title: Arterial ammonia levels in cirrhosis are determined by systemic and hepatic hemodynamics, and by organ function: a quantitative modelling study.
abstract: OBJECTIVE
  Hyperammonaemia is a common complication of chronic liver failure. Two main factors are thought to underlie this complication: a loss of hepatic detoxification function and the development of portosystemic shunting. However, few studies have tried to quantify the importance of portosystemic shunting. Here, we used a theoretical approach to test the hypothesis that the development of portosystemic shunting is sufficient to cause hyperammonaemia in cirrhosis.
  
  
  METHODS
  Two mathematical models are developed. The first one describes the main vascular resistances of the circulation and is used to provide scenarios for the distributions of organ blood flow in cirrhosis, which are necessary to run the second model. The second model predicts arterial ammonia levels resulting from ammonia metabolism in gut, liver, kidney, muscle and brain, and the distribution of organ blood flow.
  
  
  RESULTS
  The fraction of gastrointestinal blood flow shunted through collaterals was estimated to be 41% in mild cirrhosis, 69% in moderate and 85% in severe cases. In the second model, the redistribution of organ blood flow associated with severe cirrhosis was sufficient to cause hyperammonaemia, even when the hepatic detoxification function and the ammonia production were set to normal.
  
  
  CONCLUSIONS
  The model indicates that the development of portosystemic shunting in cirrhosis is sufficient to cause hyperammonaemia. Interventions that reduce the fraction of shunting may be future targets of therapy to control severity of hyperammonaemia.
authors.affiliation: CoMPLEX, University College London, London, UK.
authors.forename: Lorette
authors.initials: L
authors.lastname: Noiret
authors.forename: Stephen
authors.initials: S
authors.lastname: Baigent
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
mesh_terms: D000641:Ammonia / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003198:Computer Simulation; D006439:Hemodynamics; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D008102:Liver Circulation; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology; D008955:Models, Cardiovascular; D011168:Portal System / Q000503:physiopathology*; D012039:Regional Blood Flow; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D000641:Ammonia
keywords: ammonia; cirrhosis; fluxes; interorgan; portosystemic shunting