Abstract
Ammonia is believed to play a key role in the development of hepatic encephalopathy (HE) with increased formation of glutamine playing a central role. It has been debated whether blood ammonia enters the brain by passive diffusion and/or active transport by ion-transporters and that changes in blood pH could affect the blood-to-brain transfer of ammonia. It has also been proposed that the permeability-surface area product for ammonia across the blood–brain barrier (PSBBB) should be increased in cirrhosis and HE. In the present paper it is argued that changes in blood pH does not alter PSBBB for ammonia and the question of passive diffusion versus active transport of ammonia remains unresolved. Furthermore, recent studies do not find evidence for increased PSBBB for ammonia in cirrhosis. The main determent for cerebral uptake of blood ammonia (i.e. flux) is the arterial blood ammonia concentration. This means that the only way to protect the brain from hyperammonemia is by lowering blood ammonia, inhibit cerebral uptake of ammonia, or by manipulating cerebral ammonia metabolism so that less glutamine is produced.
Notes
13N-ammonia refers to the sum of 13NH3 and 13NH4 + because the two cannot be separated in PET studies.
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
Bhatia V, Singh R, Acharya SK (2006) Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut 55:98–104
Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653
Cooper AJ (2012) Possible treatment of end-stage hyperammonemic encephalopathy by inhibition of glutamine synthetase. Metab Brain Dis [Epub ahead of print]
Cooper AJ, McDonald JM, Gelbard AS, Gledhill RF, Duffy TE (1979) The metabolic fate of 13N-labeled ammonia in rat brain. J Biol Chem 254:4982–4992
Crone C (1963) The permeability of capillaries in various organs as determined as by use of the ‘indicator diffusion’ method. Acta Physiol Scand 58:292–305
Dadsetan S, Bak LK, Sørensen M, Keiding S, Vilstrup H, Ott P, Leke R, Schousboe A, Waagepetersen HS (2011) Inhibition of glutamine synthesis induces glutamate dehydrogenase-dependent ammonia fixation into alanine in co-cultures of astrocytes and neurons. Neurochem Int 59:482–488
Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK, Waagepetersen HS, Schousboe A, Sørensen M (2012) Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology [Epub ahead of print]
Gershoff SN, Elvehjem CA (1951) The relative effect of methionine sulfoximine on different animal species. J Nutr 45:451–458
Goldbecker A, Buchert R, Berding G, Bokemeyer M, Lichtinghagen R, Wilke F, Ahl B, Weissenborn K (2010) Blood–brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls. J Cereb Blood Flow Metab 30:1384–1393
Iversen P, Sørensen M, Bak LK, Waagepetersen HS, Vafaee MS, Borghammer P, Mouridsen K, Jensen SB, Vilstrup H, Schousboe A, Ott P, Gjedde A, Keiding S (2009) Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology 136:863–871
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 44:42–50, Erratum in: Hepatology 2006;44:1056
Kety SS (1951) The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev 3:1–41
Leke R, Bak LK, Anker M, Melø TM, Sørensen M, Keiding S, Vilstrup H, Ott P, Portela LV, Sonnewald U, Schousboe A, Waagepetersen HS (2011) Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine. Neurotox Res 19:496–510
Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310
Ong JP, Aggarwall A, Krieger D, Easley KA, Karafa MT, van Lente F, Arroliga AC, Mullen KD (2003) Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 114:188–193
Ott P, Larsen FS (2004) Blood–brain barrier permeability to ammonia in liver failure: a critical reappraisal. Neurochem Int 44:185–198
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, Selin 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
Rama Rao KV, Norenberg MD (2012) Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int 60:697–706
Rama Rao KV, Jayakumar AR, Norenberg MD (2012) Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int 61:575–580
Renkin EM (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 197:1205–1210
Sørensen M, Keiding S (2007) New findings on cerebral ammonia uptake in HE using functional 13N-ammonia PET. Metab Brain Dis 22:277–284
Sørensen M, Ott P (2012) Cerebral Ammonia Metabolism in Cirrhosis. In Keiding S, Sørensen M (eds) Functional Molecular Imaging in Hepatology. Bentham e-books, pp 153–159
Sørensen M, Munk OL, Keiding S (2009) Backflux of ammonia from brain to blood in human subjects with and without hepatic encephalopathy. Metab Brain Dis 24:237–242
Tofteng F, Hauerberg J, Hansen BA, Pedersen CB, Jørgensen L, Larsen FS (2006) Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 26:21–27
Weissenborn K, Ahl B, Fischer-Wasels D, van den Hoff J, Hecker H, Burchert W, Köstler H (2007) Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 56:1736–1742
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Sørensen, M. Update on cerebral uptake of blood ammonia. Metab Brain Dis 28, 155–159 (2013). https://doi.org/10.1007/s11011-013-9395-1
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DOI: https://doi.org/10.1007/s11011-013-9395-1