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1.
The pathogenesis of brain edema in fulminant hepatic failure is incompletely understood. Our previous studies in models of this disease suggest the presence of a cytotoxic mechanism; as cortical astrocytes appeared predominantly swollen, we hypothesized that ammonia, metabolized to glutamine solely within this cell, could play a role in brain water accumulation. We determined ammonia levels in different brain regions of rats after hepatic devascularization, a model previously shown to exhibit brain edema. Concentrations of 2.5 mM were observed in the edematous cerebral cortex. We then added several concentrations of ammonium chloride to the first cortical brain slice, a preparation used to study cytotoxic brain edema. At a final bath concentration of ammonia of 5 and 10 mM, swelling could be detected; a decrease in the space of distribution of inulin was seen at the 10 mM concentration, suggesting intracellular water accumulation. Neuropathologically, astrocytes appeared involved even at subswelling doses of ammonia. Octanoic acid, at a 10 mM concentration, also resulted in demonstrable swelling. Ammonia, at concentrations in the incubation bath that approach the levels seen in anin vivo model of brain edema, results in water accumulation of cortical brain slices. Toxins implicated in the pathogenesis of hepatic encephalopathy, such as ammonia and octanoic acid, may, result in brain water accumulation.  相似文献   

2.
Intensive liver care and management of acute hepatic failure   总被引:1,自引:0,他引:1  
In describing acute liver failure, the term fulminant hepatic failure (FHF) is used to denote patients with the most rapid progression, normally defined as the onset of encephalopathy within eight weeks of the onset of symptoms. For patients with a slower onset of encephalopathy, ranging from eight weeks to six months after the onset of symptoms, late-onset hepatic failure is the term used to reflect the overlap in clinical features with some patients with FHF. The importance of accurately determining the type of acute liver failure results from increasing evidence of an inverse relationship between the tempo of disease progression and the chances of recovery. Prognosis is also dependent on the underlying etiology. Principles of management are as follows: (1) an accurate recognition of the tempo of the hepatic failure—fulminant, late onset, acute on chronic—and the establishment of a likely etiology; (2) early detection and treatment of complications, particularly metabolic acidosis (early), renal failure, cerebral edema, and infection (late); (3) optimization of conditions for regeneration by maintenance of a near normal metabolic milieu (with removal of toxins by various methods of artificial liver support if necessary); and (4) early consideration of an orthotopic liver transplant for those patients in the poor prognosis group. Variations in the natural history and clinical features of acute liver failure (ALF) have led to a number of different classifications and subgroupings. Knowledge of these is important in relation to the assessment of prognosis and is even more important now that transplantation is a therapeutic option. Fulminant hepatic failure (FHF) is the term used to denote the subgroup where the tempo is greatest and is variously defined as the onset of encephalopathy within four weeks (1), six weeks (EASL, 1979) and eight weeks [as described by Trey and Davidson (2)] of the onset of symptoms, or within two weeks of the onset of jaundice (3). The patients with a more protracted course are designated by the terms subacute or late-onset hepatic failure (LOHF) (4) or subfulminant hepatic failure (3). The etiology of the hepatic failure also has a major influence on the likely prognosis.Presented at the Proceedings of International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.  相似文献   

3.
Background and Aim:  Cerebral edema is a major complication in patients with fulminant hepatic failure (FHF). The aim of this study was to evaluate the metabolite alterations and cerebral edema in patients with FHF using in vivo proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging, and to look for its reversibility in survivors.
Methods:  Ten FHF patients along with 10 controls were studied. Five of the 10 patients who recovered had a repeat imaging after three weeks. N-acetylaspartate, choline (Cho), glutamine (Gln), glutamine/glutamate (Glx), and myoinositol ratios were calculated with respect to creatine (Cr). Mean diffusivity (MD) and fractional anisotropy (FA) were calculated in different brain regions.
Results:  Patients exhibited significantly increased Gln/Cr and Glx/Cr, and reduced Cho/Cr ratios, compared to controls. In the follow-up study, all metabolite ratios were normalized except Glx/Cr. Significantly decreased Cho/Cr were observed in deceased patients compared to controls. In patients, significantly decreased MD and FA values were observed in most topographical locations of the brain compared to controls. MD and FA values showed insignificant increase in the follow-up study compared to their first study.
Conclusions:  We conclude that the Cho/Cr ratio appears to be an in vivo marker of prognosis in FHF. Decreased MD values suggest predominant cytotoxic edema may be present. Persistence of imaging and MRS abnormalities at three weeks' clinical recovery suggests that metabolic recovery may take longer than clinical recovery in FHF patients.  相似文献   

