What is the preferred test, serum or plasma ammonia, for diagnosing hepatic encephalopathy in patients with cirrhosis?

Serum vs Plasma Ammonia Testing in Cirrhosis

Neither serum nor plasma ammonia testing is preferred over the other for diagnosing hepatic encephalopathy in cirrhosis—both venous blood methods (serum or plasma) are acceptable, but the critical factor is proper collection technique and using the appropriate reference range for your specific laboratory method. 1

Key Guideline Recommendations on Ammonia Testing

The Korean Association for the Study of the Liver (KASL) 2020 guidelines explicitly state that "there are various methods of measuring ammonia concentrations, such as those involving the venous or arterial blood or plasma" and emphasize that "the normal range varies depending on the specific measurement method, a suitable reference value should be used." 1 This indicates no superiority of one specimen type over another.

The diagnosis of hepatic encephalopathy should be made based on clinical symptoms, not ammonia levels alone. 1

Clinical Utility of Ammonia Measurement

When Ammonia Testing Is Useful

• Rule-out value: A normal ammonia level has high negative predictive value for hepatic encephalopathy and should immediately trigger investigation for alternative causes of altered mental status (infections, metabolic derangements, intracranial hemorrhage, drug effects, seizures). 2, 3, 4

• Single measurement at presentation: The European Association for the Study of the Liver recommends measuring ammonia once at presentation in patients with delirium and liver disease to exclude hepatic encephalopathy. 3

• Prognostic information: Ammonia levels correlate with severity of hepatic encephalopathy, organ failures, and mortality risk—levels ≥79.5 µmol/L predict 28-day mortality with 68% sensitivity and 67% specificity. 5

When Ammonia Testing Is NOT Useful

• Not for diagnosis confirmation: Venous blood ammonia levels are not proportional to the degree of hepatic encephalopathy and have no association with prognosis (KASL Grade A1 recommendation). 1

• Not for monitoring therapy: The American Association for the Study of Liver Diseases states that ammonia levels should not be used to monitor treatment response, as ammonia lowering is inconsistently associated with clinical improvement. 3

• Not for staging: Ammonia cannot reliably distinguish between grades of hepatic encephalopathy. 1

Critical Collection Requirements (Regardless of Serum vs Plasma)

Improper collection technique leads to falsely elevated results and renders the test useless. 3 Essential steps include:

• 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 3
• Process within 15 minutes and analyze immediately 3
• Avoid hemolysis, which falsely elevates results 3

Clinical Algorithm for Ammonia Use

Step 1: In a cirrhotic patient with altered mental status, measure ammonia once at presentation. 3

Step 2: If ammonia is normal:

• Hepatic encephalopathy is effectively ruled out 2, 3, 4
• Immediately investigate alternative causes: spontaneous bacterial peritonitis, other infections, hypoglycemia, severe hyponatremia, intracranial hemorrhage, subdural hematoma, drug intoxication (benzodiazepines, opioids, gabapentin), uremia, seizures 2
• Obtain brain imaging (CT or MRI) for first episodes, focal signs, or non-response to treatment 2

Step 3: If ammonia is elevated:

• Diagnose hepatic encephalopathy based on clinical symptoms and exclusion of other causes 1
• Identify and treat precipitating factors (GI bleeding, infection, constipation, dehydration) 1
• Initiate lactulose or rifaximin therapy 2

Step 4: Do NOT repeat ammonia levels to guide treatment:

• Repeated measurements can help determine treatment effects in a general sense, but should not dictate therapy adjustments 1, 3
• Ammonia may remain elevated after clinical resolution 3

Common Pitfalls to Avoid

• Do not assume hepatic encephalopathy based on elevated ammonia alone—the diagnosis requires clinical symptoms and exclusion of other causes. 1, 3

• Do not delay brain imaging in first episodes or atypical presentations—structural lesions are common in cirrhotic patients, especially with alcohol use. 2

• Do not use ammonia trending to guide therapy—clinical response is what matters, not ammonia normalization. 3

• Do not overlook proper collection technique—most falsely elevated results stem from improper handling. 3

• Do not ignore normal ammonia in suspected hepatic encephalopathy—this finding mandates a comprehensive search for alternative diagnoses. 2, 3, 4