|Year : 2002 | Volume
| Issue : 1 | Page : 1-8
|Hepatic encephalpathy: New concepts of pathogenesis, biological basis and outcome
Abdulkader Mohammed Daif
Department of Medicine/Neurology, Consultant Neurologist, King Khalid University Hospital, Riyadh, Saudi Arabia
Click here for correspondence address and email
|Date of Submission||07-Nov-2001|
|Date of Acceptance||04-Dec-2001|
|How to cite this article:|
Daif AM. Hepatic encephalpathy: New concepts of pathogenesis, biological basis and outcome. Saudi J Gastroenterol 2002;8:1-8
| Introduction|| |
Hepatic encephalopathy (HE) is a syndrome seen in patients with cirrhosis of the liver. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness , . An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through porto-systemic collateral vessels  . Indeed, hepatic encephalopathy may develop in non-cirrhotic patients who have undergone portocaval shunt surgery  . The development of hepatic encephalopathy is explained to some extent by the effect of neurotoxic substances, which occurs in the setting of cirrhosis and portal hypertension.
The association between liver disease and mental disorders has been recognized since the time of Hippocrates  . Galen, the Roman physician of the 2nd century, described neurologic and psychiatric symptoms resulting not only from brain diseases but also from diseases of other organs, including the liver  .
Further studies of hepatic encephalopathy continued in the 19 th century  . Hepatolenticular degeneration associated with cirrhosis of the liver was described in the early part of the 20 th century and later was determined to be a hereditary disorder of copper metabolism  . Takeuchi et al Published the classical works on which the modern concepts of hepatic encephalopathy are based ,, .
| Epidemiology|| |
The prevalence of cognitive alterations detected by neuropsychological tests in patients with cirrhosis of the liver is approximately 20% .
The incidence of overt hepatic encephalopathy in patients with portacaval shunts is as high as 60% . The background disease, cirrhosis, is common among alcoholics, but exact figures for prevalence are not available because many of these cases are asymptomatic and are not diagnosed. Approximately 25,000 Americans die each year from cirrhosis of the liver, making it the seventh leading cause of death , .
| Clinical Features of Hepatic Encephalopathy|| |
The symptoms of hepatic encephalopathy are graded on a scale of 0-4: Grade 0, clinically normal mental status but minimal changes in memory, concentration, intellectual function, and coordination. Grade 1, mild confusion, euphoria, or depression, decreased attention, slowing of ability to perform mental tasks, irritability, and disorder of sleep pattern such as inverted sleep cycle. Grade 2, drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation usually about time. Grade 3, somnolent but can be aroused, unable to perform mental tasks, disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech. Grade 4, coma with or without response to painful stimuli
Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-term memory and concentration on mental status testing. They may show signs of asterixis, although the flapping tremor of the extremities is also seen in uremia, pulmonary insufficiency, and barbiturate toxicity , . Some patients show evidence of fetor hepaticus, a sweet, musty aroma of the breath that is believed to be secondary to the exhalation of mercaptans , . Other potential physical exam findings include hyperventilationn and decreased body temperature.
| Precipitating Factors and Hepatic Encephalopathy|| |
Well-recognized factors, which tend to precipitate encephalopathy in patients with chronic hepatocellular disease are listed in [Table - 1]  . They include a dietary protein load, constipation, and gastrointestinal hemorrhage, which can be classified as gut factors, and are consistent with the hypothesis that gut-derived nitrogenous constituents of portal venous blood contribute to HE. Such substances would probably be efficiently extracted and metabolized by the normal liver. If however, their hepatic metabolism is impaired by hepatocellular failure or they bypass hepatocytes as a consequence of their passage through intrahepatic or extra-hepatic portal-systemic venous collateral channels, these substances would tend to accumulate in peripheral blood; if some are neuroactive and can traverse the blood-brain barrier, altered brain function may occur. The importance of gut factors in the pathogenesis of HE is also suggested by ameliorations of HE associated with evacuation of the bowel and dietary protein restriction  . With the exception of sedative/hypnotic drugs, the mechanisms by which well-recognized precipitating factors trigger encephalopathy in patients with chronic liver disease are poorly understood, and the elucidation of these mechanisms would provide new insights into the pathogenesis of HE. Any factor that increases portal-systemic shunting may precipitate or exacerbate HE  . The onset of HE in the absence of an obvious precipitating factor may result from progression of the underlying liver disease with consequent deterioration of hepatocellular function. In patients with hepatocellular failure, encephalopathy is not necessarily due to HE, or to HE alone. Factors other than liver failure, such as uremia, hypoglycemia, and sedative or hypnotic drugs, may cause encephalopathy or may contribute to encephalopathy in such patients.
