Visual evoked potentials in a rabbit model of hepatic encephalopathy. II. Comparison of hyperammonemic encephalopathy, postictal coma, and coma induced by synergistic neurotoxins

To assess neuronal mechanisms of potential importance in the pathogenesis of hepatic encephalopathy, visual evoked potentials were recorded in rabbits with acute hyperammonemic encephalopathy, postictal coma, and toxin-induced coma resulting from the administration of a combination of subcoma doses of three neurotoxins: ammonia, dimethyldisulfide, and octanoic acid. The patterns of visual evoked potentials in these three syndromes were compared with those of rabbits with hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. In the absence of seizures, the patterns of visual evoked potentials associated with hyperammonemic encephalopathy and toxin-induced coma were fundamentally different from those associated with any stage of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. In contrast, the pattern of visual evoked potentials in early postictal coma induced by four different precipitating factors (including toxin-induced seizures) resembled that of late-stage hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. These findings suggest that the recording of visual evoked potentials may be of value in experimentally testing hypotheses of the pathogenesis of hepatic encephalopathy due to fulminant hepatic failure. They indicate that acute hyperammonemia is not a satisfactory model of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure, that the occurrence of seizures may lead to incorrect interpretation of experimental data from models of hepatic encephalopathy, and that the syndromes of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure and postictal coma may share similar neural mechanisms. Finally, the results of this study do not support the hypothesis that hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure is mediated by the synergistic interaction of ammonia, mercaptans, and fatty acids on the brain.     

Cerebral atrophy and convulsive seizures after recovery from cerebral edema and coma in a patient with fulminant hepatitis B

We report a 48-year-old woman who developed convulsive seizures and cerebral atrophy after recovery from fulminant hepatitis B with coma and cerebral edema at the acute stage. Neurological disturbances and cerebral signs are rare sequelae of fulminant hepatic failure (FHF); only a few cases have reported in the literature. Cortical laminar necrosis secondary to cerebral edema or delayed neuronal death due to toxic substances may have caused delayed brain atrophy and epileptogenesis.     

Reversal of the behavioral and electrophysiological abnormalities of an animal model of hepatic encephalopathy by benzodiazepine receptor ligands

Behavioral and electrophysiological evidence implicating the GABA-benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy was obtained using an improved rat model of hepatic encephalopathy caused by thioacetamide-induced fulminant hepatic failure. After the administration of thioacetamide together with supportive therapy, acute hepatocellular failure developed in rats as a result of massive hepatocellular necrosis without evidence of renal failure or hypoglycemia. The evolution of hepatic encephalopathy in this model was sufficiently slow to readily permit the staging of the syndrome. Prominent features of the encephalopathy include a marked reduction in open field activity and an abnormal visual evoked response. Both the deficits in spontaneous motor function and visual evoked response abnormalities of rats in stages III to IV hepatic encephalopathy were significantly improved after the administration of the benzodiazepine receptor ligands flumazenil or Ro 15-4513. Doses of flumazenil or Ro 15-4513 that produced these effects in rats with hepatic encephalopathy had no detectable action on either the behavior or the visual evoked responses of normal rats. The ability of benzodiazepine receptor ligands to ameliorate both the behavioral depression and the visual evoked response abnormalities associated with hepatic encephalopathy in the thioacetamide-induced rat model suggest an involvement of the GABA/benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy. In addition, the similarity of these observations to those in rabbits with hepatic encephalopathy caused by galactosamine-induced fulminant hepatic failure is compatible with the hypothesis that the mechanisms of hepatic encephalopathy in these two distinct models share a common final pathway, the allosteric enhancement of GABAergic tone through the benzodiazepine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathophysiology of Hepatic Encephalopathy: A New Look at GABA from the Molecular Standpoint

Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with either acute or chronic liver failure. More than two decades ago, the role of altered GABAergic neurotransmission was proposed following evidence of "increased GABAergic tone" in HE. Increased GABAergic tone was based on several observations: (i) Similarity of visual evoked response potential patterns between rabbits with galactosamine-induced fulminant hepatic failure and animals treated with various allosteric agonists of the GABA receptor complex (GRC). (ii) Spontaneous activities of isolated Purkinje neurons from rabbits with galactosamine-induced fulminant hepatic failure are more depressed by GRC modulator compounds compared to normal animals. (iii) Flumazenil, a high selective benzodiazepine antagonist at the GRC, ameliorates behavioral symptoms and EEG activity in some HE patients. Pathophysiological mechanisms put forward to explain increased GABAergic tone in HE include (1) increase in brain GABA content due to increased brain GABA uptake through altered permeability of the blood brain barrier, (2) alteration of the integrity of constituents of the GRC, and (3) increase of endogenous GRC modulators such as benzodiazepines (and more recently neurosteroids) with potent agonist properties at the GRC. Studies performed subsequently excluded alterations of either GABA content or GRC integrity in favor of increased brain concentrations of endogenous agonists. While the role of endogenous benzodiazepines remains controversial, the presence of neurosteroids with GABA agonist properties affords a plausible explanation for increased GABAergic tone in HE.     

Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy

Transfer of the inhibitory neurotransmitter gamma-aminobutyric acid across the normal blood-brain barrier is minimal. One prerequisite for gamma-aminobutyric acid in plasma contributing to the neural inhibition of hepatic encephalopathy would be that increased transfer of gamma-aminobutyric acid across the blood-brain barrier occurs in liver failure. The aim of the present study was to determine if brain gamma-aminobutyric acid uptake is increased in rabbits with stage II-III (precoma) hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. A modification of the Oldendorf intracarotid artery-injection technique was applied. [3H] gamma-aminobutyric acid, [14C] butanol, and 113mIn-labeled serum protein (transferrin) were injected simultaneously 4 s before decapitation. The ipsilateral brain uptake index of gamma-aminobutyric acid was determined from measurements of the 3 isotopes in 5 brain regions. Uncorrected or simple brain uptake indices of [3H] gamma-aminobutyric acid and [113mIn] transferrin were calculated using [14C] butanol as the highly extracted reference compound. The [113mIn] transferrin data were also used to "correct" the brain uptake index of [3H] gamma-aminobutyric acid for intravascular retention of [3H] gamma-aminobutyric acid. The methodology adopted minimized problems attributable to rapid [3H] gamma-aminobutyric acid metabolism, and slow brain washout and recirculation of the radiolabeled tracers. Both the uncorrected and corrected brain uptake indices of gamma-aminobutyric acid as well as the simple brain uptake index of transferrin were significantly increased in both stage II and III hepatic encephalopathy in all brain regions studied. Moreover, these brain uptake indices were significantly greater in stage III hepatic encephalopathy than in stage II hepatic encephalopathy. These findings indicate that transfer of gamma-aminobutyric acid from plasma to brain extracellular fluid is increased in the model of hepatic encephalopathy studied; hence, they provide support for the hypothesis that plasma-derived gamma-aminobutyric acid may contribute to the neural inhibition of hepatic encephalopathy due to fulminant hepatic failure.     

Reduction of highly elevated plasma levels of gamma-aminobutyric acid does not reverse hepatic coma

The pathogenesis of coma in patients with fulminant hepatic failure is still unknown, but there is some evidence that decreased hepatic metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may be involved. If this hypothesis is true, reduction of increased GABA levels in patients with hepatic encephalopathy should reduce the depth of hepatic coma. In the case described here, highly elevated plasma GABA levels were reduced by cross-circulation with baboon liver. No amelioration of the coma was observed, thus suggesting that decreased hepatic metabolism of GABA is not critically involved in hepatic encephalopathy.     

Magnetic Resonance Imaging and Localized In Vivo Proton Spectroscopy in Patients with Fulminant Hepatic Failure

Magnetic resonance imaging (MRI) and in vivo proton spectroscopic changes in the brain in three patients with fulminant hepatic failure are described. MRI showed cerebral atrophy in two and changes somewhat similar to what have been described in chronic hepatic encephalopathy. MR spectroscopy showed low myoinositol with high glutamine in grade IV coma, which returned to normal as patient showed clinical recovery. We conclude that these techniques will be useful in understanding the complex pathophysiology of fulminant hepatic failure.     