4.
Evidence from both clinical and experimental studies demonstrates that mild hypothermia prevents encephalopathy and brain edema in acute liver failure (ALF). As part of a series of studies to elucidate the mechanism(s) involved in this protective effect, groups of rats with ALF resulting from hepatic devascularization were maintained at either 37°C (normothermic) or 35°C (hypothermic), and neurological status was monitored in relation to cerebrospinal fluid (CSF) concentrations of ammonia and lactate. CSF was removed via implanted cisterna magna catheters. Mild hypothermia resulted in a delay in onset of encephalopathy and prevention of brain edema; CSF concentrations of ammonia and lactate were concomitantly decreased. Blood ammonia concentrations, on the other hand, were not affected by hypothermia in ALF rats. These findings suggest that brain edema and encephalopathy in ALF are the consequence of ammonia-induced impairment of brain energy metabolism and open the way for magnetic resonance spectroscopic monitoring of cerebral function in ALF. Mild hypothermia could be beneficial in the prevention of severe encephalopathy and brain edema in patients with ALF awaiting liver transplantation.  相似文献   

5.
Cerebral Energy Metabolism in Hepatic Encephalopathy and Hyperammonemia   总被引:2,自引:0,他引:2  
Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with severe liver disease. Although the molecular basis for the neurological disorder in HE remains elusive, elevated ammonia and its chief metabolite glutamine are believed to be important factors responsible for altered cerebral functions, including multiple neurotransmitter system(s) failure, altered bioenergetics, and more recently oxidative stress. Accumulated evidence suggests that direct interference of ammonia at several points in cerebral energy metabolism, including glycolysis, TCA cycle, and the electron transport chain, could lead to energy depletion. Additionally, recent studies from our laboratory have invoked the possibility that ammonia and glutamine may induce the mitochondrial permeability transition in astrocytes, a process capable of causing mitochondrial dysfunction. Altered mitochondrial metabolism appears to be an important mechanism responsible for the cerebral abnormalities associated with HE and other hyperammonemic states.  相似文献   

6.
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.  相似文献   

7.
During the past decade, whole organ transplantation has become the only clinically effective method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is restricted by shortage of organ donors, high cost, relatively high morbidity, and need for life-long immunosuppression. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to utilization of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Recently, advances in hepatocyte isolation and culture techniques, improved understanding of hepatocyte-matrix interactions, availability of new biomaterials, improved hollow-fiber technology, and better understanding of flow and mass transport across semipermeable membranes have resulted in the development of a new generation of liver assist devices. Some of these devices, including the one developed by the authors, are currently being tested in the clinical setting. In this paper, the past experience with liver support systems is reviewed, the present status of the field is critically examined, and the results of a phase I clinical trial with the bioartificial liver, utilizing primary porcine hepatocytes, are summarized.  相似文献   

8.
韩涛  李莹 《传染病信息》2010,23(2):72-75
急性肝衰竭是危及生命的严重疾病,脑水肿和颅内高压是其常见的致命并发症。高血氨、谷氨酰胺积聚、线粒体功能改变、氧化应激反应、血脑屏障变化及炎性细胞因子等多种因素参与其形成过程。笔者围绕急性肝衰竭并发脑水肿的发病机制与临床处理进行综述,讨论了ICU监护、低温疗法、人工肝支持系统及细胞移植在其临床救治中的作用。  相似文献   

