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Cerebral effects of ammonia in liver disease: current hypotheses

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Abstract

Hyperammonemia is necessary for development of the cerebral complications to liver disease including hepatic encephalopathy and cerebral edema but the mechanisms are unclear. Ammonia is taken up by the brain in proportion to its arterial concentration. The flux into the brain is most likely by both diffusion of NH3 and mediated transport of NH4 + . Astrocytic detoxification of ammonia involves formation of glutamine at concentrations high enough to produce cellular edema, but compensatory mechanisms reduce this effect. Glutamine can be taken up by astrocytic mitochondria and initiate the mitochondrial permeability transition but the clinical relevance is uncertain. Elevated astrocytic glutamine interferes with neurotransmission. Thus, animal studies show enhanced glutamatergic neurotransmission via the NMDA receptor which may be related to the acute cerebral complications to liver failure, while impairment of the NMDA activated glutamate-NO-cGMP pathway could relate to the behavioural changes seen in hepatic encephalopathy. Elevated glutamine also increases GABA-ergic tone, an effect which is aggravated by mitochondrial production of neurosteroids; this may relate to decreased neurotransmission and precipitation of encephalopathy by GABA targeting drugs. Hyperammonemia may compromise cerebral energy metabolism as elevated cerebral lactate is generally reported. Hypoxia is unlikely since cerebral oxygen:glucose utilisation and lactate:pyruvate ratio are both normal in clinical studies. Ammonia inhibits α-ketoglutaratedehydrogenase in isolated mitochondria, but the clinical relevance is dubious due to the observed normal cerebral oxygen:glucose utilization. Recent studies suggest that ammonia stimulates glycolysis in excess of TCA cycle activity, a hypothesis that may warrant further testing, in being in accordance with the limited clinical observations.

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Ott, P., Vilstrup, H. Cerebral effects of ammonia in liver disease: current hypotheses. Metab Brain Dis 29, 901–911 (2014). https://doi.org/10.1007/s11011-014-9494-7

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