| Biological basis|| |
There are no gross abnormalities in the brains of patients dying of hepatic coma, but microscopic examination shows diffuse hyperplasia of astrocytes of the cerebral cortex, lenticular and dentate, and of the diencephalic and other brainstem nuclei. Astrocytic swelling is of sufficient severity to cause cytotoxic cerebral edema ,, . In patients with liver cirrhosis who die in hepatic coma, microscopic examination shows characteristic Alzheimer of type II astrocytes in the cerebral cortex. These have a large vacuolated nucleus with chromatin displaced to one side. Neuronal atrophy is rare in hepatic encephalopathy, but cortical atrophy may be the result of chronic alcoholism. A diffuse laminar necrosis of the cerebral cortex is a feature of hepatocerebral degeneration. There may be microcavitation in the striatum similar to that seen in Wilson's disease .
Various pathomechanisms have been proposed for chronic and acute hepatic encephalopathy. The best known of these hypotheses concerns hyperammonemia, false neurotransmitters, and increased GABA neurotransmission.
For decades, ammonia has been thought to play an important role in the pathogenesis of HE  . It is well recognized that ammonia modulates neuronal function; it is a convulsant  . In liver failure, levels of ammonia in plasma tend to increase  , and plasma ammonia readily enters the brain  . The gastrointestinal tract and skeletal muscle are major sources of plasma ammonia. Ammonia is normally converted into urea and glutamine in the liver and into glutamine in skeletal muscle and the brain , . Hyperammonemia is associated with changes in astrocyte metabolism, and in chronic hyperammonemia changes in astrocyte morphology occur (Alzheimer type II astrocytes) , . Hyperammonemia is also associated with changes in cerebral energy metabolism , , but such changes may not contribute directly to encephalopathy and may even be secondary phenomena.
In considering the role of ammonia in HE, the following points should be taken into consideration:(1) Plasma ammonia levels have been reported to correlate poorly with the severity of HE  , although recent studies using improved methodology, suggest that this point may need revision (Ferenci P and Mullen KD, unpublished data), (2) Rogressive acute ammonia intoxication is characterized by a lethargic preconvulsive state, seizures, and postictal coma  (3) Seizures rarely occur in patients with chronic hepatocellular failure  , (4) In patients with chronic liver failure, EEG changes induced by ammonium acetate are not typical of those associated with HE  , (5) The neuroelectrophysiologic changes induced by ammonia in normal animals differ from those that occur in animal models of FHF ,, , (6) Hemodialysis, which reduces plasma ammonia levels, is associated with inconsistent ameliorations of HE  (7) Many of the documented neurotoxic effects of ammonia occur at concentrations substantially higher than those observed in humans with HE , (8) Ammonia intoxication is not associated with the subtle changes in personality and mentation and inverted sleep rhythm that are characteristic features of early stages (0-II) of HE complicating chronic liver failure ,.
In evaluating these points, ammonia concentrations associated with specific phenomena should be compared with those that occur in human liver failure. Plasma ammonia concentrations higher than those usually found in patients with liver failure are associated with effects that do not mimic HE. In particular, at concentrations of 0.75 to 1.5micro mole/L, ammonia inactivates neuronal Cl - extrusion pumps, suppresses inhibitory postsynaptic potential formation, depolarizes neurons, and, therefore, promotes phenomena attributable to increased neuronal excitation, such as a preconvulsive state and seizures ,,, . These phenomena occur at ammonia concentrations found in patients with congenital hyperammonemias , and adequately explain the clinical features of these syndromes. The question arises whether the modestly elevated plasma ammonia concentrations (0.1-0.75m mole/L) typically found in patients with precoma HE (stages I-III) are associated with enhanced neuronal inhibition that could contribute to the manifestations of HE .
According to this theory, neurotransmitter such as dopamine and noradrenaline is replaced by weaker false neurotransmitters such as octopamine and phenylethanolamine, which have increased levels in the plasma, CSF, and urine of patients with hepatic encephalopathy ,, . False neurotransmitters are generated by the action of bacteria on proteins in the gastrointestinal tract; they reach the systemic circulation via portal systemic shunts and then cross the blood-brain barrier. An imbalance of amino acids entering the brain by depletion of branched chain amino acids and elevation of aromatic amino acids (the result of decreased hepatic intake) facilitates the entry of these substances into the brain. Furthermore, false neurotransmitters are produced in the brain from aromatic amino acid precursors. The points against this hypothesis are that behavioral changes cannot be produced in experimental animals by intracerebral administration of octopamine and that therapeutic efforts to normalize plasma amino acid ratio do not lead to improvement in hepatic encephalopathy ,,.