9.
Acute liver failure has extremely high mortality without liver transplantation. We attempted to determine the value of abdominal CT scanning and liver biopsy in its management. A retrospective analysis of patients with acute liver failure was performed; demographic, clinical, radiologic and histopathologic features were noted. Over a period of 13 years, 177 patients were evaluated. The mean age was 39 years and 63% were females. The patients were divided into three groups. Fourteen percent survived with medical management (group I), 37% died (group II), and 49% had liver transplantation (group III). Most patients showed diffuse low density of the liver on CT scanning and the proportions were similar in the three groups. Moderate to large ascites was not present in group I but occurred in 31% of patients in group II and in 15% in group III. Mean hepatic volumes were similar in the three groups; however, 97% of the patients with a liver volume of less than 1000 ml either died or required liver transplantation. Liver biopsies among patients with spontaneous recovery (group I) were distinguished by the presence of regenerative changes and a hepatic parenchymal necrosis of less than 50%. These results suggest that in patients with acute liver failure a liver volume of less than 1000 ml and/or hepatic parenchymal necrosis of greater than 50% is indicative of a poor prognosis. This information may assist decision making in such patients, in particular, regarding the need for liver transplantation.  相似文献   

10.
Hepatic stimulator substance (HSS) is a known liver-specific but species-nonspecific growth factor. In the present study we examined the activity of the endogenously produced HSS in an established experimental model of fulminant hepatic failure (FHF) and encephalopathy, induced by repeated injections of thioacetamide (TAA). FHF was induced by three consecutive intraperitoneal injections of TAA (400 mg/kg body weight) in rats, at time intervals of 24 hr. The animals were killed at 0, 6, 12, or 18 hr following the last injection of TAA. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of liver thymidine kinase (EC 2.7.1.21), and the assessment of mitotic index in hepatocytes were used to estimate liver regeneration. HSS extract obtained from the livers of TAA-treated rats, sacrificed at the above-mentioned time points was tested for its activity. Increased HSS activity was noted in all TAA-treated animals, presenting a peak at 12 hr following the third TAA dose, suggesting active participation of this growth factor in hepatocyte replication in this animal model of FHF and encephalopathy. It may also be suggested that up-regulation of HSS activity could be used in future as a therapeutic approach in FHF.  相似文献   

11.
Background: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. Methods: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. Results: In the retrospective study, we established the following discrimination equation: Z = −0.89 + 1.74 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. Conclusions: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis. Received: September 4, 2001 / Accepted: May 31, 2002 Acknowledgments. Supported by a grant from the Ministry of Health and Welfare of Japan. Reprint requests to: M. Yoshiba  相似文献   

12.
Cerebral autoregulation (CA) is an most important mechanism responsible for the relatively constant blood flow supply to brain when cerebral perfusion pressure varies. Its assessment in nonacute cases has been relied on the quantification of the relationship between noninvasive beat-to-beat blood pressure (BP) and blood flow velocity (BFV). To overcome the nonstationary nature of physiological signals such as BP and BFV, a computational method called multimodal pressure-flow (MMPF) analysis was recently developed to study the nonlinear BP–BFV relationship during the Valsalva maneuver (VM). The present study aimed to determine (i) whether this method can estimate autoregulation from spontaneous BP and BFV fluctuations during baseline rest conditions; (ii) whether there is any difference between the MMPF measures of autoregulation based on intra-arterial BP (ABP) and based on cerebral perfusion pressure (CPP); and (iii) whether the MMPF method provides reproducible and reliable measure for noninvasive assessment of autoregulation. To achieve these aims, we analyzed data from existing databases including: (i) ABP and BFV of 12 healthy control, 10 hypertensive, and 10 stroke subjects during baseline resting conditions and during the Valsalva maneuver, and (ii) ABP, CPP, and BFV of 30 patients with traumatic brain injury (TBI) who were being paralyzed, sedated, and ventilated. We showed that autoregulation in healthy control subjects can be characterized by specific phase shifts between BP and BFV oscillations during the Valsalva maneuver, and the BP–BFV phase shifts were reduced in hypertensive and stroke subjects (P < 0.01), indicating impaired autoregulation. Similar results were found during baseline condition from spontaneous BP and BFV oscillations. The BP–BFV phase shifts obtained during baseline and during VM were highly correlated (R > 0.8, P < 0.0001), showing no statistical difference (paired-t test P > 0.47). In TBI patients there were strong correlations between phases of ABP and CPP oscillations (R = 0.99, P < 0.0001) and, thus, between ABP–BFV and CPP–BFV phase shifts (P < 0.0001, R = 0.76). By repeating the MMPF 4 times on data of TBI subjects, each time on a selected cycle of spontaneous BP and BFV oscillations, we showed that MMPF had better reproducibility than traditional autoregulation index. These results indicate that the MMPF method, based on instantaneous phase relationships between cerebral blood flow velocity and peripheral blood pressure, has better performance than the traditional standard method, and can reliably assess cerebral autoregulation dynamics from ambulatory blood pressure and cerebral blood flow during supine rest conditions. ICMplus (www.neurosurg.cam.ac.uk/icmplus)software is licensed by University of Cambridge, UK, and M.C. has a financial interest in a part of licensing fee.  相似文献   

