[Hepatic encephalopathy (hepatic coma)].
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Hepatic Encephalopathy↗
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Impaired metabolism of methionine in severe liver diseases. II. Clinical and experimental studies on role of impaired methionine metabolism in pathogenesis of hepatic encephalopathy.
Hepatic encephalopathy in patients with severe liver disease was associated with marked elevation of either serum methionine or blood ammonia levels or with simultaneous moderate increases in both parameters. CSF methionine levels also increased in encephalopathic patients with fulminant hepatitis and liver cirrhosis. Increased influx of methionine into the brain over the theoretical values predicted from Pardridge's equation suggested that accelerated transport of serum methionine across the blood-brain barrier was observed in these cases with hepatic encephalopathy. Hepatic encephalopathy in acute carbon tetrachloride liver injury could be obtained experimentally following intraperitoneal injection of ammonium acetate in rats, which already received intragastric administration of methionine. However, similar encephalopathy could not be observed by the administration of glycine or leucine in place of methionine. These results suggest at least that methionine and ammonia act synergistically on inducing hepatic encephalopathy.
Ammonia↗
Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy.
Hepatic encephalopathy due to cirrhosis is frequently precipitated by exogenous factors, and the effectiveness of a specific treatment with neomycin sulfate has so far not been submitted to clinical trials. Over a period of five years, 102 cirrhotic patients developed hepatic encephalopathy at admission or during hospitalization, and 39 were randomized for treatment with either neomycin sulfate or placebo. Exclusion criteria were: 1. current usage of specific treatment for hepatic encephalopathy, 2. chronic hepatic encephalopathy and 3. multiple organ failure syndrome associated with hepatic encephalopathy. The group of excluded patients (n = 63) was compared with the randomized group (n = 39), and no statistical differences were found regarding sex and age distributions, Child-Pugh classification, etiology of cirrhosis, percipitating factors and grade of hepatic encephalopathy. These same parameters were also comparable among the 20 patients who received active neomycin and the 19 who were treated with placebo. The therapy for hepatic encephalopathy consisted in the control of precipitating factors associated with 6 g of neomycin sulfate "per os" or placebo. Therapeutic failure and death by the fifth day of treatment, occurred in four patients (10.2%), two in each of the randomized groups. The time elapsed between the initiation of the therapeutic procedure and regression to grade zero of hepatic encephalopathy was 39.11 +/- 23.04 hours for the group of active neomycin, and 49.47 +/- 21.92 hours for the placebo group, but this difference did not achieve statistical significance.
Adult↗
Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy.
Hepatic encephalopathy can arise from portal-systemic shunting in the absence of intrinsic liver disease. However, there are few descriptions of this form of encephalopathy. Portal vein thrombosis is an infrequent disease that causes portal-systemic shunting. Episodic hepatic encephalopathy has been described in patients with portal vein thrombosis, but it is not known if these patients develop minimal hepatic encephalopathy. We designed a study to investigate the neurological consequences of portal vein thrombosis in patients without cirrhosis and no clinical signs of encephalopathy. For this purpose, 10 patients underwent neuropsychological tests, an oral glutamine challenge test, and brain magnetic resonance (MR) imaging. The results were compared with those obtained in 10 healthy controls. Patients with portal vein thrombosis exhibited abnormalities in the results of neuropsychological tests, oral glutamine challenge test, and MR similar to those described in hepatic encephalopathy associated with cirrhosis. MR spectroscopy revealed a decrease in myo-inositol and an increase in glutamine. The increase in glutamine correlated with an increase in ammonia following the oral glutamine challenge test, signs of increased brain water (decrease in magnetization transfer ratio), and impairment of attention tests. In conclusion, patients with noncirrhotic portal vein thrombosis develop subclinical neurological abnormalities compatible with minimal hepatic encephalopathy. These disturbances, which include signs of increase in brain water and a compensatory osmotic response (decrease in brain myo-inositol), appear to be secondary to brain exposure to ammonia induced by portal-systemic shunting.
Administration, Oral↗
Beneficial effect of pharmacological modulation of the GABAA-benzodiazepine receptor on hepatic encephalopathy in the rat: comparison with uremic encephalopathy.