Electrocorticographic changes in acute experimental hepatic insufficiency

The aim of this study was to test the application and value of electrocorticography (ECG) in the early diagnosis and characterization of electrocorticograms changes on experimental fulminant hepatic failure (FHF). Our material was composed of two groups of guinea pigs: a) ethanolamine group--42 animals with FHF induced by intrabiliary injection of 2.5 ml of monoethanolamine oleate; b) control group--10 animals submitted to intrabiliary injection of 2.5 ml of saline. Electrocorticograms recordings were taken in both groups with the electrodes implanted on the parieto-occipital regions of the skull. The hepatic failure was characterized by clinical manifestations, serum biochemical tests and histopathological findings. In the early hepatic coma the electrocorticograms could not be unequivocally distinguished from normal pattern, and alpha rhythm was recognizable in most animals. With further deterioration of the clinical condition the tracing showed progressive slowness of the normal rhythm, increased voltage and triphasic waves followed by suppression of electrical activity preceding the animal death. The electrocorticography was not suitable for the early diagnosis of hepatic coma, since the ECG alterations became evident only in overt coma. However the method could be useful for the characterization of cerebral disorders and the study of the pathogenesis of fulminant hepatic failure.     

Clinical significance of human hepatocyte growth factor in blood from patients with fulminant hepatic failure

We have recently found the presence of human hepatocyte growth factor in sera of patients with fulminant hepatic failure and have purified human hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. In this paper, we report the clinical significance of human hepatocyte growth factor in blood from patients with fulminant hepatic failure. The effect of sera or plasma from 17 patients with fulminant hepatic failure on liver cell growth was examined by use of adult rat hepatocytes in primary cultures. Sera or plasma from 16 of the 17 patients with fulminant hepatic failure stimulated DNA synthesis in hepatocytes more effectively than normal human serum. The mean growth-promoting activity for the 17 patients with fulminant hepatic failure was about 16 times higher than that obtained for normal human serum. This growth-promoting activity of the patients' blood was not related to sex, age, clinical outcome of the patients or type of fulminant hepatic failure, but was intimately related to the clinical grade of hepatic coma. Sera or plasma with Grade III and IV coma showed stimulatory activity on DNA synthesis more markedly than sera or plasma from patients with coma of less than Grade II. In the surviving group, this activity decreased as the hepatic coma of patients improved. In fact, this activity of sera from patients at the recovery stage showed no significant increase compared with that of normal human serum. In the group of terminal patients, this activity increased as the coma developed.(ABSTRACT TRUNCATED AT 250 WORDS)     

gamma-Aminobutyric acid (GABA) and hepatic encephalopathy: testing the validity of electroencephalographic evidence of the GABA hypothesis

Some GABA-ergic drugs are known to produce electroencephalographic and behavioral signs of inhibition as well as alterations of the visual evoked potential (VEP) similar in shape and parameters to those in experimental fulminant hepatic failure. These findings, along with a number of biochemical findings, were considered to support the theory attributing hepatic encephalopathy to enhanced GABA-ergic transmission. The present review demonstrates that it is uncertain whether electrographic correlates of experimental encephalopathy can be attributed to faulty GABA-ergic mechanisms; nor it is clear whether drug-induced alterations of electrocortical potentials and those recorded in acute hepatic failure share a common pathogenesis. Special emphasis is put on findings with visual evoked potentials altered by drugs acting at GABA/benzodiazepine receptors to show the diversity of changes associated with the activity of the GABA system. Attention is called to the fact that brain GABA increase as a mechanism of hepatic encephalopathy was discussed without specifying the nature and anatomical location of allegedly impaired neural circuits utilizing the neurotransmitter.     

