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Understanding the mechanisms of cerebral complications in fulminant hepatic failure: fluxes better than levels
Journal of Hepatology 37 (2002) 878–879 www.elsevier.com/locate/jhep
BEYOND THE JOURNAL Associate Editors: Guadalupe Garcia-Tsao and Ronald Oude Elferink Committee: James Boyer, Jean-Franc¸ois Dufour, Hartmut Jaeschke, Luigi Pagliaro, Jorge Rakela, Tania Roskams and Christian Trautwein
Understanding the mechanisms of cerebral complications in fulminant hepatic failure: fluxes better than levels Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Strauss GI, Knudsen GM, Kondrup J, Moller K, Larsen FS. Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark BACKGROUND & AIMS: High circulating levels of ammonia have been suggested to be involved in the development of cerebral edema and herniation in fulminant hepatic failure (FHF). The aim of this study was to measure cerebral metabolism of ammonia and amino acids, with special emphasis on glutamine metabolism. METHODS: The study consisted of patients with FHF (n ¼ 16) or cirrhosis (n ¼ 5), and healthy subjects (n ¼ 8). Cerebral blood flow was measured by the 133Xe washout technique. Blood samples for determination of ammonia and amino acids were drawn simultaneously from the radial artery and the internal jugular bulb. RESULTS: A net cerebral ammonia uptake was only found in patients with FHF (1.62 ^ 0.79 mmol £ 100 g 21 £ min 21). The cerebral glutamine efflux was higher in patients with FHF than in the healthy subjects and cirrhotics, 26.11 ^ 5.19 versus 21.93 ^ 1.17 and 21.50 ^ 0.29 mmol £ 100 g 21 £ min 21, respectively (P , 0.05). Patients with FHF who subsequently died of cerebral herniation (n ¼ 6) had higher arterial ammonia concentrations, higher cerebral ammonia uptake, and higher cerebral glutamine efflux than survivors. Intervention with short-term mechanical hyperventilation in FHF reduced the net cerebral glutamine efflux, despite an unchanged net cerebral ammonia uptake. CONCLUSIONS: Patients with FHF have an increased cerebral glutamine efflux, and short-term hyperventilation reduces this efflux. A high cerebral ammonia uptake and cerebral glutamine efflux in patients with FHF were associated with an increased risk of subsequent fatal intracranial hypertension. [Gastroenterology 2001; 121:1109–1119]
Hepatic encephalopathy and intracranial hypertension are the main features that dominate the clinical picture in fulminant hepatic failure (FHF). The standard of care includes specific measures to support the failing brain, such as assisted ventilation, and to prevent irreversible damage secondary to intracranial hypertension. Since the identification of brain edema as the underlying process that leads to brain death in advanced coma, experimental studies have recognized ammonia as a main factor in its development [1]. According to these studies, brain edema may arise from the osmotic effects of the accumulation of glutamine, the product of ammonia metabolism in astrocytes (‘the glutamine hypothesis’). Although experimental preparations were very useful for the elucidation of this hypothesis, they failed to describe the complete picture. Clinical studies conducted in recent years have recognized the important role of cerebral blood flow (CBF) [2]. In initial stages, patients with FHF exhibit a decrease in CBF, but with the progression of liver failure they develop a gradual vasodilatation with loss of autoregulation, usually accompanied by cerebral hyperemia (‘luxury perfusion’) at the time of intracranial hypertension. Experimental and clinical findings have been reconciled in a new hypothesis that proposes an initial acute osmotic change due to the generation of glutamine, followed by an increase in CBF [3]. Cerebral perfusion is a dynamic process that evolves as FHF progresses. Assessing the levels of metabolites in blood, without taking this aspect into consideration, results in a false appreciation of the metabolic processes that take place in the brain. This important study by the Copenhagen group investigates the cerebral metabolism of ammonia and amino acids in patients with FHF [4]. The authors calculated fluxes of these substances across the brain by determining CBF and by assessing arterio-venous differences. The results were compared with those of cirrhotic patients without hepatic encephalopathy and with healthy controls. Patients with FHF exhibited a striking increase in the cerebral uptake of ammonia, an increase that was higher in those
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S01 68- 8278(02)0030 9-4
Beyond the Journal
