Serum Ammonia and Hepatic Encephalopathy: A Complex Correlation
Serum ammonia levels correlate with the severity and prognosis of hepatic encephalopathy, but they cannot be used to confirm the diagnosis because ammonia may be elevated in cirrhotic patients without any encephalopathy symptoms. 1
The Nature of the Correlation
The relationship between ammonia and hepatic encephalopathy is nuanced and clinically important to understand:
Key Findings from Multiple Studies
- Ammonia is always elevated in cases of hepatic encephalopathy, establishing it as a necessary but not sufficient marker 1
- Ammonia levels correlate with both the severity/grade of hepatic encephalopathy and prognosis, making higher levels predictive of worse outcomes 1, 2
- Ammonia is an independent predictor of 28-day mortality in patients with cirrhosis and acute decompensation (hazard ratio 1.009, P < 0.001) 2
- An ammonia level ≥79.5 µmol/L predicts 28-day mortality with 68.1% sensitivity and 67.4% specificity 2
The Critical Limitation
Ammonia levels may remain elevated without any hepatic encephalopathy symptoms, and sometimes stay stable and elevated during follow-up even in patients no longer presenting with overt hepatic encephalopathy 1. This is the fundamental reason why the 2023 French guidelines explicitly recommend not measuring blood ammonia levels to confirm the diagnosis of hepatic encephalopathy 1.
Clinical Utility: When to Measure Ammonia
Diagnostic Value
A normal ammonia value casts doubt on the diagnosis of hepatic encephalopathy and should prompt investigation for alternative causes of altered mental status 1, 3. This represents the primary diagnostic utility of ammonia measurement.
- In cases of diagnostic doubt with impaired consciousness, measuring blood ammonia is suggested because normal values argue against hepatic encephalopathy 1
- Normal ammonia in suspected hepatic encephalopathy requires differentiation from other diseases causing cognitive impairment 1, 3
Prognostic and Monitoring Value
- Repeated measurements of ammonia concentrations can help determine treatment effects 1
- Lack of improvement in baseline ammonia at day 5 is associated with 70.6% mortality, making serial measurements potentially useful for risk stratification 2
- Ammonia levels in outpatients are predictive of further decompensation of cirrhosis 1
Association with Organ Dysfunction
Ammonia levels ≥79.5 µmol/L are associated with higher frequency of organ failures, including liver (P = 0.004), coagulation (P < 0.001), kidney (P = 0.004), and respiratory failure (P < 0.001) 2. This suggests ammonia reflects systemic toxicity beyond just neurological effects.
Why Ammonia Doesn't Guide Treatment
Despite the correlation with severity, ammonia levels do not guide clinical management in practice. 4 A large study of 1,202 admissions found:
- No difference in lactulose dosing between patients with normal versus elevated ammonia levels (161 mL vs 161 mL over 48 hours) 4
- No correlation between lactulose dose and ammonia level (R = 0.0026) 4
- Identical treatment regardless of whether ammonia was measured (167 mL vs 171 mL in no ammonia vs ammonia groups, P = 0.42) 4
This reflects the guideline recommendation that venous blood ammonia levels are not proportional to the degree of hepatic encephalopathy and have no association with its prognosis in terms of guiding immediate therapeutic decisions 1.
Critical Measurement Considerations
Proper collection technique is crucial because improper handling leads to falsely elevated results 1, 5:
- Collect from fasting patients when possible 1, 5
- Avoid venous stasis (no tourniquet or fist clenching) 1, 5
- Use EDTA or lithium heparin tubes 5
- Place immediately on ice 1, 5
- Process within 15 minutes and analyze immediately 5
- Sample hemolysis falsely elevates results 5
When to Suspect Alternative Diagnoses
For severe hyperammonemia (>100 µmol/L) with normal liver enzymes, consider inherited metabolic disorders, especially with family history of liver disease, neurological disorders, or severe neurological impairment 1, 6. The most common is ornithine transcarbamylase deficiency (1 in 56,500 births) 6.
The Bottom Line for Clinical Practice
Measure ammonia when the diagnosis of hepatic encephalopathy is uncertain to rule out the diagnosis if normal, but do not use ammonia levels to confirm hepatic encephalopathy or guide lactulose dosing 1. Instead, treat based on clinical severity using the West Haven criteria, recognizing that ammonia provides prognostic information about mortality risk and can be useful for monitoring treatment response over time 2.