV BCAAs have no effect on episodic HE 1

L-Ornithine L-Aspartate (LOLA)

• IV LOLA improves psychometric testing and reduces postprandial ammonia in patients with persistent HE 1
• Oral LOLA is ineffective 1

Flumazenil

• Transiently improves mental status in overt HE without improving recovery or survival 1
• Consider when benzodiazepine toxicity is suspected or to avoid intubation in marginal situations 1

Prophylaxis Strategies

Secondary Prophylaxis (After First Episode)

Secondary prophylaxis with lactulose is recommended after any episode of overt HE. 1, 2, 3

• Continue lactulose indefinitely, titrated to 2-3 soft stools daily 2, 3
• Add rifaximin 550 mg twice daily for patients with recurrent episodes despite lactulose 1, 2, 3
• Prophylaxis may only be discontinued when precipitating factors are well-controlled (infections treated, variceal bleeding resolved, liver/nutritional status significantly improved) 3

Primary Prophylaxis

• Primary prophylaxis is NOT routinely recommended except in cirrhotic patients at known high risk for developing HE 1

Supportive Care and Nutritional Management

Prevent Secondary Complications

• Provide appropriate supportive care to prevent fall-related injuries and aspiration pneumonia from altered consciousness 1
• Perform frequent mental status checks with ICU transfer if consciousness declines 3
• Monitor glucose, potassium, magnesium, and phosphate levels closely 3

Nutritional Considerations

• Address malnutrition present in ~75% of HE patients 3
• Provide moderate hyperalimentation with small, frequent meals throughout the day, including a late-night snack 3
• Do NOT restrict protein intake—excessive protein restriction is outdated and harmful 3
• Provide multivitamin supplementation 3

Special Considerations

Covert Hepatic Encephalopathy (Minimal HE and Grade I)

• Testing for covert HE should be considered in patients with impaired quality of life, employment implications, or public safety concerns (e.g., driving) 1, 2
• Treatment is not routinely recommended but may be considered when affecting daily functioning 2
• Consider animal naming test to detect covert HE 3

Liver Transplantation

Recurrent intractable overt HE with liver failure is an indication for liver transplantation evaluation. 1, 2, 3

Common Pitfalls to Avoid

• Failing to identify and treat precipitating factors, which are present in 80-90% of cases and resolve symptoms in ~90% when corrected 1, 2, 3
• Relying solely on ammonia levels for diagnosis, staging, or monitoring 1, 2, 3
• Not considering secondary prophylaxis after the first episode of overt HE 2, 3
• Inadequate titration of lactulose—either underdosing (ineffective) or overdosing (causing dehydration and worsening HE) 1, 2, 3
• Confusing HE with other causes of altered mental status without proper workup 2, 3
• Using rifaximin as monotherapy without lactulose 1, 5
• Restricting protein intake, which worsens malnutrition 3