What is the diagnosis and treatment for cirrhosis with associated hepatic encephalopathy?

Hepatic Encephalopathy in Cirrhosis: Diagnosis and Treatment

Diagnosis

Hepatic encephalopathy (HE) in cirrhosis is diagnosed clinically by identifying altered mental status in a patient with known liver disease, graded using the West Haven criteria (Grade 0-4), while simultaneously ruling out other causes of encephalopathy and identifying precipitating factors. 1

Clinical Assessment

• Mental status grading: Use West Haven criteria where Grade 0 = minimal/covert HE (only detected by psychometric testing), Grade 1 = trivial lack of awareness, Grade 2 = lethargy/personality changes, Grade 3 = somnolence/confusion, and Grade 4 = coma 1

• Physical examination findings: Look specifically for asterixis (flapping tremor), altered consciousness, confusion, impaired cognition, personality changes, and impaired memory 1, 2

• Psychometric testing: Number connection test (NCT-A and B), figure connection test for illiterate patients (FCT-A and B), digit symbol test (DST), and object assembly test (OAT) can detect covert HE, with 67-80% of recovered HE patients showing abnormalities 3

Identifying Precipitating Factors (Critical First Step)

Controlling precipitating factors is paramount, as nearly 90% of patients can be treated with just correction of the precipitating factor alone. 1

The major precipitating factors and their diagnostic workup include 1:

• Gastrointestinal bleeding: Endoscopy, complete blood count, digital rectal examination, stool blood test
• Infection: Complete blood count with differential, C-reactive protein, chest X-ray, urinalysis and urine culture, blood culture, diagnostic paracentesis
• Constipation: History-taking, abdominal X-ray
• Dehydration: Assess skin elasticity, blood pressure, pulse rate
• Renal dysfunction: Serum urea nitrogen, serum creatinine, serum cystatin C, serum electrolyte
• Electrolyte imbalances: Serum sodium and potassium concentration (hypokalemia disrupts ammonia management) 1, 4
• Medications: History of benzodiazepine or opioid use 1, 5
• Acute liver dysfunction: Liver function tests, prothrombin time

Role of Ammonia Testing

• Blood ammonia levels alone do not add diagnostic, staging, or prognostic value for HE in chronic liver disease 1
• However, a normal ammonia level should prompt reevaluation of the diagnosis to consider alternative causes of altered mental status 1

Treatment of Acute Overt HE

Non-absorbable disaccharides (lactulose or lactitol) are the first-line treatment for acute overt hepatic encephalopathy, with 70-90% recovery rates, and should be initiated immediately while simultaneously treating precipitating factors. 1, 6

Four-Pronged Management Approach 1:

1. Airway protection: Patients with Grade 3-4 HE require intensive care monitoring and may need intubation for airway protection 1, 5

2. Rule out alternative causes: Evaluate for other causes of altered mental status (infection, metabolic derangements, intracranial pathology) 1

3. Identify and treat precipitating factors: Address the specific triggers identified above 1

4. Initiate empirical HE treatment: Start lactulose immediately 1

Lactulose Dosing Protocol

For acute overt HE 1:

• Initial dose: 30-45 mL (20-30 g) orally every 1-2 hours until patient has at least 2 bowel movements per day
• Maintenance: Titrate to achieve 2-3 soft stools per day
• If unable to take orally: Administer via nasogastric tube 1
• For severe HE (Grade ≥3) or inability to take oral/NG medications: Use lactulose enema—300 mL lactulose mixed with 700 mL water, administered 3-4 times daily, retained for at least 30 minutes 1

The FDA label confirms lactulose reduces blood ammonia levels by 25-50%, with clinical response in approximately 75% of patients 6

Rifaximin as Add-On Therapy

• Rifaximin can be combined with lactulose for treatment of acute HE, though evidence is stronger for prevention than acute treatment 1
• Rifaximin 550 mg twice daily is the standard dose 7
• Important: Rifaximin alone is not recommended as first-line monotherapy for acute overt HE 1

Additional Therapies

• Oral branched-chain amino acids (BCAA) and intravenous L-ornithine L-aspartate (LOLA) or albumin can be used as adjunctive treatments 1
• Flumazenil: Only for HE precipitated by benzodiazepines; not a first-line agent 1
• Avoid: Benzodiazepines and opioids, which can precipitate or worsen HE 1, 5

Prevention of HE Recurrence (Secondary Prophylaxis)

After the first episode of overt HE, secondary prophylaxis must be initiated, as 50-70% of patients will experience recurrence within 1 year. 1

First-Line Prevention

Lactulose or lactitol is the first-line therapy for preventing HE recurrence, reducing recurrence risk by 56% (RR 0.44,95% CI: 0.31-0.64) 1, 3

• Continue lactulose at doses that maintain 2-3 soft stools daily 1
• One landmark trial showed lactulose reduced HE recurrence from 46.8% to 19.6% over 14 months (P=0.001) 3

Rifaximin Add-On for Refractory Cases

If lactulose alone fails to prevent recurrence, add rifaximin 550 mg twice daily 1, 7

• A pivotal trial showed rifaximin plus lactulose reduced breakthrough HE by 58% compared to placebo plus lactulose (22% vs 46%, P<0.001) 7
• Rifaximin also reduced HE-related hospitalizations by 50% 7
• Long-term safety: No increased risk of Clostridium difficile infection with rifaximin 1
• Rifaximin monotherapy can be considered only when lactulose is poorly tolerated 1

Nutritional Management

Protein restriction should be avoided as it induces protein catabolism, hepatic dysfunction, and sarcopenia 1

• Daily energy intake: 35-40 kcal/kg 1
• Protein intake: 1.2-1.5 g/kg daily 1
• Meal frequency: 4-6 small meals per day including a night snack to prevent sarcopenia 1

Patient and Caregiver Education

Structured education significantly improves outcomes, reducing HE-related hospitalization by 86% (HR 0.14,95% CI: 0.02-0.77) 1

Education should cover 1:

• Effects and side effects of medications (diarrhea with lactulose)
• Importance of medication adherence
• Early symptoms and signs of recurring HE
• Actions to take if recurrence begins

Liver Transplantation

Liver transplantation is indicated for 1:

• Recurrent intractable overt HE that does not respond to medical treatment
• Acute liver failure with HE (poor prognosis: 42% survival at 1 year, 23% at 3 years after an OHE episode) 1

Critical Pitfalls to Avoid

• Do not delay lactulose while waiting for ammonia levels or other test results 1
• Do not restrict protein long-term, as this worsens outcomes 1
• Do not use benzodiazepines or opioids in cirrhotic patients, as they precipitate HE 1, 5
• Do not forget to check and correct electrolytes, particularly potassium, as hypokalemia disrupts ammonia metabolism 1, 4
• Do not use rifaximin alone as first-line treatment for acute HE; always start with lactulose 1
• Do not assume normal ammonia rules out HE, but do reconsider the diagnosis if ammonia is normal 1