Clearance and production of ammonia quantified in humans by constant ammonia infusion-the effects of cirrhosis and ammonia-targeting treatments

Background & Aims: Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic enceph-alopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting drugs for HE. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. Methods: Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production was calculated as clearance multiplied by baseline ammonia concentration. Participants were re-investigated after the ammonia-targeting interventions. Results: In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and ammonia production was 49 (35-63) lmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p = 0.009). In patients with cirrhosis, ammonia clearance was 20% lower at 2.7 (2.1-3.3) L/min (p = 0.02) and production was nearly threefold higher at 131 (102-159) lmol/min (p <0.0001). Lactulose + rifaximin reduced production by 20% (2-37%, p = 0.03). The infusion was generally well-tolerated apart from in one hyper-ammonaemic patient, with cirrhosis and possible bleeding unrelated to the infusion, who developed clinical HE that reverted when infusion was discontinued. Conclusions: Whole-body ammonia clearance and production may be measured separately using the described technique. This technique identified a lower clearance and a higher production of ammonia in patients with cirrhosis, and showed that phenyl -butyrate increases clearance, whereas lactulose + rifaximin reduces production. Clinical trial number: ClinicalTrials.gov (1-16-02-297-20). & COPY; 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis, and validate the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. The results showed that patients with cirrhosis had lower ammonia clearance and higher ammonia production, and glycerol phenylbutyrate increased clearance while lactulose + rifaximin reduced production.