Is there any value in trending ammonia levels in clinical practice?

Trending Ammonia Levels: Limited Clinical Value

Trending ammonia levels does not guide clinical management of hepatic encephalopathy and should not be used to monitor treatment response, though a single initial measurement has diagnostic value when normal. 1, 2

Diagnostic Value: Single Measurement Only

When to Measure Once

• Measure ammonia once at presentation in patients with delirium/encephalopathy and liver disease to rule out hepatic encephalopathy, as a normal value has high negative predictive value and should prompt investigation for alternative diagnoses 1, 3, 4
• In patients on valproate who develop unexplained lethargy, vomiting, or mental status changes, measure ammonia once to assess for hyperammonemic encephalopathy 5
• For severe hyperammonemia (>100 μmol/L) with normal liver enzymes, consider inherited metabolic disorders 3, 6

Why Single Measurement Works

• Normal ammonia effectively excludes hepatic encephalopathy as the cause of altered mental status 1, 3, 4
• Ammonia is always elevated in hepatic encephalopathy, making it a necessary but not sufficient marker 3

Why Trending Has No Value

Does Not Guide Treatment

• Lactulose dosing in clinical practice is identical regardless of ammonia level or whether ammonia was measured at all 2
• A study of 1,202 admissions found no correlation between ammonia levels and lactulose dose administered (R = 0.0026), with patients receiving an average of 161-171 mL over 48 hours regardless of ammonia status 2
• The role of ammonia measurement in guiding hepatic encephalopathy treatment has not been well studied, and ammonia levels are not used to monitor therapy 1
• Ammonia lowering is inconsistently associated with clinical treatment response 1

Ammonia Levels Are Unreliable for Monitoring

• Ammonia may remain elevated after clinical hepatic encephalopathy resolution, making serial values misleading 1
• Ammonia levels are highly variable and labile, increasing 12% at 1 hour and 18% at 2 hours after a protein meal 7
• Sample handling, processing, and protein intake significantly impact ammonia levels across different sites 7
• Correlation between fresh and frozen samples is only modest (r = 0.62), limiting reliability of serial measurements 7

Limited Exceptions Where Trending May Have Value

Asymptomatic Valproate-Induced Hyperammonemia

• If asymptomatic ammonia elevation occurs on valproate, close monitoring of plasma ammonia levels is required, and if elevation persists, discontinuation should be considered 5
• This is the only FDA-endorsed scenario for trending ammonia 5

Potential Prognostic Value (Not Treatment Guidance)

• Post-recovery ammonia levels after hepatic encephalopathy may predict future episodes, with hospitalization rates increasing at levels 1.5x normal 1
• Ammonia levels in outpatients may predict further decompensation of cirrhosis 3
• However, this prognostic information does not translate to actionable treatment modifications 1, 2

Critical Measurement Pitfalls

Proper Collection Technique Essential

• Collect from fasting patients when possible 3
• Avoid venous stasis—no tourniquet or fist clenching 3
• Use EDTA or lithium heparin tubes 3
• Place immediately on ice and process within 15 minutes 3
• Improper handling leads to falsely elevated results that may prompt unnecessary interventions 3

Interpretation Caveats

• Venous blood ammonia levels are not proportional to the degree of hepatic encephalopathy and have no association with prognosis 4, 6
• Patients without hepatic encephalopathy and even without liver disease can display hyperammonemia 1
• Ammonia metabolism involves multiple organs beyond the liver, limiting specificity 4

Bottom Line Algorithm

1. Measure ammonia once in patients with altered mental status and suspected hepatic encephalopathy 1, 3
2. If normal: Aggressively pursue alternative diagnoses 1, 3, 4
3. If elevated: Treat hepatic encephalopathy based on clinical severity, not ammonia level 1, 2
4. Do not repeat ammonia to guide lactulose dosing or assess treatment response 1, 2
5. Exception: Trend only in asymptomatic patients on valproate with incidental hyperammonemia 5