The basis of this hypothesis for hepatic encephalopathy is that GABA, generated within the nervous tissue from decarboxylation of glutamate, causes neuroinhibition by facilitating entry of chloride into cells, resulting in decrease of neurotransmission . . An extension of this hypothesis is that endogenous benzodiazepine ligands, rather than GABA, are mediators of hepatic encephalopathy. Supporting evidence for this is the susceptibility of hepatic encephalopathy patients to the neuroinhibitory effects of benzodiazepines and the beneficial effects on hepatic encephalopathy of flumazenil, a benzodiazepine antagonist ,, .
Manganese blood concentrations
Blood concentration of Manganese was significantly higher in patients with previous portosystemic shunting. Thorough neurologic assessment using the Columbia rating scale revealed a high incidence of extrapyramidal symptoms in the absence of overt encephalopathy. Likewise, a recent neuropsychiatric evaluation of a comparable study population demonstrated a pattern of symptoms reflecting striatopallidonigral dysfunction  . Strikingly similar behavioral symptoms, intellectual deficits, and language disturbances are found with damage to the prefrontal cortex, basal ganglia lesions  , and manganese intoxication  . Studies of autopsied brain tissue from patients who died from hepatic failure and from primates after chronic Mn inhalation revealed a selective loss of pallidal postsynaptic dopamine D2 binding sites , .
Basal ganglia dysfuction
Based on the brain imaging studies and other hypotheses, hepatic encephalopathy has been proposed to be a consequence of basal ganglia dysfunction  .
| Pathomechanism of hepatic encephalopathy in acute liver failure|| |
In contrast to the hepatic encephalopathy in chronic liver disease, hepatic encephalopathy in acute liver failure is sudden in onset. Brain ammonia levels are markedly increased  . Glutamate plays an important role in the pathogenesis of this condition, as cerebro spinal fluid (CSF) glutamate is increased in acute liver failure as a result of its decreased uptake  . Exposure of the astrocytes to glutamate results in swelling and explains the marked cerebral edema  . Increased glutamatergic neurotransmission explains the hyperexcitability and seizures.
| Differential Diagnosis|| |
Several disorders related to acute and chronic alcoholism can mimic hepatic encephalopathy, i.e. alcohol intoxication, delirium tremens, and Korsakoffs syndrome. Other metabolic encephalopathies also should be considered in the differential diagnosis, particularly uremic encephalopathy. Wilson's disease should be excluded in patients with liver disease and neurologic abnormalities. Other conditions to be considered in the differential diagnosis are meningitis, subdural hematoma, and hypoglycemia. History and physical examination can differentiate hepatic encephalopathy from most of these conditions. Chronic cases of hepatic encephalopathy with dementia need to be differentiated from other causes of dementia.
| Diagnostic Workup|| |
The most important initial evaluation is a thorough general medical examination with emphasis on the nervous system. There are no diagnostic liver function test abnormalities, although elevated blood ammonia levels are suggestive for diagnosis of hepatic encephalopathy in the proper clinical setting. Examination of CSF is not remarkable. Special examinations are:(1) Neuropsychological testing. This is important in the early stages. Several test batteries are available for this purpose. Reitan's trail-making test is quite simple and enables serial assessment of the mental state ,, . In patients with overt hepatic encephalopathy, one should document the cognitive deficits for follow-up assessment. (2) Neurophysiological assessment. Electroencephgarphy (EEG) is the most widely used test for this purpose. Abnormalities seen are bilateral synchronous delta waves and triphasic waves seen mostly in the frontal regions. However, these are not specific for hepatic encephalopathy as they are also seen in other metabolic encephalopathies and patients under the influence of psychotropic medications , . EEG provides diagnostic information, but there is no good correlation between the stage of hepatic encephalopathy and degree of EEG abnormality. (3) Neuroradiological assessment: Brain CT-Scan may document cerebral edema in acute stages and cerebral atrophy in chronic cases; CT scan also may rule out other intracranial pathology if there is doubt in the diagnosis. Magnetic resonance (MRI) techniques offer new insights into hepatocerebral disorders and serve as a tool to study biochemical and structural changes of the brain. It is currently anticipated that these noninvasive procedures may permit a sensitive and reliable assessment of hepatocerebral disease' and would provide a better understanding of causal versus associated pathogenetic events in HE ,,, . Geissler et al. , investigated changes of cerebral metabolism and morphology in patients without HE, as opposed to those with subclinical and overt HE. