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Bone morphogenetic proteins-2/4/7 (BMP-2/4/7) are important cytokines in systemic tissue morphogenesis. It has been demonstrated BMPs may have positive effects on liver repair and regeneration after hepatic injury. However, their function in the liver still remains unclear. D-galactosamine (D-gal) is a hepatotoxin used to induce hepatic failure. We employed D-gal and rat hepatoma cell line (1548) to investigate BMP-2/4/7 expression in hepatic injury induced by D-gal and probe their relations with liver repair and regeneration in hepatic injury. LDH release, mRNA and protein expression were detected. Results indicated that BMP-2/4/7 expression was activated by injury of rat hepatoma cells. It is indicative that repair and regeneration of the liver after hepatic injury and morphogenesis in early embryos seem to proceed through the same process. BMPs may be not only associated with hepatic injury after repair and regeneration, but also involved in chronic liver.

Bone morphogenetic proteins-2/4/7 (BMP-2/4/7) are important cytokines in systemic tissue morphogenesis. It has been demonstrated BMPs may have positive effects on liver repair and regeneration after hepatic injury. However, their function in the liver still remains unclear. D-galactosamine (D-gal) is a hepatotoxin used to induce hepatic failure. We employed D-gal and rat hepatoma cell line (1548) to investigate BMP-2/4/7 expression in hepatic injury induced by D-gal and probe their relations with liver repair and regeneration in hepatic injury. LDH release, mRNA and protein expression were detected. Results indicated that BMP-2/4/7 expression was activated by injury of rat hepatoma cells. It is indicative that repair and regeneration of the liver after hepatic injury and morphogenesis in early embryos seem to proceed through the same process. BMPs may be not only associated with hepatic injury after repair and regeneration, but also involved in chronic liver.

INTRODUÇÃO: O Transplante de fígado evoluiu nas últimas décadas, sempre em busca de melhorar a sobrevida do paciente e do enxerto. Importante causa de morbi-mortalidade é a disfunção precoce do enxerto (DPE) e o não funcionamento primário do enxerto (NFP). Diversos biomarcadores vem sendo estudados, porém ainda não há um consenso. Com isso tivemos a hipótese científica de avaliar e quantificar a função hepática avaliada pele verde de indocianina (VI) após o transplante de fígado. OBJETIVO: Avaliar a disfunção precoce do enxerto pela taxa de depuração plasmática do (VI) no pós-operatório imediato de transplante hepático. MÉTODO: Estudo clinico, de julho de 2014 a junho de 2015, prospectivo e observacional. Um total de 40 pacientes fizeram parte desta análise pela pulso-densitometria, usando o sistema de Limon (Impulse Medical System, Munique, Alemanha). Foram avaliados também o índice de risco de doadores (DRI), os critérios de Wagener e de Olthoff e preditores prognósticos pós-transplante de fígado. Todos os testes realizados levaram em consideração um alfa bidirecional de 0,05 e intervalo de confiança (IC) de 95% e foram realizados com apoio computacional dos softwares IBM SPSS 25 (Statistical Package for the Social Sciences) e Excel 2016® (Microsoft Office). RESULTADOS: Um total de 40 pacientes foram avaliados. A idade média foi de 53 anos e a maioria do sexo masculino (70%). A etiologia da cirrose mais comum foi hepatite por vírus C (42,5%). Os pacientes eram Child C em 45% dos casos. A taxa de retenção o verde de indocianina em 15 minutos (R15) permaneceu aumentada nos dias 1 e 3 de pós operatório ( > 10%) e normalizou no 7º dia de pós operatório ( < 10%). A taxa de depuração manteve valores normais, com 18,5% no 1º dia; 20,3 no 3º e 20,4 no 7º dia pós operatório. A comparação com os critérios de Olthoff e Wagener não mostrou diferença estatística (p=0,467 e p=0,178). Na comparação com DRI > 1,5 encontrou-se p=0,066, e com desfecho negativo (Perda do enxerto ou óbito) em p=0,063. A depuração do verde de indocianina mostrou relação significativa com o grau de lesão histológica pós isquemia e reperfusão (p=0,030). CONCLUSÃO: A reserva funcional hepática apresenta-se diminuída no pós operatório recente de transplante de fígado com melhora ao final da primeira semana. A depuração hepática do verde de indocianina não relaciona-se com a disfunção