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A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans

Increased blood ammonia (NH(3)) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH(3). Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH(3) concentrat...

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Autores principales: Levitt, David G, Levitt, Michael D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973424/
https://www.ncbi.nlm.nih.gov/pubmed/29872332
http://dx.doi.org/10.2147/CEG.S160921
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author Levitt, David G
Levitt, Michael D
author_facet Levitt, David G
Levitt, Michael D
author_sort Levitt, David G
collection PubMed
description Increased blood ammonia (NH(3)) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH(3). Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH(3) concentration is complicated by the need to account for a variety of reactions carried out in multiple organs. This review presents a detailed quantitative analysis of the major factors determining blood-NH(3) homeostasis – the N metabolism of urea, NH(3), and amino acids by the liver, gastrointestinal system, muscle, kidney, and brain – with the ultimate goal of creating a model that allows for prediction of blood-NH(3) concentration. Although enormous amounts of NH(3) are produced during normal liver amino-acid metabolism, this NH(3) is completely captured by the urea cycle and does not contribute to blood NH(3). While some systemic NH(3) derives from renal and muscle metabolism, the primary site of blood-NH(3) production is the gastrointestinal tract, as evidenced by portal vein-NH(3) concentrations that are about three times that of systemic blood. Three mechanisms, in order of quantitative importance, release NH(3) in the gut: 1) hydrolysis of urea by bacterial urease, 2) bacterial protein deamination, and 3) intestinal mucosal glutamine metabolism. Although the colon is conventionally assumed to be the major site of gut-NH(3) production, evidence is reviewed that indicates that the stomach (via Helicobacter pylori metabolism) and small intestine and may be of greater importance. In healthy subjects, most of this gut NH(3) is removed by the liver before reaching the systemic circulation. Using a quantitative model, loss of this “first-pass metabolism” due to portal collateral circulation can account for the hyperammonemia observed in chronic liver disease, and there is usually no need to implicate hepatocyte malfunction. In contrast, in acute hepatic necrosis, hyperammonemia results from damaged hepatocytes. Although muscle-NH(3) uptake is normally negligible, it can become important in severe hyperammonemia. The NH(3)-lowering actions of intestinal antibiotics (rifaximin) and lactulose are discussed in detail, with particular emphasis on the seeming lack of importance of the frequently emphasized acidifying action of lactulose in the colon.
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spelling pubmed-59734242018-06-05 A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans Levitt, David G Levitt, Michael D Clin Exp Gastroenterol Review Increased blood ammonia (NH(3)) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH(3). Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH(3) concentration is complicated by the need to account for a variety of reactions carried out in multiple organs. This review presents a detailed quantitative analysis of the major factors determining blood-NH(3) homeostasis – the N metabolism of urea, NH(3), and amino acids by the liver, gastrointestinal system, muscle, kidney, and brain – with the ultimate goal of creating a model that allows for prediction of blood-NH(3) concentration. Although enormous amounts of NH(3) are produced during normal liver amino-acid metabolism, this NH(3) is completely captured by the urea cycle and does not contribute to blood NH(3). While some systemic NH(3) derives from renal and muscle metabolism, the primary site of blood-NH(3) production is the gastrointestinal tract, as evidenced by portal vein-NH(3) concentrations that are about three times that of systemic blood. Three mechanisms, in order of quantitative importance, release NH(3) in the gut: 1) hydrolysis of urea by bacterial urease, 2) bacterial protein deamination, and 3) intestinal mucosal glutamine metabolism. Although the colon is conventionally assumed to be the major site of gut-NH(3) production, evidence is reviewed that indicates that the stomach (via Helicobacter pylori metabolism) and small intestine and may be of greater importance. In healthy subjects, most of this gut NH(3) is removed by the liver before reaching the systemic circulation. Using a quantitative model, loss of this “first-pass metabolism” due to portal collateral circulation can account for the hyperammonemia observed in chronic liver disease, and there is usually no need to implicate hepatocyte malfunction. In contrast, in acute hepatic necrosis, hyperammonemia results from damaged hepatocytes. Although muscle-NH(3) uptake is normally negligible, it can become important in severe hyperammonemia. The NH(3)-lowering actions of intestinal antibiotics (rifaximin) and lactulose are discussed in detail, with particular emphasis on the seeming lack of importance of the frequently emphasized acidifying action of lactulose in the colon. Dove Medical Press 2018-05-24 /pmc/articles/PMC5973424/ /pubmed/29872332 http://dx.doi.org/10.2147/CEG.S160921 Text en © 2018 Levitt and Levitt. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Review
Levitt, David G
Levitt, Michael D
A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
title A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
title_full A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
title_fullStr A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
title_full_unstemmed A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
title_short A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
title_sort model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973424/
https://www.ncbi.nlm.nih.gov/pubmed/29872332
http://dx.doi.org/10.2147/CEG.S160921
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