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

TY - JOUR

T1 - Clearance and production of ammonia quantified in humans by constant ammonia infusion - the effects of cirrhosis and ammonia targeting treatments

AU - Eriksen, Peter Lykke

AU - Djernes, Lars

AU - Vilstrup, Hendrik

AU - Ott, Peter

PY - 2023/8

Y1 - 2023/8

N2 - BACKGROUND & AIMS: 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. 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 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 11% (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.IMPACT AND IMPLICATIONS: High blood ammonia plays a key role in liver cirrhosis related brain dysfunction. However, the relative roles of increased ammonia production and reduced ammonia clearance are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By use of this test, it was possible to show that patients with liver cirrhosis have decreased ammonia clearance and increased ammonia production compared with healthy persons and to quantify distinctively different ammonia-targeting treatment effects. The test presented holds several perspectives for future studies of normal physiology and pathophysiology, not least in regard to elucidating effects of ammonia-targeting therapies.CLINICAL TRIAL NUMBER: ClinicalTrials.gov (1-16-02-297-20).

AB - BACKGROUND & AIMS: 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. 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 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 11% (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.IMPACT AND IMPLICATIONS: High blood ammonia plays a key role in liver cirrhosis related brain dysfunction. However, the relative roles of increased ammonia production and reduced ammonia clearance are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By use of this test, it was possible to show that patients with liver cirrhosis have decreased ammonia clearance and increased ammonia production compared with healthy persons and to quantify distinctively different ammonia-targeting treatment effects. The test presented holds several perspectives for future studies of normal physiology and pathophysiology, not least in regard to elucidating effects of ammonia-targeting therapies.CLINICAL TRIAL NUMBER: ClinicalTrials.gov (1-16-02-297-20).

KW - ammonia metabolism

KW - glycerol phenylbutyrate

KW - hepatic encephalopathy

KW - lactulose

KW - liver cirrhosis

KW - rifaximin

KW - Liver Cirrhosis/complications

KW - Phenylbutyrates

KW - Ammonia/metabolism

KW - Humans

KW - Male

KW - Lactulose/therapeutic use

KW - Hepatic Encephalopathy/drug therapy

KW - Hyperammonemia/drug therapy

KW - Rifaximin/therapeutic use

UR - http://www.scopus.com/inward/record.url?scp=85160548481&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2023.03.042

DO - 10.1016/j.jhep.2023.03.042

M3 - Journal article

C2 - 37061198

SN - 0168-8278

VL - 79

SP - 340

EP - 348

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 2

ER -