Hepatic encephalopathy is ameliorated by drugs acting on the central GABAA-benzodiazepine receptor complex. To investigate whether these effects are specific for hepatic encephalopathy or just reflect a nonspecific arousal reaction, various benzodiazepine antagonists like flumazenil or with inverse agonistic properties (Ro 15-4513, Ro 15-3505) were studied in uremic encephalopathy in rats after bilateral ureteral ligation (n = 20) and compared with hepatic encephalopathy caused by thioacetamide-induced acute liver failure (n = 33). As soon as the animals developed clear signs of metabolic encephalopathy, their motor activity was recorded in an animal activity meter for 10 min. Furthermore, a composite score was calculated by grading various behavioral signs from 0 = absent to 3 = apparently normal. Rats were then injected with coded preparations of Ro 15-4513 (0.5, 2.5 and 5 mg/kg body wt intraperitoneally), flumazenil (2.5, 10, 25 and 40 mg/kg), Ro 15-3505 (10 mg/kg) or vehicle, and the measurements were repeated. The code was broken after the completion of the study. Pretreatment motor activity was decreased both in hepatic and uremic encephalopathy (20.7 +/- 6.4 [S.E.M.] and 41.3 +/- 37.1 movements/10 min). In hepatic encephalopathy motor activity and the composite score were improved both by 5 mg/kg Ro 15-4513 (by 293%, p less than 0.05) and by 10 mg/kg Ro 15-3505 (by 509%, p greater than 0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Diagnosis and treatment of hepatic encephalopathy.
Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia's key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.
Electroencephalography↗
Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy.
Hepatic encephalopathy and brain edema are important complications in the course of a patient with acute liver failure. Presumed unrelated for many years, increasing evidence suggests that an increase in brain water is seen in all forms of hepatic encephalopathy. Ammonia, traditionally linked to the pathogenesis of hepatic encephalopathy, plays an important role in the increase in brain water. In acute liver failure, an osmotic disturbance in the astrocyte, in combination with an alteration of cerebral blood flow results in overt brain edema and intracranial hypertension. In cirrhosis, magnetic resonance techniques indicate the presence of a brain osmotic disturbance. Several clinical factors modulate the development of brain swelling.
Ammonia↗
Animal models of hepatic encephalopathy.
Hepatic encephalopathy is a neuropsychiatric syndrome associated with acute liver failure, chronic parenchymal liver disease, or portosystemic anastomosis. Many approaches have been used to develop suitable models of hepatic encephalopathy, each with specific advantages and disadvantages. The most commonly used models have been the surgical hepatectomy and liver devascularization procedures, and hepatotoxins such as galactosamine and acetaminophen. Drug-toxicity models may be clinically more relevant. The specific requirements of experiments to study a particular aspect of encephalopathy also influence the choice of animal model. Animal models will play a central role in future research into hepatic encephalopathy to better understand its pathophysiology and to develop newer therapeutic modalities for this condition.
Animals↗
Movement dysfunction and hepatic encephalopathy.
Hepatic encephalopathy is characterized by a variety of neurological symptoms. The occurrence of movement disorders is exceptional and is usually part of a clinical syndrome called acquired hepatocerebral degeneration, which is a subtype of chronic recurrent hepatic encephalopathy. The clinical picture is usually progressive and pathologic findings include regional astroglial and neuronal abnormalities found predominantly in cortex and basal ganglia. As for hepatic encephalopathy in general, the pathophysiology of this disorder is unknown but hyperammonemia and/or brain manganese overload may play a role. Medical treatment is often disappointing but in selected cases liver transplantation may be curative.
Brain↗
Surgical treatment of severe postshunt hepatic encephalopathy.
Hepatic encephalopathy is a major complication of portal-systemic shunts with an incidence ranging up to 52%. A small fraction of these patients are refractory to medical therapy. Shunt ligation and colonic procedures are the main surgical approaches. The goal of the latter is to diminish the colonic absorption of nitrogenous substances which are involved in the pathophysiology of hepatic encephalopathy. Six patients, whose average age was 55.7 +/- 2.6 years, were operated for severe postshunt encephalopathy requiring 4.3 +/- 0.9 admissions for a total duration of 76 +/- 26 days over 1-11 years. One patient had undergone a splenoral shunt and 5 had a portacaval shunt. One ligation of the shunt and 5 colon exclusions were performed. The average postoperative hospital stay was 21.5 +/- 3.9 days. The mean follow-up was 47 +/- 20 months. The patient with the shunt ligation remains free of encephalopathy 94 months after the procedure and has not bled from his esophageal varices. Among the 5 colon exclusion patients, there were 1 death and 3 complications. Three patients were completely relieved of their hepatic encephalopathy. One of those 3 died of a subarachnoid hemorrhage 28 months after the surgery. The fourth still needs medication to control a persistent, although improved, encephalopathy that required 2 further hospitalizations. Colon exclusion is a useful intervention in very selected cases. It has a lower operative mortality than total colectomy and the advantage over shunt ligation of not reestablishing hypertension in the portal system.