Autoradiographic analysis of GABA-benzodiazepine receptors in an animal model of acute hepatic encephalopathy

To complement analogous studies using conventional ligand-membrane binding assays, the densities of gamma-aminobutyric acid and benzodiazepine receptors in the brain have been assessed using an autoradiographic technique in an animal model of hepatic encephalopathy. Hepatic encephalopathy due to fulminant hepatic failure was induced in rabbits by the intravenous injection of galactosamine. The specific binding of three radiolabeled ligands was assessed densitometrically in several microregions of cerebral cortex, hippocampus and cerebellum. [3H]Muscimol was used to assess gamma-aminobutyric acid receptor density and [3H]flunitrazepam or [3H]Ro 15-1788 was used to assess benzodiazepine receptor density. No significant differences were observed between the magnitude of binding of the three ligands to each of the microregions of brain from control rabbits and rabbits in Stage III or IV hepatic encephalopathy. These findings suggest that the behavioral expression of hepatic encephalopathy in the model studied is not dependent upon an increase in the number of gamma-aminobutyric acid or benzodiazepine receptors, but do not conflict with the hypothesis that gamma-aminobutyric acid-ergic tone is increased in hepatic encephalopathy.     

Hepatic encephalopathy. Experimental studies in a rat model of fulminant hepatic failure

A new approach to pathogenetic study of hepatic encephalopathy was recently undertaken in order to identify the neurological alterations of the brain which characterize the coma. In this study attention was firstly addressed to a correct and objective evaluation of the comatose state in rats with fulminant hepatic failure induced by galactosamine. For this purpose visual evoked potentials were utilized since this electrophysiological test proved reliable and sensitive on the basis of an extensive pharmacological study. Two different stages of coma were identified in the rat and they were named mild and severe. Receptor binding studies performed on brain membranes of these rats show in the mild stage an increased number of low and high affinity GABA receptors and a decreased affinity of dopamine receptors. The severe stage is characterized by the persistence of only high affinity GABA receptors and a reduced number of dopamine receptors. This imbalance between inhibitory and excitatory receptor systems may explain the generalized central nervous system depression which characterizes the hepatic encephalopathy while the increased number of benzodiazepine receptors found in both stages of coma may account for the brain supersensitivity to sedative administration of patients with liver disease and for the sedative-induced episodes of coma. These receptor alterations may be attributed to a disuse and/or a partial degeneration of nerve terminals due to peripheral neurotoxins (i.e., ammonia, mercaptans, short chain fatty acids) and the decrease of glutamate decarboxylase activity and of zinc levels in brain tissues seems to be respectively a direct and an indirect demonstration of this phenomenon. Bearing in mind the supersensitivity of the GABA-benzodiazepine receptor system and their reciprocal interaction, a benzodiazepine antagonist was administered to rats in mild stage of encephalopathy. Electrophysiological and benzodiazepine binding studies demonstrated that this treatment can temporarily counteract some of the neurological disturbances of the earlier stage of coma and act as antidote of the sedative-induced episodes of coma.     

Synaptic membrane complex carbohydrates in experimental hepatic encephalopathy

To evaluate further the status of synaptic plasma membranes (SPMs) in the brain in the syndrome of hepatic encephalopathy (HE) lipid- and protein-bound sialic acid and ganglioside and protein composition were investigated in SPMs from the brains of six rabbits with galactosamine-induced fulminant hepatic failure and five normal rabbits. HE was associated with no appreciable changes in the Chromatographic pattern of gangliosides or the concentration of protein-bound sialic acid, but the syndrome was associated with a 20% increase in lipid-bound sialic acid and, as assessed electrophoretically, an increase in the concentration of a protein with a molecular weight of about 70 kDa. Thus, changes in the composition of complex carbohydrates and protein in SPMs occur in a model of HE. The findings raise the possibility that nonhumoral factors, such as increased sialylation of glycolipids, contribute to the generation of abnormal neurotransmission in HE.     