who subsequently died of cerebral herniation. Brain edema appeared to depend on the amount of ammonia to which the brain was exposed. In accordance with the glutamine hypothesis, the rise in the uptake of ammonia resulted in intracranial hypertension and in a higher glutamine efflux, probably an indicator of greater glutamine synthesis. The results of Strauss et al. therefore implicate ammonia in the pathogenesis of cerebral complications in FHF, as it has been similarly implicated in hepatic encephalopathy in cirrhosis [5]. Lack of correlation between blood ammonia levels and the degree of neurologic dysfunction has been a classic argument against the ‘ammonia hypothesis’. The original method of modeling brain uptake was to assume an instant equilibrium between capillary and tissue. Thus, cerebral uptake of ammonia would relate to CBF and the arterial concentration of ammonia. At a stable CBF, the amount of ammonia in brain tissue will correlate with arterial ammonia. Strauss et al. assessed the effects of decreasing CBF on cerebral ammonia uptake. The decrease in CBF was achieved through hyperventilation, an effective measure used to decrease intracranial hypertension, that was thought to diminish brain exposure to ammonia. The objective was to elucidate the relationship between changes in the generation of glutamine and intracranial hypertension. Nevertheless, while hyperventilation reduced CBF, it did not modify cerebral ammonia uptake. In other studies, hypothermia and indomethacin, which are other measures that reduce CBF in FHF, decreased ammonia uptake to a larger extent than would be expected by their effect on CBF [6,7]. Furthermore, prior isotopic studies reveal an increase in the permeability of the blood–brain barrier to ammonia in patients with liver failure [8]. Thus, the kinetics of ammonia uptake are more complex than previously assumed. Involvement of the microcirculation, with changes in capillary recruitment and astrocyte-endothelial cell interactions, appears to be a key point in this process. A better understanding of microcirculatory changes may allow the development of new therapies that decrease the entrance of ammonia into cerebral tissue. Blood ammonia is derived from deamination of amino acids [9]. Several tissues, such as the brain and the skeletal muscle, detoxify ammonia by converting it to glutamine, that is in turn metabolized back to ammonia in the splanchnic organs, resulting in the release of large amounts of ammonia into the portal circulation. In the liver, ammonia is transformed into urea, which is the end product of nitrogen metabolism. When there is a decrease in the rate of urea synthesis, as occurs in liver failure, an increase in protein degradation may ultimately cause a rise in ammonia levels. Strauss et al. found a negative nitrogen balance in the brain of patients with FHF, similar to that described in skeletal muscle [10]. In both tissues, the release of glutamine was several-fold greater than would be expected by only ammonia detoxification, probably as a result of increased protein degradation. Fasting and malnutrition, which are amenable
879
to nutritional intervention [11], may have favored the increase in protein degradation. However, except for branched-chain amino acids, these patients show high blood levels of amino acids [4,10] and it is difficult to envision how supplying more amino acids would decrease protein degradation. Furthermore, the surplus nitrogen provided by nutritional intervention may increase the load of ammonia precursors. An interesting observation by Strauss et al. is that short-term hyperventilation changed the cerebral nitrogen balance from negative towards normal. The authors proposed that this effect may be through an increase in the rate of protein synthesis induced by alkalosis. It would have been interesting to know if a similar effect also occurred in skeletal muscle. Thus, these results suggest that in contrast to nutritional interventions, it might be possible to stimulate a net protein positive balance without surplus nitrogen. In conclusion, the study of Strauss et al. highlights the importance of ammonia fluxes in the development of neurological complications in FHF and provides important information on the characteristics of the nitrogen pathways that may lead to future therapeutic interventions. Juan Co´ rdoba Liver Unit, Hospital Universitari Vall d’Hebron, Paseo Vall d’Hebron 119, Barcelona 08035, Spain
References [1] Cordoba J, Blei AT. Brain edema and hepatic encephalopathy. Semin Liver Dis 1996;16:271–280. [2] Larsen FS. Cerebral circulation in liver failure: Ohm law in force. Semin Liver Dis 1996;16:281–292. [3] Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999;31:771–776. [4] Strauss GI, Knudsen GM, Kondrup J, Moller K, Larsen FS. Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Gastroenterology 2001;121:1109–1119. [5] Butterworth RF, Giguere JF, Michaud J, Lavoie J, Layrargues GP. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 1987;6:1–12. [6] Jalan R, Damink SWMO, Deutz NE, Lee A, Hayes PC. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999;354:1164–1168. [7] Clemmesen JO, Hansen BA, Larsen FS. Indomethacin normalizes intracranial pressure in acute liver failure: a 23-year-old woman treated with indomethacin. Hepatology 1997;26:1423–1425. [8] Lockwood AH, Yap EW, Wong WH. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab 1991;11:337–341. [9] Cooper JL, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev 1987;67:440–519. [10] Clemmesen JO, Kondrup J, Ott P. Splachnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology 2000;118:1131–1139. [11] Plauth M, Merli M, Weimann A, Ferenci P, Mueller MJ. ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr 1997;16:43–55.