precoce do enxerto avaliada pelos critérios de Oltoff e Wagener. Por outro lado ela tem uma relação significativa inversamente proporcional ao grau da lesão hepática pós isquemia e reperfusão / INTRODUCTION: Liver transplantation has evolved in the last decades, alway seeking to improve patient and graft survival. Important cause of morbidity and mortality is early graft dysfunction (EGD) and primary non-graft function (NGF). Several biomarkers have been studied, but there is still no consensus. With this we had the scientific hypothesis to evaluate and quantify the hepatic function evaluated by indocyanine green (IG) after liver transplantation. OBJECTIVE: To evaluate the early graft dysfunction by the plasma clearance rate of (IG) in the immediate postoperative period of liver transplantation. METHOD: Clinical study, from July 2014 to June 2015, prospective and observational. A total of 40 patients were part of this analysis by pulse-densitometry, using the Limon system (Impulse Medical System, Munich, Germany). Donor risk index (DRI), Wagener and Olthoff criteria, and prognostic predictors after liver transplantation were also evaluated. All the tests performed into account a bidirectional Alpha of 0.05 and a 95% confidence interval (CI) and were performed with computational support of the software IBM SPSS 25 (Statistical Package for the Social Sciences) and Excel 2016 (Microsoft Office). RESULTS: A total of 40 patients were evaluated. The mean age was 53 years and the majority of them was male (70%). The most common etiology of cirrhosis was C virus hepatitis (42.5%). The patients were Child C in 45% of cases. The indocyanine green retention rate in 15 minutes (R15) was increased on days 1 and 3 postoperatively ( > 10%) and normalized on the 7th postoperative day ( < 10%). The ICG clearance rate maintained normal values, with 18.5% in the 1st day; 20.3 in the 3rd and 20.4 in the 7th postoperative day. The comparison with Olthoff and Wagener criteria showed no statistical difference (p=0,467 e p=0,178). In the comparison with DRI > 1.5 a p = 0.066 was found; and with negative outcome (Loss of graft or death) a p = 0.063 was found. The clearance of indocyanine green showed a significant relation with the degree of histological lesion after ischemia and reperfusion (p = 0.030). CONCLUSION: The liver functional reserve is decreased in the recent postoperative period of liver transplantation with improvement at the end of the first week. Hepatic clearance of indocyanine green is not related to early graft dysfunction assessed by Oltoff and Wagener criteria. On the other hand, it has a significant relationship inversely proportional to the degree of ischemia and reperfusion hepatic injury

What is known and objective: Amiodarone, a commonly used class III antiarrhythmic agent notable for a relatively long half-life of up to 6 months and its pronounced adverse effect profile, is used for both acute and chronic management of cardiac arrhythmias. Chronic use of amiodarone has been associated with asymptomatic hepatotoxicity; however, acute toxicity is thought to be uncommon. There are only six reported cases of acute liver failure (ALF) secondary to amiodarone. In all these cases the outcome of death during the same hospitalization resulted. We aimed to report the only case of acute liver failure secondary to amiodarone infusion in the existing literature where the patient survived. Case summary: A 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. She was diagnosed with acute liver failure (ALF) secondary to an amiodarone adverse drug reaction, with a calculated score of seven on the Naranjo adverse drug reaction probability scale. Amiodarone was immediately withheld, and N-acetylcysteine (NAC) was initiated. Clinical improvement was seen within 48 hours of holding the drug and within 24 hours of initiating NAC. On post-hospital follow-up visit she was reported to have complete recovery. What is new and conclusion: This report emphasizes the importance of monitoring liver enzymes and mental status while a patient is being administered IV amiodarone. N-acetylcysteine administration may have possibly contributed to the early and successful recovery from ALF in our patient. To date, she is the only patient in the existing literature who has been reported to survive ALF secondary to amiodarone administration.