Prognostic factors for fatal outcomes prior to receiving liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure

BACKGROUND AND AIM: Many patients continue to die due to the rapid development of cerebral edema and/or multiple organ failure prior to receiving a liver transplantation. METHODS: We investigated the prognostic factors associated with 1-week fatal outcomes after the diagnosis of fulminant hepatic failure, which were associated with fatal outcomes prior to receiving liver transplantation, in 104 patients with non-acetaminophen-related fulminant hepatic failure. RESULTS: With a multivariate logistic regression analysis, age (>40 years), systemic inflammatory response syndrome (SIRS) and plasma prothrombin activities (40 years), cause of fulminant hepatic failure (viral hepatitis), plasma prothrombin activity (相似文献   

Cytotoxic Edema Is Responsible for Raised Intracranial Pressure in Fulminant Hepatic Failure: In Vivo Demonstration Using Diffusion-Weighted MRI in Human Subjects

It is not clear whether cerebral edema in fulminant hepatic failure is predominantly vasogenic or cytotoxic, though cytotoxic edema due to astrocyte swelling is more likely. Diffusion-weighted magnetic resonance imaging can differentiate vasogenic from cytotoxic edema. We performed diffusion-weighted imaging in patients with fulminant hepatic failure to clarify the issue by measuring apparent diffusion coefficient, which quantifies movement of water molecule across cell membrane. Seven patients with fulminant hepatic failure underwent conventional and diffusion-weighted magnetic resonance imaging. Apparent diffusion coefficient was measured in four cortical areas and 12 deep white and gray matter regions in both cerebral hemispheres. Thirteen healthy subjects served as controls. The apparent diffusion coefficient values in patients and controls were compared using Wilcoxon signed rank test. Two patients who survived underwent repeat imaging using same protocol. Patients with FHF had significantly lower apparent diffusion coefficient in all cortical and deep white and gray matter regions of interest compared to controls (p < 0.001), suggesting cytotoxic cell swelling. In two survivors with repeat imaging, one showed complete resolution while the changes persisted in the other, suggesting ischemic injury. Cerebral edema in fulminant hepatic failure is predominantly due to cytotoxic edema.     

Monitoring of neurotransmitter amino acids by means of an indwelling cisterna magna catheter: a comparison of two rodent models of fulminant liver failure.

Alterations of brain and cerebrospinal fluid amino acids have consistently been described in human and experimental fulminant liver failure. To evaluate the significance of such changes in the pathogenesis of hepatic encephalopathy in fulminant liver failure, brain and cerebrospinal fluid amino acids (glutamate, aspartate, GABA, glycine, taurine) were measured at various stages during the development of neurological dysfunction in rats after hepatic devascularization or thioacetamide treatment to induce acute liver failure. To facilitate repetitive removal of cerebrospinal fluid, a technique employing long-term implantation of cisterna magna catheters in conscious, freely moving rats was developed. Brain but not cerebrospinal fluid concentrations of the excitatory amino acids glutamate and aspartate were reduced in both animal models of fulminant liver failure in parallel with deterioration of neurological status. Brain and cerebrospinal fluid GABA levels were not significantly altered. Cerebrospinal fluid glycine levels were increased two to three times in parallel with increasing brain glycine content in the devascularized rat but were unchanged in thioacetamide-induced liver failure, suggesting distinct pathophysiological mechanisms in these two experimental situations. On the other hand, onset of coma in both animal models of fulminant liver failure was accompanied by significantly increased cerebrospinal fluid taurine levels. We suggest that such changes result from taurine release from astrocytes in brain into the extracellular fluid; this is consistent with taurine's role in the regulation of intracellular osmolarity in brain. Sequential measurements of amino acids in the cerebrospinal fluid of small rodents with indwelling cisterna magna catheters adds a useful new approach for exploring the neurobiology of hepatic encephalopathy in fulminant liver failure.     

Factor VII levels as a guide to prognosis in fulminant hepatic failure.

