Hepatic encephalopathy in acute liver failure: role of the glutamate system.
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Ammonia↗
Biomedical subjects
R F Butterworth
Publications and source records attributed to R F Butterworth.
Epidemic of seasonal ataxia in Nigeria following ingestion of the African silkworm Anaphe venata: role of thiamine deficiency?
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Adolescent↗
Selective increases of extracellular brain concentrations of aromatic and branched-chain amino acids in relation to deterioration of neurological status in acute (ischemic) liver failure.
Previous reports based on studies in brain tissue from humans and experimental animals suggest that aromatic amino acids (AAAs) and branched-chain amino acids (BCAA's) accumulate in brain in acute liver failure. In order to assess these changes in relation to the severity of neurological impairment and to the degree of hyperammonemia, AAAs and BCAAs were measured in vivo by cerebral microdialysis in frontal cortex of rats at various stages during the development of hepatic encephalopathy due to acute liver failure resulting from portacaval anastomosis followed by hepatic artery ligation. Extracellular brain concentrations of AAAs and of valine and leucine were elevated 2 to 4-fold following hepatic devascularization and these increases were significantly correlated to arterial ammonia concentration (r= 0.71-0.84, p<0.05). Extracellular concentrations of tyrosine paralleled the deterioration of neurological status in acute liver failure rats. In view of their role as precursors of monoamine neurotransmitters, ammonia-induced alterations of intracellular/extracellular brain concentration ratios for AAAs could account for altered neuronal excitability and contribute to the encephalopathy characteristic of acute liver failure.
Amino Acids↗
Distinctive pattern of Bergmann glial pathology in human hepatic encephalopathy.
Alzheimer type II astrocytosis is the pathological hallmark of hepatic encephalopathy. These astrocytes undergo a characteristic morphological change and, in addition, lose immunoreactivity for glial fibrillary acidic protein (GFAP). However, a previous study in the portacaval shunted rat, a model of hepatic encephalopathy, revealed increased rather than decreased GFAP immunoreactivity in Bergmann glia, a specialized group of cerebellar astrocytes. In the present study, sections of cerebellar vermis from 15 cirrhotic patients with hepatic encephalopathy and varying degrees of Alzheimer type II astrocytosis were stained using antisera to GFAP. The Bergmann glial cells did not show altered GFAP immunoreactivity compared to controls. In addition, the degree of GFAP immunoreactivity was not correlated with the degree of Alzheimer type II change nor related to the aetiology of the liver disease. These results suggest a differential response of Bergmann glia in human hepatic encephalopathy.
Adult↗
Portacaval shunting and hyperammonemia stimulate the uptake of L-[3H] arginine but not of L-[3H]nitroarginine into rat brain synaptosomes.
Elevated activities of nitric oxide synthase (NOS) have been reported previously in the brains of portacaval-shunted (PCS) rats, a model of chronic hepatic encephalopathy (HE). As L-arginine availability for nitric oxide synthesis depends on a specific uptake mechanism in neurons, we studied the kinetics of L-[3H]-arginine uptake into synaptosomes prepared from the brains of PCS rats. Results demonstrate that L-arginine uptake is significantly increased in cerebellum (60%; p < 0.01), cerebral cortex (42%; p < 0.01), hippocampus (56%; p < 0.01), and striatum (51%; p < 0.01) of PCS rats compared with sham-operated controls. Hyperammonemia in the absence of portacaval shunting also stimulated the transport of L-[3H]arginine; kinetic analysis revealed that the elevated uptake was due to increased uptake capacity (Vmax) without any change in affinity (Km). Incubation of cerebellar synaptosomes with ammonium acetate for 10 min caused a dose-dependent stimulation of L-[3H]arginine uptake. Neither portacaval shunting nor hyperammonemia had any significant effect on the synaptosomal uptake of NG-nitro-L-[3H]arginine. These studies demonstrate that increased NOS activity observed in experimental HE may result from increased availability of L-arginine resulting from a direct stimulatory effect of ammonia on L-arginine transport.
Acetates↗
Increased density of catalytic sites and expression of brain monoamine oxidase A in humans with hepatic encephalopathy.