A presente análise das três séries históricas, compondo um total de 42 casos de hepatopatias fulminantes da região Amazônica, teve por objetivos o estudo de aspectos morfológicos e imuno-histoquímicos no diagnóstico diferencial entre febre amarela (FA), hepatite de Lábrea (HL) e de outras entidades. Visou, ainda, aprimorar o conhecimento de aspectos da morfogênese da morte hepatocelular, de eventual fibrose, relacionando-as aos padrões de regeneração e de lesões vasculares, conforme recentemente descrito na gênese de hepatopatias crônicas. Dentre o extenso painel de critérios histológicos aqui estudados, os padrões de morte hepatocelular e sua distribuição, incluindo corpos apoptóticos medio-zonais, assim como a balonização foram os achados mais característicos da FA, enquanto as células em mórula foram o principal achado na HL. Dezenove casos bem caracterizados (10 FA e 9 HL) foram então submetidos a estudos imuno-histoquímicos para a detecção dos antígenos da FA, AgHBs e antígeno do vírus da hepatite D (VHD), sendo então demonstrado que, em ambas as doenças, mas principalmente na HL, flebite, principalmente de ramos da veia porta, foi evidente e deve ter tido participação na patogênese do dano hepático, com extensa extinção parenquimatosa hepática e aproximação de espaços porta. O padrão de regeneração também foi marcante: nos casos de FA, um elevado índice de proliferação celular foi observado enquanto que, na HL, multinucleações e transformação pseudoacinar, associadas a depósitos portais de colágeno do tipo I e de fibras elásticas, foram encontrados. Concluindo, a pesquisa imuno-histoquímica de antígenos virais permitiu a caracterização etiológica dos casos destas importantes séries históricas de hepatopatias fulminantes da Amazônia, mesmo em amostras arquivadas em parafina por até sete décadas. Permitiu, ainda, o relato original de cinco casos de possível superposição de infecção pelos vírus da FA, VHB e/ou VHD. Dentre os aspectos histopatológicos, o quadro dominante na FA fulminante incluiu apoptose medio-zonal associada com flebite portal e um alto índice de proliferação celular, em pacientes sem evidência de dano hepático prévio. Por outro lado, a HL fulminante mostrou extensa necrose lítica de hepatócitos, associada à flebite portal e de veia hepática e à presença de células em mórula, em pacientes com evidências morfológicas de doença hepática crônica. / This study aimed at assessing morphological and immunohistochemical aspects useful for the differential diagnosis of yellow fever (YF), Labrea hepatitis (LH) and other entities by revisiting 42 fulminant hepatic failure cases, from three historical series from Amazon Basin. Additional studies were performed aiming at further understanding the morphogenesis of hepatocelular death, in relation to regeneration and fibrosis patterns and to vascular lesions, as recently described in chronic hepatic diseases. Among the extensive panel of histological criteria studied, liver cell death pattern and distribution, including midzonal apoptotic bodies, as well as hepatocelular ballooning degeneration were YF most characteristic findings, while morula cells were the major hint for LH. Five cases were herein suggested as coinfected with YF, HBV and/or HDV, a finding not previously reported. Nineteen well characterized cases (10 YF and 9 LH) were further submitted to immunohistochemical studies for YF antigen, HBsAg and Delta virus Ag. In both diseases, but mainly in LH, phlebitis, mainly of portal vein branches, was evident and closely related to the degree of hepatocellular damage, with severe hepatic parenchymal extinction and portal tract approximation. Regeneration pattern was also remarkable: in YF cases, a high hepatocellular proliferative index was detected whereas in LH, multinucleation and pseudo-acinar transformation, associated with portal type I collagen and elastic fiber deposition were found. In conclusion, immunohistochemical viral antigen detection yielded further etiological characterization of these important historical cases of fulminant hepatic failure from Amazon Basin, even in paraffin samples stored for up to seven decades. YF morphology depicted midzonal apoptosis, portal phlebitis and a high hepatocellular proliferative index, in patients without evidence of previous hepatic injury. On the other hand, fulminant LH showed extensive lytic hepatocellular necrosis, portal and hepatic vein phlebitis and the presence morula cells, in patients with morphological evidences of chronic liver disease.

A presente análise das três séries históricas, compondo um total de 42 casos de hepatopatias fulminantes da região Amazônica, teve por objetivos o estudo de aspectos morfológicos e imuno-histoquímicos no diagnóstico diferencial entre febre amarela (FA), hepatite de Lábrea (HL) e de outras entidades. Visou, ainda, aprimorar o conhecimento de aspectos da morfogênese da morte hepatocelular, de eventual fibrose, relacionando-as aos padrões de regeneração e de lesões vasculares, conforme recentemente descrito na gênese de hepatopatias crônicas. Dentre o extenso painel de critérios histológicos aqui estudados, os padrões de morte hepatocelular e sua distribuição, incluindo corpos apoptóticos medio-zonais, assim como a balonização foram os achados mais característicos da FA, enquanto as células em mórula foram o principal achado na HL. Dezenove casos bem caracterizados (10 FA e 9 HL) foram então submetidos a estudos imuno-histoquímicos para a detecção dos antígenos da FA, AgHBs e antígeno do vírus da hepatite D (VHD), sendo então demonstrado que, em ambas as doenças, mas principalmente na HL, flebite, principalmente de ramos da veia porta, foi evidente e deve ter tido participação na patogênese do dano hepático, com extensa extinção parenquimatosa hepática e aproximação de espaços porta. O padrão de regeneração também foi marcante: nos casos de FA, um elevado índice de proliferação celular foi observado enquanto que, na HL, multinucleações e transformação pseudoacinar, associadas a depósitos portais de colágeno do tipo I e de fibras elásticas, foram encontrados. Concluindo, a pesquisa imuno-histoquímica de antígenos virais permitiu a caracterização etiológica dos casos destas importantes séries históricas de hepatopatias fulminantes da Amazônia, mesmo em amostras arquivadas em parafina por até sete décadas. Permitiu, ainda, o relato original de cinco casos de possível superposição de infecção pelos vírus da FA, VHB e/ou VHD. Dentre os aspectos histopatológicos, o quadro dominante na FA fulminante incluiu apoptose medio-zonal associada com flebite portal e um alto índice de proliferação celular, em pacientes sem evidência de dano hepático prévio. Por outro lado, a HL fulminante mostrou extensa necrose lítica de hepatócitos, associada à flebite portal e de veia hepática e à presença de células em mórula, em pacientes com evidências morfológicas de doença hepática crônica. / This study aimed at assessing morphological and immunohistochemical aspects useful for the differential diagnosis of yellow fever (YF), Labrea hepatitis (LH) and other entities by revisiting 42 fulminant hepatic failure cases, from three historical series from Amazon Basin. Additional studies were performed aiming at further understanding the morphogenesis of hepatocelular death, in relation to regeneration and fibrosis patterns and to vascular lesions, as recently described in chronic hepatic diseases. Among the extensive panel of histological criteria studied, liver cell death pattern and distribution, including midzonal apoptotic bodies, as well as hepatocelular ballooning degeneration were YF most characteristic findings, while morula cells were the major hint for LH. Five cases were herein suggested as coinfected with YF, HBV and/or HDV, a finding not previously reported. Nineteen well characterized cases (10 YF and 9 LH) were further submitted to immunohistochemical studies for YF antigen, HBsAg and Delta virus Ag. In both diseases, but mainly in LH, phlebitis, mainly of portal vein branches, was evident and closely related to the degree of hepatocellular damage, with severe hepatic parenchymal extinction and portal tract approximation. Regeneration pattern was also remarkable: in YF cases, a high hepatocellular proliferative index was detected whereas in LH, multinucleation and pseudo-acinar transformation, associated with portal type I collagen and elastic fiber deposition were found. In conclusion, immunohistochemical viral antigen detection yielded further etiological characterization of these important historical cases of fulminant hepatic failure from Amazon Basin, even in paraffin samples stored for up to seven decades. YF morphology depicted midzonal apoptosis, portal phlebitis and a high hepatocellular proliferative index, in patients without evidence of previous hepatic injury. On the other hand, fulminant LH showed extensive lytic hepatocellular necrosis, portal and hepatic vein phlebitis and the presence morula cells, in patients with morphological evidences of chronic liver disease.