What is the recommended management of hepatic encephalopathy in an adult with chronic liver disease?

Management of Hepatic Encephalopathy in Chronic Liver Disease

Start lactulose 25 mL orally every 12 hours immediately, titrate to achieve exactly 2–3 soft bowel movements daily, and systematically search for precipitating factors—correcting these factors alone resolves approximately 90% of cases. 1

Immediate Four-Pronged Approach

Every patient with overt hepatic encephalopathy requires simultaneous implementation of four critical steps 2, 1:

1. Stabilize altered consciousness and protect the airway 1
2. Exclude alternative causes of altered mental status (intracranial hemorrhage, infection, metabolic derangements) 1, 3
3. Identify and correct precipitating factors (present in 80–90% of episodes) 1
4. Start empirical lactulose treatment without delay 1

Identification and Correction of Precipitating Factors

This is the cornerstone of management because correcting precipitating factors alone resolves hepatic encephalopathy in approximately 90% of patients 2, 1. Systematically evaluate and treat the following 1:

• Gastrointestinal bleeding: Obtain CBC, perform digital rectal exam, check stool occult blood, and proceed to endoscopy when indicated; treat with blood transfusion, endoscopic hemostasis, and vasoactive medications 1
• Infection: Order CBC with differential, CRP, chest X-ray, urinalysis/culture, blood cultures, and diagnostic paracentesis; start empiric broad-spectrum antibiotics immediately if infection is suspected 1, 3
• Constipation: Evaluate clinically and with plain abdominal radiography; manage with enemas or osmotic laxatives 1
• Dehydration: Hold diuretics and administer intravenous albumin or isotonic fluids after assessing skin turgor, vital signs, and basic metabolic panel 1
• Electrolyte disturbances: Correct sodium to target 140–145 mmol/L along with potassium, magnesium, and phosphate abnormalities 1
• Renal dysfunction: Monitor BUN, serum creatinine, cystatin C, and electrolytes; adjust nephrotoxic medications and optimize volume status 1

First-Line Pharmacologic Treatment

Lactulose is the first-line treatment for all grades of overt hepatic encephalopathy 2, 1, 3:

• Start lactulose 25 mL (or 20–30 g) orally every 12 hours 1
• Titrate to achieve exactly 2–3 soft bowel movements per day—not diarrhea 1
• Underdosing leads to treatment failure; overdosing causes dehydration, hypernatremia, aspiration risk, and severe perianal irritation 1
• Achieves clinical response in approximately 75% of patients 1
• If oral intake is impossible, administer via nasogastric tube 1

Management by Encephalopathy Grade

Grades I–II (Mild-to-Moderate)

• Manage on a medical ward with frequent mental status checks, though ICU is preferable 1
• Transfer to ICU immediately if level of consciousness declines 1
• Avoid sedatives (benzodiazepines, opioids) because they worsen encephalopathy and have delayed clearance in liver failure 1
• Perform head CT to exclude intracranial hemorrhage 1, 3
• Closely monitor glucose, potassium, magnesium, and phosphate levels 1

Grades III–IV (Severe)

Patients with grade III–IV encephalopathy require immediate ICU admission with endotracheal intubation for airway protection 1:

• Intubate immediately—patients cannot protect their airway and are at high risk of aspiration 1
• Elevate head of bed to 30° 1
• Minimize stimulation and Valsalva-type maneuvers 1
• Deliver lactulose via nasogastric tube if oral intake is impossible 1
• Treat seizures with phenytoin rather than sedatives 1
• Use low-dose propofol only if sedation is absolutely necessary (may reduce cerebral blood flow) 1
• For intracranial hypertension: give intravenous mannitol 0.5–1 g/kg as a bolus (repeat once or twice if serum osmolality < 320 mosm/L) 1
• Lactulose enema protocol (when oral/NG administration is not feasible): 300 mL lactulose mixed with 700 mL water, administered 3–4 times daily, retained in the intestine for at least 30 minutes until clinical improvement 1

Adjunctive Therapies for Acute Episodes

When lactulose alone is insufficient, consider the following evidence-based adjuncts 1:

• Intravenous albumin 1.5 g/kg/day combined with lactulose improves clinical recovery within 10 days (75% vs 53.3%; p = 0.03) 1
• Rifaximin 550 mg twice daily added to lactulose leads to faster recovery (76% vs 44% within 10 days; p = 0.004) and shorter hospital stay (5.8 days vs 8.2 days; p = 0.001) 1
• Intravenous L-ornithine-L-aspartate (LOLA) 30 g/day added to lactulose lowers hepatic encephalopathy grade within 1–4 days (odds ratio 2.06–3.04) and shortens time to symptom recovery (1.92 days vs 2.50 days; p = 0.002) 1
• Oral branched-chain amino acids 0.25 g/kg/day may be used as adjuncts in patients unresponsive to standard therapy 2, 1

Secondary Prophylaxis (Mandatory After First Episode)

Secondary prophylaxis with lactulose is mandatory after the first episode of overt hepatic encephalopathy—this is a Grade I, strong recommendation 2, 1, 3:

• Continue lactulose indefinitely, titrated to 2–3 soft stools daily 1, 3
• Add rifaximin 550 mg twice daily after a second episode or when recurrence occurs despite lactulose alone 1, 3, 4
• Rifaximin plus lactulose reduces recurrence risk by 58% (22.1% vs 45.9%; NNT = 4) and lowers hospitalization risk by 31% (13.6% vs 22.6%; NNT = 9) 1
• Long-term rifaximin therapy (>24 months) is safe and well tolerated 1
• Without secondary prophylaxis, 50–70% of patients experience recurrence within one year 1

Nutritional Management

Do not restrict protein—this worsens malnutrition and sarcopenia, which are risk factors for hepatic encephalopathy 1, 5:

• Provide adequate protein intake (1.2–1.5 g/kg/day) 5
• Offer moderate hyperalimentation with small, frequent meals throughout the day 1, 5
• Include a late-night snack 1, 5
• Avoid fasting periods which worsen hepatic encephalopathy 1

Role of Ammonia Testing

• A normal blood ammonia level should prompt reevaluation for alternative causes of altered mental status 2, 3
• Elevated ammonia does not correlate with encephalopathy severity or prognosis and has limited utility beyond excluding hepatic encephalopathy when normal 2, 1, 3

Liver Transplantation Evaluation

• Evaluate for liver transplantation after the first episode of overt hepatic encephalopathy 1, 3
• Recurrent intractable overt hepatic encephalopathy with liver failure is a formal indication for liver transplantation 2, 1, 3, 5
• Overall survival after an overt encephalopathy episode is 42% at 1 year and 23% at 3 years 1

Critical Pitfalls to Avoid

• Failing to systematically search for precipitating factors, which cause 90% of cases 1
• Not titrating lactulose adequately to achieve exactly 2–3 stools per day 1
• Confusing hepatic encephalopathy with other causes of altered mental status without exclusion of alternative diagnoses 1
• Not initiating secondary prophylaxis after the first episode 1
• Relying exclusively on ammonia levels for diagnosis—they lack diagnostic, staging, or prognostic value 2, 1
• Restricting protein intake, which worsens outcomes 1, 5
• Using benzodiazepines, which have delayed clearance and exacerbate encephalopathy 1

Agents NOT Recommended

• Neomycin and metronidazole are not recommended because of significant adverse effects (intestinal malabsorption, nephro-/ototoxicity for neomycin; peripheral neuropathy for metronidazole) 1
• Rifaximin monotherapy is not recommended as first-line treatment for acute overt encephalopathy; evidence quality does not support it as a first-line agent 1