Altered biogenic amine metabolism and function are believed to underlie certain of the neuropsychiatric symptoms, e.g., depression, mania, and anxiety, encountered in clinical hepatic encephalopathy (HE). We therefore investigated the activity of the degradative enzyme monoamine oxidase (MAO) and its binding parameters using [3H]Ro 41-1049 (defining MAO-A) and [3H]Ro 19-6327 (Lazabemide; defining MAO-B) in autopsied brain tissue from male cirrhotic patients with HE. The MAO-B parameters in HE patient tissue were not significantly different from those determined for control tissue. In contrast, increases in MAO-A activities in HE patient frontocortical (by approximately 50%) and cerebellar (by approximately 145%) tissues were observed, confirming our previous findings using comparable tissues. Increases in the abundance of the active MAO-A protein were of the same order of magnitude, e.g., in frontal cortex by approximately 85% and in cerebellum by approximately 225%. Reverse transcriptase-polymerase chain reaction indicated an increase in the level of gene expression (by approximately 155%) and thus offers some of the first evidence of a transcriptional event potentially mediating MAO-A function in human brain tissue. The levels of biogenic amine acid metabolites were increased as expected. As HE patients are most often treated for their hepatic symptoms rather than their neuropsychiatric manifestations, they represent an important "untreated" psychiatric population. The present findings are therefore not only important for our understanding of the pathophysiology of HE but also extremely relevant to our understanding of the pharmacotherapy of other neuropsychiatric disorders in which biogenic amine and MAO-A dysfunction is indicated.
Adenosine Triphosphatases↗
An image of the brain in patients with liver disease.
As imaging techniques have advanced from those that are based on tissue density and hence are strictly anatomical in nature, to include those based on physiologic and biochemical factors, the expectation has grown that imaging will be used to evaluate patients with diseases that are caused by disordered metabolism. In this review, recent advances in neuroimaging are discussed that have led to new insights into the pathophysiology of hepatic encephalopathy, a common condition that is caused by the failure of the liver to remove metabolic wastes from the blood.
Animals↗
The portacaval-shunted rat: a new model for the study of the mechanisms controlling voluntary ethanol consumption and ethanol preference?
Portacaval anastomosis (PCA) is a surgical procedure whereby blood from the portal vein is shunted into the inferior vena cava. PCA in the rat results in a significant increase (from 0.77 +/- 0.26 to 3.51 +/- 0.37 g of ethanol/kg/day) in voluntary ethanol consumption in a free-choice paradigm between water and 5% ethanol solution. After PCA surgery, increased voluntary ethanol consumption starts abruptly at 6 to 7 days and is maintained for > 28 weeks. Voluntary ethanol consumption in rats after PCA results in blood ethanol levels up to 158 mg%. After PCA, the ethanol preference ratio (defined as the percentage of total fluid intake constituted by ethanol) increased from 19 +/- 2% to 78 +/- 2% (P < 0.001). Administration of the nonselective opioid receptor antagonist naloxone (5 mg/kg, sc) resulted in a significant 6-fold attenuation of voluntary ethanol consumption by rats with PCA, an effect that was not mediated by an effect on locomotor activity. These findings, together with previous reports of widespread alterations of the mu- and delta-opioid receptors in the brain after PCA, suggest that increased voluntary ethanol consumption and ethanol preference in PCA rats may result from activation of the endogenous opioid system. Preliminary studies suggest that rats with PCA manifest behavioral signs consistent with the development of dependence. The portacaval-shunted rat may provide a useful preparation for the study of mechanisms, in particular those involving the liver, implicated in the development of increased voluntary ethanol consumption and ethanol preference.
Alcohol Drinking↗
Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy.
Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
Animals↗
Vesicular dysfunction during experimental thiamine deficiency is indicated by alterations in dopamine metabolism.
Experimental and clinical studies indicate that catecholamines play an important role in the neurobehavioural symptomatology of thiamine deficiency. Given the cerebral region-selective vulnerability and the behavioural impairment commonly encountered in thiamine deficiency, we undertook to investigate regional catecholamine metabolism in the brains of pyrithiamine-induced thiamine-deficient rats. Dopamine metabolism was unaffected in the striatum. In contrast, other regions also known to be involved in sensory processing and intellectual function (e.g., frontal cortex, hypothalamus, thalamus), but having a greater noradrenergic input, had increased levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and decreased levels of other dopaminergic metabolites including noradrenaline. In these regions levels of the vesicular amine transporter, defined by tetrabenazine-sensitive [3H]ketanserin binding, were also decreased. Our data suggest a region-selective vesicular dysfunction resulting in intraneuronal release, and subsequent degradation, of dopamine. These disruptions of dopamine and consequently noradrenaline metabolism may account for certain neurobehavioural deficits commonly encountered in thiamine deficiency.
Adrenergic Uptake Inhibitors↗
Arginine-related guanidino compounds and nitric oxide synthase in the brain of ornithine transcarbamylase deficient spf mutant mouse: effect of metabolic arginine deficiency.