BEYOND THE JOURNAL Associate Editors: Guadalupe Garcia-Tsao and Ronald Oude Elferink Committee: James Boyer, Jean-Franc¸ois Dufour, Hartmut Jaeschke, Luigi Pagliaro, Jorge Rakela, Tania Roskams and Christian Trautwein
Understanding the mechanisms of cerebral complications in fulminant hepatic failure: fluxes better than levels Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Strauss GI, Knudsen GM, Kondrup J, Moller K, Larsen FS. Department of Hepatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark BACKGROUND & AIMS: High circulating levels of ammonia have been suggested to be involved in the development of cerebral edema and herniation in fulminant hepatic failure (FHF). The aim of this study was to measure cerebral metabolism of ammonia and amino acids, with special emphasis on glutamine metabolism. METHODS: The study consisted of patients with FHF (n ¼ 16) or cirrhosis (n ¼ 5), and healthy subjects (n ¼ 8). Cerebral blood flow was measured by the 133Xe washout technique. Blood samples for determination of ammonia and amino acids were drawn simultaneously from the radial artery and the internal jugular bulb. RESULTS: A net cerebral ammonia uptake was only found in patients with FHF (1.62 ^ 0.79 mmol £ 100 g 21 £ min 21). The cerebral glutamine efflux was higher in patients with FHF than in the healthy subjects and cirrhotics, 26.11 ^ 5.19 versus 21.93 ^ 1.17 and 21.50 ^ 0.29 mmol £ 100 g 21 £ min 21, respectively (P , 0.05). Patients with FHF who subsequently died of cerebral herniation (n ¼ 6) had higher arterial ammonia concentrations, higher cerebral ammonia uptake, and higher cerebral glutamine efflux than survivors. Intervention with short-term mechanical hyperventilation in FHF reduced the net cerebral glutamine efflux, despite an unchanged net cerebral ammonia uptake. CONCLUSIONS: Patients with FHF have an increased cerebral glutamine efflux, and short-term hyperventilation reduces this efflux. A high cerebral ammonia uptake and cerebral glutamine efflux in patients with FHF were associated with an increased risk of subsequent fatal intracranial hypertension. [Gastroenterology 2001; 121:1109–1119]
Hepatic encephalopathy and intracranial hypertension are the main features that dominate the clinical picture in fulminant hepatic failure (FHF). The standard of care includes specific measures to support the failing brain, such as assisted ventilation, and to prevent irreversible damage secondary to intracranial hypertension. Since the identification of brain edema as the underlying process that leads to brain death in advanced coma, experimental studies have recognized ammonia as a main factor in its development [1]. According to these studies, brain edema may arise from the osmotic effects of the accumulation of glutamine, the product of ammonia metabolism in astrocytes (‘the glutamine hypothesis’). Although experimental preparations were very useful for the elucidation of this hypothesis, they failed to describe the complete picture. Clinical studies conducted in recent years have recognized the important role of cerebral blood flow (CBF) [2]. In initial stages, patients with FHF exhibit a decrease in CBF, but with the progression of liver failure they develop a gradual vasodilatation with loss of autoregulation, usually accompanied by cerebral hyperemia (‘luxury perfusion’) at the time of intracranial hypertension. Experimental and clinical findings have been reconciled in a new hypothesis that proposes an initial acute osmotic change due to the generation of glutamine, followed by an increase in CBF [3]. Cerebral perfusion is a dynamic process that evolves as FHF progresses. Assessing the levels of metabolites in blood, without taking this aspect into consideration, results in a false appreciation of the metabolic processes that take place in the brain. This important study by the Copenhagen group investigates the cerebral metabolism of ammonia and amino acids in patients with FHF [4]. The authors calculated fluxes of these substances across the brain by determining CBF and by assessing arterio-venous differences. The results were compared with those of cirrhotic patients without hepatic encephalopathy and with healthy controls. Patients with FHF exhibited a striking increase in the cerebral uptake of ammonia, an increase that was higher in those
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S01 68- 8278(02)0030 9-4
Beyond the Journal
