Variability and Lability of Ammonia Levels in Healthy Volunteers and Patients With Cirrhosis: Implications for Trial Design and Clinical Practice

Introduction: Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. Methods: We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). Results: Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P< 0.001). In 237 HVs, ammonia levels varied significantly between sites (P< 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). Discussion: Sample handling, processing, and protein intake impact ammonia levels across sites.