Treatment of Hyperammonemia Due to NASH
For hyperammonemia in the context of NASH, immediately stop all protein intake, provide IV glucose (8-10 mg/kg/min) and lipids to prevent catabolism, initiate ammonia-scavenging agents (sodium benzoate and sodium phenylacetate), and prepare for urgent hemodialysis if ammonia levels exceed 300 μmol/L or if moderate-to-severe encephalopathy develops. 1, 2, 3
Understanding NASH-Related Hyperammonemia
NASH causes hyperammonemia through a distinct mechanism compared to cirrhosis:
- Urea cycle dysfunction occurs at the pre-cirrhotic stage in NASH patients, with reduced expression and activity of urea cycle enzymes leading to impaired ammonia detoxification capacity 4
- This functional reduction in ureagenesis results in hyperammonemia even before cirrhosis develops, distinguishing NASH from other liver diseases 4
- Ammonia directly activates hepatic stellate cells, promoting fibrosis progression and worsening the underlying NASH pathology 4
Immediate Management Protocol
Stop Nitrogen Load and Prevent Catabolism
- Discontinue all oral protein intake immediately to reduce nitrogen load and prevent further ammonia production 1, 2
- Provide adequate calories (≥100 kcal/kg daily) through IV glucose infusion at 8-10 mg/kg/min 1, 2
- Add IV lipids starting at 0.5 g/kg daily, up to 3 g/kg daily, to prevent protein catabolism which drives further ammonia generation 1, 2
Critical pitfall: Do not extend protein restriction beyond 48 hours, as prolonged restriction paradoxically promotes catabolism and worsens hyperammonemia 2
Pharmacological Ammonia-Scavenging Therapy
Initiate IV nitrogen scavengers immediately:
- For patients <20 kg: 250 mg/kg IV over 90 minutes as loading dose, then same dose as continuous maintenance over 24 hours
- For patients >20 kg: 5.5 g/m² IV over 90 minutes as loading dose, then same dose as continuous maintenance over 24 hours
Sodium phenylacetate dosing (same as sodium benzoate): 1, 3
- For patients <20 kg: 250 mg/kg IV over 90 minutes, then continuous maintenance
- For patients >20 kg: 5.5 g/m² IV over 90 minutes, then continuous maintenance
L-arginine hydrochloride: 200 mg/kg (for <20 kg) or 4 g/m² (for >20 kg) may be considered, though this is primarily indicated for urea cycle disorders rather than NASH-related hyperammonemia 1, 3
Administration note: These agents must be diluted in sterile 10% dextrose and administered via central venous catheter to avoid burns from peripheral administration 3
Kidney Replacement Therapy Decision Algorithm
Indications for Urgent Dialysis
Consider hemodialysis or continuous kidney replacement therapy when: 1, 2, 3
- Ammonia levels exceed 300 μmol/L
- Moderate-to-severe encephalopathy develops (altered mental status, confusion, lethargy)
- Seizures occur
- Neurological status deteriorates despite medical management
- Ammonia levels remain persistently elevated after 3-4 hours of ammonia-scavenging therapy
Choice of Dialysis Modality
- High-dose continuous venovenous hemodialysis (CVVHD) is first-line when available, with blood flow rate 30-50 mL/min and dialysis fluid flow rate/Qb ratio >1.5 1
- Intermittent hemodialysis achieves the most rapid ammonia clearance, reducing levels by 50% within 1-3 hours, making it ideal for rapidly deteriorating patients 5, 1, 3
- Hybrid therapy (HD followed by CVVHD) is recommended for ammonia levels >1,500 μmol/L to achieve rapid initial reduction while preventing rebound hyperammonemia 5
Critical consideration: The duration of hyperammonemic coma before dialysis initiation is the most important prognostic factor for neurological outcomes, not the rate of ammonia clearance itself 1, 6
Monitoring During Treatment
Check the following parameters every 3-4 hours until ammonia normalizes: 1, 2
- Plasma ammonia levels
- Neurological status (Glasgow Coma Scale, level of consciousness)
- Electrolytes, particularly during CKRT
- Blood glucose
- Venous or arterial blood gases
Sample collection pitfall: Ammonia samples must be collected from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid falsely elevated results 1
Protein Reintroduction
Once ammonia levels decrease below 200 μmol/L on two consecutive hourly measurements: 5, 1
- Gradually reintroduce protein starting at 0.25 g/kg daily
- Increase incrementally up to 1.5 g/kg daily over 48 hours
- Continue ammonia-scavenging agents during this transition to prevent rebound
Transition to Oral Management
After ammonia normalization and neurological improvement: 3
- Transition to oral sodium phenylbutyrate for long-term ammonia control
- Implement dietary protein restriction tailored to maintain ammonia in normal range
- Continue nutritional supplementation to prevent catabolism
Key Clinical Pitfalls to Avoid
- Do not delay treatment waiting for confirmatory testing – initiate therapy immediately based on clinical suspicion and elevated ammonia 2
- Do not use rigid ammonia thresholds alone – the patient's evolving clinical status (encephalopathy severity, neurological deterioration) should guide treatment intensity 1, 2
- Do not continue protein intake during acute hyperammonemia, as this directly contradicts the fundamental principle of reducing nitrogen load 6
- Do not restrict protein beyond 48 hours without reintroduction, as this triggers catabolism and paradoxically worsens hyperammonemia 2
- Recognize that respiratory alkalosis is an early distinguishing feature of hyperammonemia that differentiates it from other causes of encephalopathy 6