Levels of clotting factors II, V, and VII were measured on admission and then daily in 12 patients with grade IV hepatic coma due to fulminant hepatic failure. Factor VII levels obtained within 36 hours of the development of grade IV coma were not of value in predicting which patients would subsequently recover consciousness. Four of the latter group had levels below 9% at this time while the levels in three of the seven fatal cases were higher. Serial determinations were of more value and levels rose rapidly in those patients who ultimately made a complete recovery.     

Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure.

Cerebral edema is a serious complication of the encephalopathy in fulminant hepatic failure. It is a major cause of death. The mechanisms responsible for its formation are unclear, and the aim of this study was to investigate the ultrastructural appearance of brain capillaries by scanning electron microscopy. Samples of cerebral cortex were obtained immediately after death from nine patients with fulminant hepatic failure (seven cases due to acetaminophen overdose, one caused by hepatitis B and one caused by non-A, non-B hepatitis) by needle biopsy at the site of insertion of an extradural pressure transducer to monitor intracranial pressure. The intercellular tight junctions between capillary endothelial cells were intact. The endothelial cells were swollen, with increased numbers of vesicles and vacuoles. The basement membranes were enlarged and vacuolized and the pericytes had increased numbers of vesicles and vacuoles, indicative of passage of fluid by this route. Marked intracellular swelling of the perivascular astroglial foot processes was present. Thus mainly cytotoxic mechanisms, with cellular swelling, and to a lesser extent vasogenic mechanisms, with altered blood-brain barrier permeability, appear to be involved in the cerebral edema of fulminant hepatic failure.     

暴发性肝功能衰竭患者的临床特征及其预后的影响因素

目的 分析各种原因所致肝功能衰竭患者的临床特征及其预后的影响因素,为选择临床治疗方案及判断预后提供依据. 方法 统计分析死亡和生存的肝功能衰竭患者的肝功能、肾功能、凝血酶原时间,血氨、血糖、血清淀粉酶和脂肪酶、血清皮质醇、血清肿瘤坏死因子(TNF)α水平,终末期肝病(MELD)评分及性别、年龄、有无并发症等因素的差异.根据不同资料分别采用均数比较、x2检验、Biraviate相关性检验和Logistic多元回归分析进行统计学分析. 结果 所观察的85例患者病死率为65%(55/85),以重叠感染者病死率最高(HBV和HEV重叠感染者为8/10,HCV和HEV重叠感染者为6/8),年龄和性别对病死率无明显影响(P值分别为0.423和0.728);病因分析中,以HBV感染者最多(52%,44/85),其次为HEV感染(39%,33/85);血清生化指标中,总胆红素定量、凝血酶原时间、胆固醇、尿素氮、肌酐和空腹血糖水平与预后相关(P值分别为0.005、0.001、0.001、0.005、0.010和0.049).并发症中,死亡组肝性脑病、肝肾综合征和肾上腺功能不全发生率明显高于生存组(P值分别为0.005、0.012和0.025).但应用Logistic多元回归分析结果 显示,只有凝血酶原时间与预后相关(P=0.035); MELD评分在死亡组明显高于生存组(t=18.236,P<0.01),且在并发肝性脑病和肝肾综合征患者中明显升高,并与血清TNFα水平呈正相关(r=0.585,P<0.01).结论 HBV感染是暴发性肝功衰竭的主要病因;病毒重叠感染者病死率最高;血清总胆红素定量、凝血酶原时间、胆固醇和空腹血糖含量以及肝性脑病、肝肾综合征和肾上腺功能不全的发生可能与预后相关;MELD评分是可以预测患者预后的指标.     

Neurological sequelae in patients recovered from fulminant hepatic failure.

Two teenage patients with fulminant hepatic failure progressing to grade 4 encephalopathy with clinical signs of cerebral oedema are described, in whom permanent neurological injury (involving the brain stem in one and the cerebral cortex in the other) was the sequel to an otherwise full recovery. The present day management of cerebral oedema may, as in these two cases, ensure the survival of patients with fulminant hepatic failure who would previously have been likely to die from the effects of raised intracranial pressure. As a result it is now possible more recovered cases will be seen with residual neurological deficits, a previously very rarely recorded event.