Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome

Albrecht, Jan; Jones, E. Anthony

doi:10.1016/s0022-510x(99)00169-0

Cited by 253 publications

(165 citation statements)

References 81 publications

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“…The theories of the pathogenesis of hepatic coma in ALF are not discussed here except to list those most widely accepted. 4 These include ammonia accumulation (with depletion of brain glutamate), 5,6 endogenous benzodiazepine accumulation (leading to neural inhibition through ␥-aminobutyric acid type A-receptor activation), 7,8 and generation of false neurotransmitters from gut-derived amines (again leading to neural inhibition). 9 Thus, removal of nitrogenous waste and the ability to perform a number of biotransformatory functions with regard to ammonia metabolism can be considered important functions of a BAL.…”

Section: Essential Metabolic Functionsmentioning

confidence: 99%

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Tsiaoussis

Newsome

Nelson

et al. 2001

Liver Transplantation

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Liver failure, notwithstanding advances in medical management, remains a cause of considerable morbidity and mortality in the developed world. Although bioartificial liver (BAL) support systems offer the potential of significant therapeutic benefit for such patients, many issues relating to their use are still to be resolved. In this review, these issues are examined in terms of the functions required, the cells of choice in such a system, and the most appropriate environment to optimize the function of such cells T he development of nonbiological systems to support critically ill patients with acute liver failure (ALF) that incorporate plasmapheresis, 1 charcoal hemoperfusion, 2 and ultrafiltration techniques 3 has not had a significant impact on survival. Consequently, hepatocytebased biological systems have attracted intense interest worldwide but have also generated most of the controversy. Uncertainty exists about the most suitable biological component and the risk for zoonoses and immune rejection in the host. In addition, the optimization of culture conditions and thus metabolic function of the biological component have not been systematically studied, although continuing improvements in these areas have rendered this therapeutic avenue in ALF more promising. To compound matters, the question of which aspects of hepatocyte metabolism in an artificial liver are required to sustain life and promote recovery remains largely unanswered, further limiting development. In this review, the biological substrate of such systems is critically examined and insights are provided into the ideal system.

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Section: Essential Metabolic Functionsmentioning

confidence: 99%

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Tsiaoussis

Newsome

Nelson

et al. 2001

Liver Transplantation

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“…The cellular and molecular mechanisms for the development of HE remain unclear but the hyperammonemic condition is considered essential for the severity of the disease. 1,2 In the brain, the predominant route for ammonia metabolism is by glutamine synthesis via the enzyme glutamine synthetase (GS), which is exclusively located in the astrocytes. 3 Consequently, during acute hyperammonemic conditions, brain glutamine levels are increased in HE patients, [4][5][6] which has been suggested as the principal cause leading to astrocyte swelling and cerebral edema.…”

Section: Introductionmentioning

confidence: 99%

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Dadsetan

Kukolj

Bak

et al. 2013

J Cereb Blood Flow Metab

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Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of 15 NH 4 þ in alanine during acute hyperammonemia. We observed a fourfold increased amount of 15 NH 4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to 15 NH 4 Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of 15 NH 4 into alanine together with increased 15 N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy.

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“…Liver failure with decreased production of urea and/or portosystemic shunting leads to hyperammonemia, which in turn leads to increased brain uptake of ammonia from blood. 1,2 It is widely accepted that hyperammonemia has a central role in the development of HE 3 although the precise mechanisms remain unsolved. When bloodborne ammonia enters the brain, it is rapidly incorporated into glutamine by glutamine synthetase (GS) which is located in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Effect of Glutamine Synthetase Inhibition on Brain and Interorgan Ammonia Metabolism in Bile Duct Ligated Rats

Fries

Dadsetan

Keiding

et al. 2013

J Cereb Blood Flow Metab

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Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of 15 NH 4 þ into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of 15 NH 4 þ into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of 15 NH 4 þ into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of 15 N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.

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Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome

Cited by 253 publications

References 81 publications

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

Effect of Glutamine Synthetase Inhibition on Brain and Interorgan Ammonia Metabolism in Bile Duct Ligated Rats

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