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal. / Hepatic encephalopathy (HE) is a neuropsychiatric disorder occurring in both acute and chronic liver diseases. Depending on the duration and degree of hepatic dysfunction, HE may be present as one of two major types; portal-systemic encephalopathy (PSE) (chronic liver failure) and fulminant hepatic failure (FHF) (acute liver failure). Hyperammonemia is a key feature of both PSE and FHF and it is strongly suggested that ammonia toxicity is implicated directly or indirectly in the pathogenesis of both forms of HE. The present thesis comprises 5 articles demonstrating various aspects of the pathophysiology and new approaches to the treatment of HE. In chapter 2.1; article 1, using in vivo microdialysis, brain extracellular glutamate levels were found to be increased in correlation with arterial ammonia levels and the degree of neurological impairment in rats with FHF due to liver devascularization. N-methyl-D-aspartate (NMDA) receptor binding was found to be unchanged in rats with liver devascularization compared to control rats. Treatments for both forms of HE continue to focus on ammonia-lowering strategies. When administered to portacaval shunted (PCS) rats, L-ornithine-Laspartate (OA), two substrates of the urea cycle, was observed to result in a lowering of plasma ammonia and increased plasma urea levels as well as protection against ammonia-induced coma (chapter 2.2; article 2). In acute liver failure, peripheral ammonia is removed via muscle glutamine synthetase (GS). This was confirmed in the study (chapter 2.3; article 3) in rats with liver devascularization where OA also lowered plasma ammonia and protected rats against coma and brain edema. GS activity in muscle was increased following OA treatment. Mild hypothermia was shown to be protective against coma and brain edema in rats with liver devascularization (chapter 2.5; article 5). In mildly hypothermie rats, plasma ammonia levels were unaffected whereas cerebrospinal fluid (CSF) ammonia levels were lowered suggesting that hypothermia prevents increased ammonia uptake into brain. This protective effect was associated with a decrease in extracellular brain glutamate levels, supporting the proposal that glutamate may be implicated in the pathogenesis of brain edema in FHF. Although the precise pathophysiologic mechanisms responsible for HE in FHF are not completely understood, an increased glutamatergic neurotransmission could contribute to this phenomenon. Another potential neurotoxin, manganese, is believed to be implicated in the pathogenesis of PSE. Manganese levels were found to be increased in both autopsied brain tissue from patients and in brain tissue from experimental animal models of PSE (chapter 2.4; article 4). It is suggested that manganese deposition is responsible for the signal hyperintensities on T1-weighted magnetic resonance (MR) images and the extrapyramidal symptoms found in PSE. / L'encéphalopathie hépatique (EH) est un désordre neuropsychiatrique que l'on retrouve soit dans la période aiguë ou la phase chronique d'une maladie du foie. Ainsi, selon la durée de l'atteinte hépatique, l'EH peut se présenter de 2 façons : la première étant l'encéphalopathie porto-systémique et la seconde l'encéphalopathie rencontrée au cours des hépatites fulminantes. L'encéphalopathie porto-systémique est secondaire à la dérivation portosystémique du sang veineux tel que rencontré spontanément lors de l'hypertension portale ou soit suite à une anastomose portocave chirurgicale ou radiologique (shunt intra-hépatique porto systémique transjugulaire ou TIPS). Cliniquement, l'EH portosystémique est un syndrome neurologique qui se développe lentement; le stade précoce est souvent peu apparent et se caractérise par des modifications du cycle du sommeil ainsi que des changements mineurs de personnalité. Une baisse du niveau d’attention ainsi qu'une incoordination musculaire apparaissent ensuite, progressant lentement vers la léthargie, la stupeur et le coma. Du point de vue