Abstract
In patients with hepatic encephalopathy (HE) the blood concentration of ammonia is usually highly elevated. Ammonia readily enters brain cells from the blood, and toxic effects of ammonia on brain metabolism and neurotransmission are believed to play a key role in the pathogenesis of HE. It has, however, been a matter of great controversy whether backflux of unmetabolized ammonia (NH3 + NH4 +) from brain cells to the blood occurs in man. In the present analysis of data from a dynamic PET study of brain 13N–ammonia metabolism in healthy subjects and cirrhotic patients with and without HE, we provide the first unambiguous evidence for backflux of ammonia from brain cells to the blood in man. The high temporal and spatial resolution of modern PET technology was employed to distinguish between unidirectional blood-brain transport of ammonia and subsequent metabolism of the ammonia in the brain. In all 16 subjects, clearance of the unidirectional transport of 13N–ammonia from the blood to brain cells (K1) was higher than the metabolic clearance of 13N–ammonia from the blood (Kmet=K1 k3/(k2+k3). This can only be explained by backflux (k2) of ammonia from brain cells to the blood. In conclusion, backflux of ammonia from the brain to the blood does indeed occur in both healthy subjects and cirrhotic patients with and without hepatic encephalopathy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Notes
In this paper, the term ammonia refers to the sum of the unionized NH3 and the ionized NH4 +.
References
Ahl B, Weissenborn K, van den Hoff J, Fischer-Wasels D, Köstler H, Hecker H, Burchert W (2004) Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis. Hepatology 40:73–79
Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: A new look at ammonia. Metab Brain Dis 17:221–227
Cooper AJL, McDonald JM, Gelbard AS, Gledhill RF, Duffy TE (1979) The metabolic rate of 13N labelled ammonia in rat brain. J Biol Chem 254:4982–4992
Crone C (1964) Permeability of capillaries in various organs as determined by use of the indicator diffusion method. Acta Physiol Scand 58:292–305
Gjedde A (1982) Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: a re-examination. Brain Res 257:237–274
Iversen P, Sørensen M, Bak LK, Waagepetersen HS, Vafae MS, Borghammer P, Mouridsen K, Jensen SB, Vilstrup H, Schousboe A, Ott P, Gjedde A, Keiding S (2008) Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology (in press)
Keiding S, Sørensen M, Bender D, Munk OL, Ott P, Vilstrup H (2006) Brain metabolism of 13N–ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography. Hepatology 43:42–50. Correction in Hepatology 44:1056
Kety SS (1951) The theory and application of the exchange of inert gas at lung and tissues. Pharmacol Rev 3:1–41
Lockwood AH, McDonald JM, Reiman RE, Gelbard AS, Laughlin JS, Duffy TE, Plum F (1979) The dynamics of ammonia metabolism in man. J Clin Invest 63:449–460
Lockwood AH, Bolomey L, Napoleon F (1984) Blood-brain barrier to ammonia in humans. J Cerebral Blood Flow Metab 4:516–522
Lockwood AH, Wack DS (2006) To the editor: The brain permeability-surface product for ammonia. Hepatology 44:1052–1053
Lockwood AH (2007) Controversies in ammonia metabolism: implications for hepatic encephalopathy. Metab Brain Dis 22:285–289
Munk OL, Bass L, Roelsgaard K, Bender D, Hansen SB, Keiding S (2001) Liver Kinetics of Glucose analogs measured in Pigs by PET: Importance of dual-input blood sampling. J Nucl Med 42:795–801
Nieves E, Rosenspire KC, Filc-DeRicco S, Gelbard AS, Cooper AJ (1986) High-performance liquid chromatographic on-line flow-through radioactivity detector system for analyzing amino acids and metabolites labeled with nitrogen-13. J Chromatogr 383:325–337
Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 151:303–310
Ott P, Larsen FS (2004) Blood-brain barrier permeability to ammonia in liver failure: a critical reappraisal. Neurochem Int 44:185–198
Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7
Phelps ME, Hoffman EJ, Raybaud C (1977) Factors which affect cerebral uptake and retention of 13NH3. Stroke 8:694–702
Phelps ME, Huang SC, Hoffman EJ, Selis C, Kuhl DE (1981) Cerebral extraction of N-13 ammonia: its dependence on cerebral blood flow and capillary permeability-surface area product. Stroke 12:607–619
Raichle ME, Larson KB (1981) The significance of the NH3-NH4 + equilibrium on the passage of 13N-ammonia from blood to brain. A new regional residue detection model. Circ Res 48:913–937
Renkin EM (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 197:1205–1210
Rosenspire KC, Schwaiger M, Mangner TJ, Hutchins GD, Sutorik A, Kuhl DE (1990) Metabolic fate of [13N]ammonia in human and canine blood. J Nucl Med 31:163–167
Sørensen M, Keiding S (2006) Ammonia metabolism in cirrhosis. In D Häussinger, G Kircheis, F Schliess (eds.), Hepatic Encephalopathy and Nitrogen Metabolism, Springer pp. 406–419
Sørensen M, Keiding S (2007) New findings on cerebral ammonia uptake in HE using functional 13N–ammonia. Metab Brain Dis 22:277–284
Acknowledgements
The study was supported by grants from the Danish Medical Research Council (22-02-0337) and the Novo Nordisk Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sørensen, M., Munk, O.L. & Keiding, S. Backflux of ammonia from brain to blood in human subjects with and without hepatic encephalopathy. Metab Brain Dis 24, 237–242 (2009). https://doi.org/10.1007/s11011-008-9126-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-008-9126-1