Patients with hepatic encephalopathy (HE) may present different neurological alterations including impaired cognitive function and altered motor activity and coordination. HE may lead to coma and death. Many of these neurological alterations are the consequence of altered neurotransmission. Hyperammonemia is a main contributor to the alterations in neurotransmission and in neurological functions in HE. Both glutamatergic and GABAergic neurotransmission are altered in animal models of HE. We review some of these alterations, especially those alterations in glutamatergic neurotransmission responsible for some specific neurological alterations in hyperammonemia and HE: the role 1) of excessive NMDA receptors activation in death induced by acute hyperammonemia; 2) of impaired function of the glutamate-nitric oxide-cGMP pathway, associated to NMDA receptors, in cognitive impairment in chronic HE; 3) of increased extracellular glutamate and activation of metabotropic glutamate receptors in substantia nigra in hypokinesia in chronic HE. The therapeutic implications are discussed. We also review the alterations in the function of the neuronal circuits between basal ganglia-thalamus-cortex modulating motor activity and the role of sequential alterations in glutamatergic and GABAergic neurotransmission in these alterations. HE would be a consequence of altered neuronal communication due to alterations in general neurotransmission involving different neurotransmitter systems in different neurons.

Attention deficit is an early event in the cognitive impairment of patients with minimal hepatic encephalopathy (MHE). The underlying mechanisms remain unclear. Mismatch negativity (MMN) is an auditory event-related potential that reflects an attentional trigger. Patients with schizophrenia show impaired attention and cognitive function, which are reflected in altered MMN. We hypothesized that patients with MHE, similarly to those with schizophrenia, should show MMN alterations related with attention deficits. The aims of this work were to assess whether (1) MMN is altered in cirrhotic patients with MHE, compared to those without MHE, (2) MMN changes in parallel with performance in attention tests and/or MHE in a longitudinal study, and (3) MMN predicts performance in attention tests and/or in the Psychometric Hepatic Encephalopathy Score (PHES). We performed MMN analysis as well as attention and coordination tests in 34 control subjects and in 37 patients with liver cirrhosis without MHE and 23 with MHE. Patients with MHE show reduced performance in selective and sustained attention tests and in visuomotor and bimanual coordination tests. The MMN wave area was reduced in patients with MHE, but not in those without MHE. In the longitudinal study, MMN area improved in parallel with performance in attention tests and PHES in 4 patients and worsened in parallel in another 4. Logistic regression analyses showed that MMN area predicts performance in attention tests and in PHES, but not in other tests or critical flicker frequency. Receiver operating characteristic curve analyses showed that MMN area predicts attention deficits in the number connection tests A and B, Stroop tasks, and MHE, with sensitivities of 75%-90% and specificities of 76%-83%. Conclusion: MMN area is useful to diagnose attention deficits and MHE in patients with liver cirrhosis. (HEPATOLOGY 2012;55:530-539) A pproximately 33%-50% of patients with liver cirrhosis without clinical symptoms of encephalopathy show minimal hepatic encephalopathy (MHE), which can be unveiled using psychometric tests or neurophysiological analysis. [1][2][3][4] Patients with MHE show attention deficits and mild cognitive impairment. MHE reduces quality of life and is associated with increased risk of suffering with work, driving, and home accidents as well as clinical hepatic encephalopathy (HE) and reduced life span. [5][6][7][8][9][10] Attention deficits are an early manifestation of MHE. [11][12][13][14][15][16] Amodio et al. 16 reported that MHE affects primarily selective attention control. Weissenborn et al. 15 reported that patients with MHE show dysfunction in all attention subsystems. The brain areas involved in the attention system and the alterations

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The NMDA type of glutamate receptors modulates learning and memory. Excessive activation of NMDA receptors leads to neuronal degeneration and death. Hyperammonemia and liver failure alter the function of NMDA receptors and of some associated signal transduction pathways. The alterations are different in acute and chronic hyperammonemia and liver failure. Acute intoxication with large doses of ammonia (and probably acute liver failure) leads to excessive NMDA receptors activation, which is responsible for ammonia-induced death. In contrast, chronic hyperammonemia induces adaptive responses resulting in impairment of signal transduction associated to NMDA receptors. The function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal models of chronic liver failure or hyperammonemia and in homogenates from brains of patients died in hepatic encephalopathy. The impairment of this pathway leads to reduced cGMP and contributes to impaired cognitive function in hepatic encephalopathy. Learning ability is reduced in animal models of chronic liver failure and hyperammonemia and is restored by pharmacological manipulation of brain cGMP by administering phosphodiesterase inhibitors (zaprinast or sildenafil) or cGMP itself. NMDA receptors are therefore involved both in death induced by acute ammonia toxicity (and likely by acute liver failure) and in cognitive impairment in hepatic encephalopathy.

The mechanisms by which liver failure alters motor function remain unclear. It has been suggested that liver disease alters the neuronal circuit between basal ganglia and cortex that modulates motor function. Activation of group I metabotropic glutamate receptors in the nucleus accumbens (NAcc) by injecting (S)-3,5-dihydroxyphenylglycine (DHPG) activates this circuit and induces locomotion We analysed by in vivo brain microdialysis the function of the circuits that modulate motor function in rats with liver failure due to portacaval shunt (PCS). We inserted cannulae in the NAcc and microdialysis probes in the NAcc, ventral pallidum (VP), substantia nigra pars reticulata (SNr), medio-dorsal thalamus (MDT), ventro-medial thalamus (VMT) or prefrontal cortex (PFCx). We injected DHPG in the NAcc and analysed extracellular neurotransmitters concentration in these areas. The results indicate that in control rats DHPG induces locomotion by activating the 'normal' neuronal circuit: NAcc --> VP --> MDT --> PFCx. In PCS rats this circuit is not activated. In PCS rats, DHPG injection activates an 'alternative' circuit: NAcc --> SNr --> VMT --> PFCx. This circuit is not activated in control rats. DHPG injection increases dopamine in the NAcc of control but not of PCS rats, and glutamate in PCS but not in control rats. DHPG-induced increase in dopamine would activate the 'normal' neuronal circuit, while an increase in glutamate would activate the 'alternative' circuit. The identification of the mechanisms responsible for altered motor function and coordination in liver disease would allow designing treatments to improve motor function in patients with hepatic encephalopathy.