Can High Ammonia Cause Somnolence?
Yes, elevated ammonia levels directly cause somnolence and other neurological symptoms through hepatic encephalopathy, particularly in patients with cirrhosis and liver dysfunction. 1, 2
Pathophysiological Mechanism
Ammonia is central to the pathogenesis of hepatic encephalopathy (HE) and acts as a neurotoxin that produces altered mental status ranging from subtle cognitive changes to deep somnolence and coma. 1, 3 The mechanism involves:
- Astrocyte swelling and brain edema caused by ammonia accumulation, which directly impairs neurological function 4
- Disruption of neurotransmission, mitochondrial dysfunction, and oxidative stress that collectively produce the spectrum of encephalopathic symptoms including somnolence 3
- Correlation with severity: Higher ammonia levels are associated with more severe grades of hepatic encephalopathy, with somnolence representing grade 2-3 encephalopathy 1, 5, 6
Diagnostic Considerations
A normal ammonia level has high negative predictive value and should prompt immediate investigation for alternative causes of somnolence such as intracranial hemorrhage, septic encephalopathy, hyponatremia, Wernicke's encephalopathy, or medication effects. 1, 2
Key diagnostic principles:
- Ammonia is always elevated in hepatic encephalopathy, making it a necessary but not sufficient marker 2
- Measure ammonia once at presentation in patients with altered mental status and liver disease to rule out HE as the cause 7, 2
- Blood ammonia levels correlate with HE severity, with higher levels predicting worse outcomes and increased mortality 1, 5, 6
Critical Measurement Technique
Improper collection leads to falsely elevated results. 2 Essential steps include:
- Collect from fasting patients when possible 2
- Avoid venous stasis (no tourniquet or fist clenching) 2
- Use EDTA or lithium heparin tubes 2
- Place immediately on ice and process within 15 minutes 2
Clinical Thresholds and Prognosis
An ammonia level ≥79.5 µmol/L predicts 28-day mortality with 68% sensitivity and 67% specificity, and is associated with higher frequency of multi-organ failures. 5
- Levels >100 µmol/L predict severe HE with 70% accuracy 8
- Levels >200 µmol/L are associated with 55% risk of intracranial hypertension in acute liver failure 8
- Lack of improvement in ammonia by day 5 is associated with 70.6% mortality 5
Treatment Approach
Do not delay treatment while waiting for ammonia results—hepatic encephalopathy is a clinical diagnosis requiring immediate empirical therapy. 2
First-Line Management
- Lactulose 30-45 mL every 1-2 hours until achieving at least 2 bowel movements daily, then maintenance dosing for 2-3 soft stools daily 7, 9, 10
- Lactulose reduces blood ammonia by 25-50%, with clinical response in approximately 75% of patients 10
Second-Line and Adjunctive Therapy
- Rifaximin 400 mg three times daily or 550 mg twice daily can be combined with lactulose for better outcomes (76% vs 44% recovery rates) 7, 9
- L-ornithine-L-aspartate (LOLA) 30 g/day IV as additional therapy to lower plasma ammonia 7, 9
Nutritional Management
- Protein intake 1.2-1.5 g/kg/day (do not restrict protein as it worsens outcomes) 7, 9
- Energy intake 35-40 kcal/kg/day with frequent small meals (4-6 times daily including nocturnal snack) 7, 9
Common Pitfalls
- Do not use serial ammonia levels to monitor therapy response—ammonia may remain elevated after clinical resolution, and ammonia lowering is inconsistently associated with treatment response 1, 2
- Evaluate clinical improvement based on mental status, not ammonia values 7, 2
- In patients with severe hyperammonemia (>100 µmol/L) but normal liver enzymes, consider inherited metabolic disorders 2
Long-Term Considerations
Secondary prevention should be initiated after the first episode, as 50-70% will experience recurrence within 1 year. 7, 9 Overall survival after an episode of overt HE is only 42% at 1 year and 23% at 3 years, warranting consideration for liver transplantation evaluation in severe or refractory cases. 7, 9