The sparse-fur (spf) mouse, with an X-linked hepatic ornithine transcarbamylase (OTC, E.C.2.1.3.3) deficiency, exhibits significantly lower levels of arginine in the brain as compared to normal controls. In the present study, the effect of a sustained lower metabolic arginine was studied by measuring the levels of several arginine-related guanidino compounds in brain. The concentrations of gamma-guanidinobutyric acid (gamma-GBA), N-alpha-acetylarginine (N-alpha-AA), argininic acid (Arg-A), guanidinoacetic acid (GAA), and creatine were significantly lower in spf mice as compared to controls. Since arginine is the precursor for nitric oxide, we also measured the activity of nitric oxide synthase which was significantly reduced in cerebellum, striatum, hippocampus and cerebral cortex of spf mice. The changes seen in cerebral guanidino compound and nitric oxide metabolism of spf mice could be due to a sustained deficiency of arginine, caused by a metabolic block in the area cycle.
Animals↗
Nitric oxide synthase activities are selectively decreased in vulnerable brain regions in thiamine deficiency.
Pyrithiamine-induced thiamine deficiency in the rat exhibits many neuropathological and biochemical similarities to Wernicke's Encephalopathy in human. Activities of constitutive nitric oxide synthase (NOS) were measured in vulnerable (thalamus and cerebellum) and non-vulnerable (hippocampus and striatum) brain regions of pyrithiamine-induced thiamine-deficient rats. NOS activities were significantly decreased in the thalamus (by 26%, P < 0.05) of presymptomatic thiamine-deficient rats compared to pair-fed controls. Following onset of symptoms, in addition to thalamus (-38%, P < 0.01), cerebellum (-50%, P < 0.01) also manifested significantly decreased activities of NOS. Hippocampal and striatal activities of NOS were unchanged at both presymptomatic and symptomatic stages of thiamine deficiency. Selectively decreased activities of neuronal NOS in the thalamus and the cerebellum extends the previous observations of region-selective metabolic changes and, ultimately, neuronal cell loss observed in thiamine deficiency.
Animals↗
Na+,K(+)-ATPase activity is selectively increased in thalamus in thiamine deficiency prior to the appearance of neurological symptoms.
The relationship between progression of neurological status and the activities of both Na+,K(+)- and Mg(2+)-dependent-ATPase (adenosine 5'-triphosphate phosphohydrolase) was investigated in brain regions of pyrithiamine-induced thiamine deficient rats. Thalamic Na+,K(+)-ATPase activity was selectively increased by 200% (P < 0.01) prior to the appearance of symptoms of thiamine deficiency and normalized in symptomatic rats. This selective transitory activation precludes a mediation by brain soluble fraction Na+,K(+)-ATPase modifiers as does the unaltered distribution in regional high-affinity [3H]ouabain binding densities observed throughout the time-course used in these experiments. Na+,K(+)-ATPase maintains cellular ionic gradients and has been implicated in neurotransmitter uptake and release mechanisms. The fact that the increased thalamic Na+,K(+)-ATPase activity coincides with the early alterations in serotonin metabolism observed in similarly treated animals and the concomitantly early increase in glucose utilization previously observed in the thalamus of thiamine-deficient rats is discussed.
Animals↗
Portacaval anastomosis induces region-selective alterations of the endogenous opioid system in the rat brain.
Portacaval anastomosis (PCA) in the rat results in a broad spectrum of neurological and neurobehavioral changes, including alterations of circadian rhythms, impaired locomotor activity, and reflexes, as well as decreased threshold to noxious stimuli. In addition, following portacaval shunting, rats drink significantly more ethanol in a free-choice drinking paradigm. Available evidence suggests that many of these behavioral changes may be modulated by the endogenous opioid system of the brain. To evaluate this possibility, the effects of PCA on circulating beta-endorphin (beta-EP), as well as beta-EP content in the pituitary and specific brain nuclei, was evaluated using a sensitive radioimmunoassay. Furthermore, the characteristics and regional densities of mu and delta opioid receptors in the brains of PCA and sham-operated control rats were studied using an in vitro technique, as well as quantitative receptor autoradiography and the specific ligands 125I [D-Ala2, MePhe4, Met(o)ol5]enkephalin (FK 33-824) and 125I [2-D-penicillamine, 5-D-penicillamine]-enkephalin (DPDPE) for micro and delta sites, respectively. PCA resulted in region-selective modifications of beta-EP in brain, but not in pituitary or blood. Autoradiographic studies revealed a generalized decrease in mu binding sites (up to 70% decreases compared with sham-operated controls) and region-selective alterations of delta receptor densities following PCA. Portacaval-shunted rats drank significantly more ethanol in a free-choice drinking paradigm, an effect that was significantly attenuated by the administration of the opiate antagonist naloxone. Increased ethanol preference thus appeared to result from modifications of the endogenous opioid system in nucleus accumbens of rats following PCA.
Alcohol Drinking↗
Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure.