who subsequently died of cerebral herniation. Brain edema appeared to depend on the amount of ammonia to which the brain was exposed. In accordance with the glutamine hypothesis, the rise in the uptake of ammonia resulted in intracranial hypertension and in a higher glutamine efflux, probably an indicator of greater glutamine synthesis. The results of Strauss et al. therefore implicate ammonia in the pathogenesis of cerebral complications in FHF, as it has been similarly implicated in hepatic encephalopathy in cirrhosis [5]. Lack of correlation between blood ammonia levels and the degree of neurologic dysfunction has been a classic argument against the ‘ammonia hypothesis’. The original method of modeling brain uptake was to assume an instant equilibrium between capillary and tissue. Thus, cerebral uptake of ammonia would relate to CBF and the arterial concentration of ammonia. At a stable CBF, the amount of ammonia in brain tissue will correlate with arterial ammonia. Strauss et al. assessed the effects of decreasing CBF on cerebral ammonia uptake. The decrease in CBF was achieved through hyperventilation, an effective measure used to decrease intracranial hypertension, that was thought to diminish brain exposure to ammonia. The objective was to elucidate the relationship between changes in the generation of glutamine and intracranial hypertension. Nevertheless, while hyperventilation reduced CBF, it did not modify cerebral ammonia uptake. In other studies, hypothermia and indomethacin, which are other measures that reduce CBF in FHF, decreased ammonia uptake to a larger extent than would be expected by their effect on CBF [6,7]. Furthermore, prior isotopic studies reveal an increase in the permeability of the blood–brain barrier to ammonia in patients with liver failure [8]. Thus, the kinetics of ammonia uptake are more complex than previously assumed. Involvement of the microcirculation, with changes in capillary recruitment and astrocyte-endothelial cell interactions, appears to be a key point in this process. A better understanding of microcirculatory changes may allow the development of new therapies that decrease the entrance of ammonia into cerebral tissue. Blood ammonia is derived from deamination of amino acids [9]. Several tissues, such as the brain and the skeletal muscle, detoxify ammonia by converting it to glutamine, that is in turn metabolized back to ammonia in the splanchnic organs, resulting in the release of large amounts of ammonia into the portal circulation. In the liver, ammonia is transformed into urea, which is the end product of nitrogen metabolism. When there is a decrease in the rate of urea synthesis, as occurs in liver failure, an increase in protein degradation may ultimately cause a rise in ammonia levels. Strauss et al. found a negative nitrogen balance in the brain of patients with FHF, similar to that described in skeletal muscle [10]. In both tissues, the release of glutamine was several-fold greater than would be expected by only ammonia detoxification, probably as a result of increased protein degradation. Fasting and malnutrition, which are amenable
879
to nutritional intervention [11], may have favored the increase in protein degradation. However, except for branched-chain amino acids, these patients show high blood levels of amino acids [4,10] and it is difficult to envision how supplying more amino acids would decrease protein degradation. Furthermore, the surplus nitrogen provided by nutritional intervention may increase the load of ammonia precursors. An interesting observation by Strauss et al. is that short-term hyperventilation changed the cerebral nitrogen balance from negative towards normal. The authors proposed that this effect may be through an increase in the rate of protein synthesis induced by alkalosis. It would have been interesting to know if a similar effect also occurred in skeletal muscle. Thus, these results suggest that in contrast to nutritional interventions, it might be possible to stimulate a net protein positive balance without surplus nitrogen. In conclusion, the study of Strauss et al. highlights the importance of ammonia fluxes in the development of neurological complications in FHF and provides important information on the characteristics of the nitrogen pathways that may lead to future therapeutic interventions. Juan Co´ rdoba Liver Unit, Hospital Universitari Vall d’Hebron, Paseo Vall d’Hebron 119, Barcelona 08035, Spain
References [1] Cordoba J, Blei AT. Brain edema and hepatic encephalopathy. Semin Liver Dis 1996;16:271–280. [2] Larsen FS. Cerebral circulation in liver failure: Ohm law in force. Semin Liver Dis 1996;16:281–292. [3] Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999;31:771–776. [4] Strauss GI, Knudsen GM, Kondrup J, Moller K, Larsen FS. Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Gastroenterology 2001;121:1109–1119. [5] Butterworth RF, Giguere JF, Michaud J, Lavoie J, Layrargues GP. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 1987;6:1–12. [6] Jalan R, Damink SWMO, Deutz NE, Lee A, Hayes PC. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999;354:1164–1168. [7] Clemmesen JO, Hansen BA, Larsen FS. Indomethacin normalizes intracranial pressure in acute liver failure: a 23-year-old woman treated with indomethacin. Hepatology 1997;26:1423–1425. [8] Lockwood AH, Yap EW, Wong WH. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab 1991;11:337–341. [9] Cooper JL, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev 1987;67:440–519. [10] Clemmesen JO, Kondrup J, Ott P. Splachnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology 2000;118:1131–1139. [11] Plauth M, Merli M, Weimann A, Ferenci P, Mueller MJ. ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr 1997;16:43–55.