P2 Whole-Body Clearance and Production of Ammonia Quantified by Constant Ammonia Infusion – The Effects of Cirrhosis and Ammonia Targeting Treatments

Background: Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting HE drugs. Aim: 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 10 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 as clearance times 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 production 49 (35-63) μmol/min. Phenylbutyrate increased clearance by 12% (4–19%, P=0.009). Patients with cirrhosis had a 20% decreased ammonia clearance of 2.7 (2.1–3.3) L/min (p = 0.02) and a nearly tripled production to 131 (102–159) μmol/min (P<0.0001). Lactulose + rifaximin reduced production by 20% (2–37%, P=0.03). The infusion was generally well-tolerated save one hyperammonaemic patient with cirrhosis with 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 by the technique used. The method identified a lower clearance and a higher production in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. The method may be used to examine a range of questions related to normo-/pathophysiology and ammonia-targeting treatment mechanisms (see Figure 1).Figure 1.: Ammonia infusion results on cirrhotic patients.