Hepatic Encephalopathy↗
[Therapy of hepatic encephalopathy].
Hepatic encephalopathy is a clinical syndrome which appears in the course of hepatic failure. It is due to porto-caval shunts. The major symptoms of hepatic encephalopathy are alterations of intellectual functions, changes of personality and an impairment of neuromuscular functions. The morphological basis of all these changes are a cerebral atrophy, partial cortico-medullary necrosis and the occurrence of macroglial cells. Pathogenetically either an augmented influx of toxic substances from the gut or an increased production of false neurotransmitters might be responsible. Therapeutically restriction of protein intake, sterilisation of the gut and application of branched-chain amino acids or their keto analogs are the major steps for an improvement of the disease.
Amino Acids, Branched-Chain↗
Management of agitation and convulsions in hepatic encephalopathy.
Hepatic encephalopathy represents a reversible decrease in neurological function caused by liver disease. Overall incidence of seizures in hepatic encephalopathy varies between 2% and 33%. Non-convulsive status epilepticus may be particularly common in these patients. Psychiatric disturbances manifest as agitation, personality change, delusions, etc. Aims of seizure management include treatment of basic disease, correction of precipitant factors, imaging of head, and choice of a pharmacologically safe agent. It is important to consider non-convulsive status epilepticus and rule it out by an EEG. Absolute data for safety profile of drugs in liver disease is still not clear, as changes of pharmacokinetics make choice of drugs difficult. Free drug concentrations may be higher, making plasma concentration monitoring essential in such circumstances. A single seizure may not require therapy. However when started, antiepileptic drugs are usually discontinued early. Drugs with sedative effects are best avoided because of a risk of precipitating coma. Phenytoin and gabapentin are relatively preferred drugs; however, monitoring of drug levels is desirable. Management of agitation includes physical restraint and medication. Benzodiazepines are best avoided. Haloperidol is a safer choice in the presence of liver disease. Overall management of neuropsychiatric state aims at management of underlying pathology, the resolution of which leads to improvement in the clinical symptomatology.
Hepatic Encephalopathy↗
[Current possibilities in the therapy of hepatic encephalopathy].
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome associated with acute or chronic liver disease. It is generally considered a metabolic and potentially reversible syndrome. An important component of HE is increased neuro-inhibition caused by reduced hepatic metabolism of gut-derived nitrogenous substances and by activation of the postsynaptic GABAA-receptor complex in the central nervous system. Effective conventional therapy of HE includes prevention of precipitating factors, restriction of dietary protein an administration of lactulose (or lactitol) and possibly also of antibiotics. In addition, animal studies and uncontrolled clinical studies indicate that the benzodiazepine antagonist flumazenil effectively diminishes the increased neuroinhibition in certain patients with HE. However, these favourable flumazenil effects must be confirmed in larger randomized and placebo-controlled multicenter studies before flumazenil can be regarded as a useful new addition to current management of patients with acute or chronic hepatic encephalopathy.
Combined Modality Therapy↗
[Rifaximin in the treatment of hepatic encephalopathy].
Hepatic encephalopathy is a frequent and serious complication of liver cirrhosis. Usually it is treated by non-absorbable disaccharides or antibiotics and its treatment is often difficult and associated with undesirable effects. The objective of our investigation was to evaluate the safety and effectiveness of a new antibiotic used in this indication--rifaximine. With rifaximine, 400 mg three times per day, a total of 25 patients were treated for a 10-day period. Significant improvement of the manifestations of encephalopathy occurred (evaluated by the grade of encephalopathy, test of combining numerals, the degree of flapping tremor and the arterial ammonia level). None of the patients developed undesirable effects. Rifaximine seems an effective, safe drug for hepatic encephalopathy.
Anti-Infective Agents↗
Cerebral changes in hepatic encephalopathy.