anatomopathologique, l'EH porto-systémique est caractérisée par une astrocytose sans évidence d'altérations neuronales structurelles. L'hyperammonémie est une caractéristique importante de l'EH portosystémique et de l'encéphalopathie aiguë des hépatites fulminantes. Il est admis que l'ammoniaque est impliquée directement et/ou indirectement dans la pathogénèse dans ces deux types d'EH. À forte concentration, l'ammoniaque a le potentiel d'affecter le système nerveux central de diverses façons. Il y a d'abord un effet direct de l'ion ammonium sur la neurotransmission inhibitrice ou excitatrice ainsi qu'une inhibition de l'enzyme a-cétoglutarate déshydrogénase dans le cycle de Krebs, ce qui a comme conséquence directe d'altérer le métabolisme énergétique du cerveau. Cependant, le métabolisme énergétique du cerveau ne semble affecté que dans les stades très avancés de l'EH porto-systémique ou d'encéphalopathie aiguë des hépatites fulminantes. L'insuffisance hépatique chronique se traduit par une augmentation des concentrations de manganèse dans le sang et le cerveau. Une sélectivité des dépôts de manganèse est l'hypothèse la plus probable afin d'expliquer les signaux hyperintenses localisés dans le pallidum tel que démontré par l'imagerie par résonance magnétique chez les patients cirrhotiques. La section 2.5 démontre que les dépôts de manganèse sont augmentés dans les globus pallidus prélevés à partir d’autopsie du tissu cérébral chez des patients cirrhotiques. La concentration de manganèse est aussi élevée dans le globus pallidus dans deux modèles animaux d'insuffisance hépatique chronique. De plus, une corrélation a été établie entre le degré de dérivation porto-systémique et la quantité de dépôts de manganèse. Au contraire, le manganèse cérébral n'est pas augmenté dans un modèle animal d'hépatite fulminante, ce qui suggère que l'accumulation découle de l'insuffisance hépatique chronique, plus particulièrement suite à une dérivation porto-systémique. L'EH est caractérisée par des perturbations de plusieurs systèmes de neurotransmission cérébrale. Le système glutamatergique est celui qui a été le plus étudié et on croit qu'il est impliqué dans la pathogénèse de l'EH. Des nouveaux traitements sont requis pour traiter ou stabiliser l'EH chez les patients atteints d'EH porto-systémique ou d'encéphalopathie aiguë afin d'augmenter la période de temps nécessaire pour pouvoir effectuer une transplantation. Les traitements actuels sont soit inefficaces ou comportent des effets secondaires très néfastes. Afin de traiter l'EH porto-systémique, on préconise comme thérapie des stratégies axées sur la diminution de l'ammoniaque sérique. La L-ornithine-L-aspartate (OA) est composée de deux substrats du cycle de l'urée qui se sont avérés efficaces pour réduire l'ammoniaque et améliorer les symptômes cliniques chez des patients hyperammonémiques ayant une EH portosystémique. Nous avons démontré un effet protecteur de l'OA sur le coma précipité par une infusion d'ammoniaque chez des rats ayant une dérivation porto-cave. L'effet protecteur s'accompagne d'une réduction significative de l'ammoniaque plasmatique ainsi que d'une augmentation significative de l'urée plasmatique, ce qui suggère que la réduction de la concentration plasmatique de l'ammoniaque est en partie le résultat d'une augmentation de la synthèse d'urée par le foie. Nous croyons aussi que l'OA peut, par l'intermédiaire des transaminases, mener à la production de trois molécules de glutamate. Ce substrat (le glutamate) peut ensuite stimuler l'activité de la glutamine synthétase dans les muscles, le foie et le cerveau pour ainsi former de la glutamine. Cette possibilité est soutenue par l'augmentation du glutamate et de la glutamine dans le plasma et le liquide céphalo-rachidien (LCR). Contrairement à l'EH porto-systémique, l’insuffisance hépatique fulminante (HF) progresse très rapidement en quelques heures ou jours seulement, vers un état mental altéré, la stupeur et finalement le coma. Les convulsions sont rares mais des myoclonies sont souvent rencontrées avant le coma. Dans cette condition, le taux de mortalité est élevé et la mort est souvent causée par une hernie du tronc cérébral secondaire à une hypertension intracrânienne causée par un oedème cérébral massif. L'oedème cellulaire