It has been proposed that alterations of excitatory and inhibitory amino acids play a role in the pathogenesis of hepatic encephalopathy in acute liver failure. To evaluate this possibility, in vivo cerebral microdialysis was used to sample extracellular concentrations of amino acids in the frontal cortex of unanesthetized rats at various times during the progression of encephalopathy resulting from acute liver failure. Liver failure was induced by portacaval anastomosis followed 24 hours later by hepatic artery ligation. Dialysate concentrations of amino acids were measured by high-performance liquid chromatography (HPLC) with fluorescence detection. Deterioration of neurological status was accompanied by two- to four-fold increases in extracellular glutamate, glutamine, and glycine; concentrations of gamma-aminobutyric acid (GABA) and taurine were unchanged. Densities of binding sites for the glutamate (N-methyl-D-aspartate [NMDA]) receptor ligand 3H-MK801, assessed using quantitative receptor autoradiography, however, were unchanged in the frontal cortex of rats at coma stages of ischemic liver failure. Increased extracellular glutamate concentrations were positively correlated with the severity of encephalopathy and with arterial ammonia concentrations. Such changes may result from an ammonia-induced reduction in the capacity for astrocytes to uptake glutamate. Increased extracellular glutamate in brain, together with increases in concentrations of glycine, a positive allosteric modulator of glutamate (NMDA) receptors, are consistent with increased NMDA-related glutamatergic neurotransmission in this model of acute liver failure. Increased extracellular glutamate, therefore, could contribute to the pathogenesis of hepatic encephalopathy and brain edema in acute liver failure.
Animals↗
Increased blood manganese in cirrhotic patients: relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms.
Increasing evidence suggests that manganese deposition is responsible for the T1-weighted magnetic resonance imaging (MRI) signal hyperintensity consistently observed in pallidum of cirrhotic patients. However, the relationship between blood manganese and the etiology or severity of liver disease, as well as the neurological symptomatology in these patients, has not been well established. In the present study, blood manganese concentrations were measured by atomic absorption spectrometry together with MRI and neurological evaluation in 57 cirrhotic patients with various etiologies and severity of liver disease. Blood manganese concentrations were elevated in 67% of cirrhotic patients and were significantly higher in patients with previous portacaval anastomoses or transjugular intrahepatic portosystemic shunt (TIPS). Pallidal signal hyperintensity was observed in 88% of patients, and significant correlations were demonstrated between blood manganese and pallidal index (PI) (a measure of pallidal signal hyperintensity), as well as Child-Pugh score. Assessment of extrapyramidal symptoms using the Columbia rating scale revealed a significant incidence of tremor, rigidity, or akinesia in up to 89% of cirrhotic patients. However, there was no significant correlation between blood manganese and extrapyramidal symptoms, although severity of akinesia was significantly greater in Child-Pugh C patients. Extrapyramidal symptoms could result from a toxic effect of manganese on basal ganglia dopaminergic function. These findings further support a role for manganese in the etiology of pallidal MRI signal hyperintensity in patients with chronic liver disease.
Adult↗
Taurine in hepatic encephalopathy.
Liver and brain are the major organs responsible for taurine synthesis. In both acute and chronic liver failure, brain taurine concentrations are decreased and, since taurine appears to be implicated in K+ and Ca2+ homeostasis in brain, such losses could contribute to the pathophysiology of hepatic encephalopathy. Furthermore, taurine concentrations in cerebrospinal fluid in experimental acute liver failure are increased early in the progression of encephalopathy and prior to the onset of cerebral edema, a potentially fatal complication of acute liver failure. These findings suggest an osmoregulatory role for taurine in brain in acute liver failure. Monitoring of cerebrospinal fluid taurine may be of prognostic value in this severe, frequently fatal disorder.
Animals↗
Neuroactive amino acids in hepatic encephalopathy.
There is abundant evidence to suggest that alterations of excitatory and inhibitory amino acids play a significant role in the pathogenesis of hepatic encephalopathy (HE) in both acute and chronic liver diseases. Brain glutamate concentrations are reduced in patients who died in hepatic coma as well as in experimental HE, astrocytic reuptake of glutamate is compromised in liver failure and postsynaptic glutamate receptors (both NMDA and non-NMDA subclasses) are concomitantly reduced in density. Recent studies in experimental acute liver failure suggest reduced capacity of the astrocytic glutamate transporter in this condition. Together, this data suggests that neuron-astrocytic trafficking of glutamate is impared in HE. Other significant alterations of neuroactive amino acids in HE include a loss of taurine from brain cells to extracellular space, a phenomenon which could relate both to HE and to brain edema in acute liver failure. Increased concentrations of benzodiazepine-like compounds have been reported in human and experimental HE. Clinical trials with the benzodiazepine antagonist flumazenil reveal a beneficial effect in some patients with HE; the mechanism responsible for this effect, however, remains to be determined.
Amino Acids↗