Hepatic encephalopathy (HE) accompanied by an impairment of consciousness from orientation disorder (grade II) to coma (grade IV) is considered to be overt HE and is treated as an emergency. However, subclinical hepatic encephalopathy (SHE) can be detected by sensitive and quantitative neuropsychological examinations in cirrhotic patients without overt HE. The introduction of the SHE concept is clinically important for preventing the deterioration of SHE (grades 0 and I) to overt HE (grade II and more severe), prolonging the compensated state of cirrhosis without its deterioration to hepatic failure, and the continuation of patient treatment at home. We developed a new diagnostic method for SHE using a quantitative neuropsychological test, with the computerization of all operations. Evaluations of cerebral function and morphology are useful for the determination of the pathophysiology of HE, and assist the diagnosis of SHE. The latencies of the P3 wave in the visually evoked potential and the P300 wave in the event-related potential are prolonged in cirrhotic patients with SHE and are well expressed in three-dimensional coloured topograms (brain mapping). Automated polysomnographic analysis is useful for continuous-monitoring electroencephalograms (EEG) and for the detection of the sleep disturbance observed in cirrhotic patients with SHE. Brain atrophy in computed tomography (CT), magnetic resonance imaging (MRI) and high signals in the basal ganglia in the MR-T1-weighted images have frequently been observed in patients with SHE. The reduction of regional cerebral blood flow (rCBF) by 99mtechnetium-1, 1-ethylcysteinate dimer (99mTc-ECD)-single photon emission computed tomography (SPECT) and the choline/N-acetylaspartic acid ratio by proton-magnetic resonance spectroscopy (1H-MRS) were observed in the hippocampus in patients with SHE. These approaches (cerebral function tests and imaging diagnoses of the brain) can also be used to evaluate the effectiveness of treatments for HE; for example, branched-chain amino acid (BCAA) was shown by automated continuous polysomnographic analysis to be a psychotropic drug which acts directly on the central nervous system and the clinical significance of choline administration to HE patients is now being evaluated by 1H-MRS and neuropsychological tests.
Brain↗
The pathogenesis of hepatic encephalopathy.
Hepatic encephalopathy remains a complex clinicopathological problem. Much is known about the biochemical derangements in liver, blood, and brain. The precise pathogenetic mechanism for central nervous system dysfunction remains to be determined. Ammonia continues to be considered as an important neurotoxin and may act synergistically with other toxic substances. Disturbances of amino acid balance may result in a disproportion of inhibitory and excitatory neurotransmitters in the brain. Alternatively, some amino acids may act as false neurotransmitters. Recent clinical and laboratory data have advanced the hypothesis that gamma-aminobutyric acid (GABA) absorbed from the gut may enter the brain and exert a profound inhibitory effect. Drugs which antagonize the GABA-benzodiazepate receptor may offer symptomatic improvements in hepatic encephalopathy.
Amino Acids↗
DNA synthesis in Alzheimer type II astrocytosis. The question of astrocytic proliferation and mitosis in experimentally induced hepatic encephalopathy.
Hepatic encephalopathy is associated with development of Alzheimer type II astrocytosis consisting of large, pale, frequently paired astrocytic nuclei. Previous studies have suggested that the paired forms are a manifestation of astrocytic proliferation and that the two nuclei of paired forms are in separate cells and have an equal (diploid) DNA complement. A model of hepatic encephalopathy can be produced using methionine sulfoximine to inhibit irreversibly the enzyme glutamine synthetase, resulting in elevated brain ammonia levels and development of Alzheimer type II astrocytosis. Using this model Sprague-Dawley rats were simultaneously injected with methionine sulfoximine 300 mg/kg and tritiated thymidine 15 mCi/kg. Autoradiography of cerebral sections from animals killed 18 to 36 hours after the injection revealed many heavily labeled cortical Alzheimer type II astrocytic nuclei. These findings are consistent with DNA synthesis and mitotic division of Alzheimer type II astrocytes.
Alzheimer Disease↗
Changes in brain catecholamine levels in human cirrhotic hepatic encephalopathy.
Hepatic encephalopathy (HE) is currently felt to be secondary to a disturbance in the metabolism of cerebral catecholamines with a decline in dopamine and noradrenaline and a rise in the false neurotransmitter octopamine. The aim of this study was to evaluate brain tissue levels of dopamine, noradrenaline, and octopamine in patients with cirrhosis and HE. This study includes 34 patients: 22 were cirrhotic, 12 were control subjects. Among the 22 cirrhotic patients, 19 had HE, three did not. Tissue specimens were obtained at necropsy from the locus niger, caudate nucleus, hypothalamus, thalamus and frontal cortex, and from the frontal cortex during neurosurgical procedures. Our results showed that (1) dopamine and noradrenaline levels are identical in cirrhotic patients with or without HE and in patients without liver disease (P < 0.05); (2) octopamine levels are higher in control subjects than in patients with cirrhosis and HE. In conclusion, there is no decline in dopamine and noradrenaline levels in the brain tissues of cirrhotic patients with HE, and this is in contradication with the animal findings; octopamine levels are not raised. Hepatic encephalopathy in human liver cirrhosis does not seem to be secondary to a disturbance in cerebral catecholamines.
Brain↗