des astrocytes est fréquemment observé mais l'astrocytose Alzheimer de Type II (voir insuffisance hépatique chronique) n'est pas une caractéristique neuropathologique de l'hépatite fulminante. L'ammoniaque est aussi incriminée dans la physiopathologie de ce type d'encéphalopathie. Afin d'élucider davantage la pathophysiologie de l'encéphalopathie des HF, nous avons mesuré, par le biais d'une microdialyse cérébrale in vivo, les concentrations extracellulaires des acides aminés dans le cortex frontal de rats atteints d'HF induite par dévascularisation hépatique afin d'établir une relation avec le degré d'atteinte neurologique. Dans ce modèle, on retrouve un oedème cérébral accompagné d'une augmentation de l'eau, tel que mesurée dans le cortex frontal. Les concentrations extracellulaires de glutamate sont significativement élevées trois heures avant le début du stade précoma et continuent à augmenter jusqu'à l'état comateux. Ces données suggèrent que l'HF mène à une augmentation de la libération de glutamate et/ou une diminution de la recapture du glutamate de l'espace extracellulaire. Récemment, des études sur le tissu cérébral de rats encéphalopathiques suite à une HF ont révélé une diminution de la concentration protéique et de l'expression génique de GLT-1, un transporteur astrocytaire du glutamate. L'augmentation de la production de la glutamine via la glutamine synthétase est aussi possiblement impliquée dans la pathogénèse de ce type d'encéphalopathie. Cependant, l'augmentation constante des concentrations de glutamine extracellulaire n'est pas corrélée avec la sévérité de l'encéphalopathie. Ceci suggère que la glutamine joue un rôle plutôt mineur dans la pathogénèse de l'oedème cérébral. Les traitements de l'encéphalopathie des HF sont axés sur le contrôle de l'hypertension intracrânienne. La transplantation hépatique demeure le traitement ultime mais d'autres traitements sont nécessaires afin de prolonger la vie des patients en attente de transplantation. Des stratégies visant à diminuer les taux d'ammoniaque ont été développées depuis qu'une étude récente a démontré que la survenue d'hernie cérébrale chez les patients souffrant d'HF était corrélée à la concentration artérielle d'ammoniaque. Nous avons démontré que l'infusion d'OA chez des rats ayant subi une dévascularisation hépatique entraînait un délai significatif avant l'apparition du coma, et une diminution significative de l'ammoniaque du plasma et du LCR comparativement aux contrôles. Cette diminution d'ammoniaque était accompagnée d'une réduction du contenu cérébral en eau. Le glutamate et la glutamine plasmatiques furent aussi significativement augmentés et puisque le cycle de l'urée est non-fonctionnel dans un foie dévascularisé, la réduction d'ammoniaque ne pouvait donc être induite que par la stimulation de la glutamine synthétase des muscles squelettiques. Le glutamate présent dans le LCR diminue parallèlement à la réduction du contenu cérébral en eau. Un autre des traitements qui fut récemment développé pour contrôler l'encéphalopathie des HF est l'hypothermie modérée. En réduisant la température corporelle de rats ayant subi une dévascularisation hépatique à 34°C, nous avons démontré un effet protecteur de cette procédure sur l'apparition du coma et de l'oedème cérébral. Les niveaux des acides aminés furent aussi mesurés en utilisant la méthode de microdialyse cérébrale in vivo et nous avons démontré une diminution du glutamate extracellulaire chez les rats protégés par l’hypothermie. Les mécanismes possiblement impliqués dans l'action bénéfique de l'hypothermie modérée incluent la diminution du transfert de l'ammoniaque sanguin vers le cerveau et la diminution des concentrations extracellulaires cérébrales d'acides aminés excitateurs tels que le glutamate. Ces résultats ajoutent davantage de crédibilité à la notion que la disponibilité élevée du glutamate dans l'espace extracellulaire et donc, une neurotransmission glutamatergique élevée, est impliquée dans la pathogénèse de certaines des complications cérébrales rencontrées au cours de l'HF. Ces résultats appuient aussi l'hypothèse que l'hypothermie modérée peut s'avérer une méthode efficace de prévention de l'encéphalopathie et de l'oedème cérébral, deux complications cérébrales très sévères de l'HF.