13.
Abstract: This work was undertaken to investigate whether treatment with melatonin prevents oxidative stress and changes in the expression and activity of factor erythroid 2‐related factor 2 (Nrf2)‐mediated antioxidant enzymes in an animal model of fulminant hepatic failure of viral origin. Rabbits were experimentally infected with 2 × 104 hemagglutination units of a rabbit hemorrhagic disease virus (RHDV) isolate and received melatonin at two concentrations of 10 mg/kg and 20 mg/kg at 0, 12 and 24 hr postinfection. Blood transaminases, blood lactate dehydrogenase, liver concentration of thiobarbituric reactive acid substances and the liver oxidized to reduced glutathione ratio significantly increased at 36 hr postinfection in infected animals. Significant decreases were found in the mRNA levels and in the liver activities of Mn‐superoxide dismutase, glutathione peroxidase and glutathione‐S‐transferase in infected rabbits. These effects were prevented by melatonin administration in a concentration‐dependent manner. Melatonin treatment was not accompanied by changes in protein levels of Kelch‐like ECH‐associating protein 1 (Keap1) but resulted in an increased protein expression of Nrf2 in the cytoplasm and the nucleus, which was confirmed by the results of Nrf2 immunostaining. Nuclear extracts from livers of melatonin‐treated rats displayed an enhanced antioxidant responsive element (ARE)‐binding activity of Nrf2. Our results suggest a potential hepatoprotective role of melatonin in fulminant hepatic failure, partially mediated through the abrogation of oxidative stress and the prevention of the decreased activity of antioxidant enzymes via the Nrf2 pathways.  相似文献   

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BACKGROUND: Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats. METHOD: Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N(omega)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-alpha (TNF- alpha) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay. RESULTS: Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- alpha as compared with rats treated with L-canavanine or N/S (P < 0.01). CONCLUSION: Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure.  相似文献   

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In this decade, the brain argueably stands as one of the most exciting and challenging organs to study. Exciting in as far as that it remains an area of research vastly unknown and challenging due to the very nature of its anatomical design: the skull provides a formidable barrier and direct observations of intraparenchymal function in vivo are impractical. Moreover, traumatic brain injury (TBI) brings with it added complexities and nuances. The development of irreversible damage following TBI involves a plethora of biochemical events, including impairment of the cerebral vasculature, which render the brain at risk to secondary insults such as ischemia and intracranial hypertension. The present review will focus on alterations in the cerebrovasculature following TBI, and more specifically on changes in cerebral blood flow (CBF), mediators of CBF including local chemical mediators such as K+, pH and adenosine, endothelial mediators such as nitric oxide and neurogenic mediators such as catecholamines, as well as pressure autoregulation. It is emphasized that further research into these mechanisms may help attenuate the prevalence of secondary insults and therefore improve outcome following TBI.  相似文献   

20.
INTRODUCTION Fulminant hepatic failure (FHF) is an infrequent but dreadful disease, defined by the appearance of hepatic encephalopathy within 8 wk after the onset of jaundice in patients with no known chronic liver disease[1]. Most FHF patients rapidly d…  相似文献   

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