Causes and Treatment of Encephalopathy
Causes of Encephalopathy
Encephalopathy has multiple etiologies that must be systematically excluded before attributing altered mental status to a single cause, with hepatic encephalopathy being the most common in cirrhotic patients but requiring differentiation from infectious, metabolic, structural, and toxic causes. 1
Hepatic Encephalopathy - Precipitating Factors
The most critical aspect of managing hepatic encephalopathy is identifying precipitating factors, which are present in 80-90% of cases and resolve symptoms in approximately 90% when corrected: 1, 2, 3
- Infections (spontaneous bacterial peritonitis, urinary tract infections, pneumonia) 1, 2
- Gastrointestinal bleeding (variceal or non-variceal) 1, 2, 3
- Constipation 1, 2, 3
- Dehydration and electrolyte disturbances (hyponatremia, hypokalemia) 1, 2, 3
- Sedative medications (benzodiazepines, opioids) 1, 2
- Proton pump inhibitor use 1
- Hepatocellular carcinoma 4
Other Causes to Exclude
Brain imaging (CT or MRI) should be performed in first-time presentations, as intracranial hemorrhage risk is 5-fold increased in cirrhotic patients: 1, 3
- Intracranial hemorrhage or stroke 1, 3
- Infectious encephalitis (HSV, VZV, CMV in immunocompromised) 1
- Metabolic encephalopathy (uremia, hypoglycemia, hypoxia) 1
- Toxic encephalopathy (alcohol, drugs) 1
- In returning travelers: malaria, tuberculous meningitis, dengue, Japanese encephalitis 1
Treatment of Hepatic Encephalopathy
Four-Pronged Management Approach
Treatment follows a systematic four-step approach: airway protection for altered consciousness, exclusion of alternative causes, identification and correction of precipitating factors, and empirical hepatic encephalopathy treatment. 1, 2
Step 1: Initial Stabilization
- Grade III-IV encephalopathy requires ICU admission with airway protection and intensive monitoring 1, 2
- Grade I-II encephalopathy can be managed on a medicine ward with frequent mental status checks 2
- Avoid sedatives as they worsen encephalopathy and have delayed clearance in liver failure 2
Step 2: Identify and Correct Precipitating Factors
This is the cornerstone of management and resolves nearly 90% of cases: 1, 2, 3
- Treat infections with appropriate antibiotics 1, 2
- Control gastrointestinal bleeding 1, 2
- Correct dehydration and electrolyte abnormalities 1, 2, 3
- Discontinue sedatives and unnecessary medications 1, 2
- Relieve constipation 1, 2, 3
Step 3: Pharmacologic Treatment
First-Line: Lactulose
Lactulose is the first-line treatment for overt hepatic encephalopathy, with dosing titrated to achieve 2-3 soft stools daily. 1, 2, 3, 5
Dosing regimen: 5
- Acute treatment: 30-45 mL (20-30 grams) orally every 1-2 hours until bowel movement occurs, then reduce to maintenance dosing 1, 5
- Maintenance: 30-45 mL three to four times daily, adjusted to produce 2-3 soft stools per day 5
- Rectal administration: 300 mL lactulose mixed with 700 mL water/saline as retention enema for 30-60 minutes every 4-6 hours when oral route unavailable 5
Mechanism: Acidification of the gastrointestinal tract inhibits ammonia production by coliform bacteria 6
Common pitfall: Overuse of lactulose can cause aspiration, dehydration, hypernatremia, and severe perianal irritation—do not use excessive doses beyond what achieves 2-3 stools daily 1, 2
Second-Line: Rifaximin
Rifaximin is recommended as secondary prophylaxis after recurrent episodes of overt hepatic encephalopathy, typically added to lactulose: 1, 2, 3
- Dosing: 550 mg twice daily 6
- Mechanism: Decreases intestinal ammonia production by altering gastrointestinal flora with minimal systemic absorption 6
- Rifaximin is equal or superior to lactulose in clinical studies with fewer side effects 6, 7
Step 4: Nutritional Management
Address malnutrition present in approximately 75% of patients: 2, 3
- Provide moderate hyperalimentation with small, frequent meals throughout the day, including a late-night snack 2, 3
- Protein intake: Start at 0.5 g/kg/day and progressively increase to 1-1.5 g/kg/day 8
- Prefer dairy products and vegetable-based diets over meat-based protein 8
- Multivitamin supplementation is generally recommended 2
Prophylaxis Strategies
Secondary prophylaxis with lactulose is mandatory after any episode of overt hepatic encephalopathy to prevent recurrence. 1, 2, 3
- After first episode: Continue lactulose at maintenance dosing (2-3 soft stools daily) 1, 2, 3
- After recurrent episodes: Add rifaximin 550 mg twice daily to lactulose 1, 2, 3
- Prophylaxis may only be discontinued when precipitating factors are well-controlled, infections treated, variceal bleeding resolved, or liver function significantly improved 3
Diagnostic Considerations
Blood Ammonia Levels
Blood ammonia levels do not add diagnostic, staging, or prognostic value for hepatic encephalopathy; however, a normal ammonia level should prompt reconsideration of the diagnosis. 1, 2, 3
Screening for Covert (Minimal) Hepatic Encephalopathy
- Use the animal naming test to detect covert hepatic encephalopathy 1, 2
- A therapeutic trial with lactulose or rifaximin may strengthen the diagnosis 1
- Consider testing in patients with impaired quality of life, work performance, or driving ability 1
Special Considerations
Liver Transplantation
Recurrent intractable overt hepatic encephalopathy with liver failure is an indication for liver transplantation evaluation. 1, 2, 3
- A single episode of hepatic encephalopathy should prompt evaluation for transplantation 2
- Neurological work-up should be performed before transplantation to exclude other causes of neurological disorders 1
TIPS Placement
A single episode of hepatic encephalopathy is not a contraindication to TIPS placement 1
Common Pitfalls to Avoid
- Failing to identify and correct precipitating factors, which resolve 90% of cases 1, 2, 3
- Not titrating lactulose adequately to achieve 2-3 stools per day 1, 2
- Confusing hepatic encephalopathy with other causes of altered mental status without proper exclusion 1, 2
- Relying exclusively on ammonia levels for diagnosis 1, 2, 3
- Not implementing secondary prophylaxis after the first episode 1, 2, 3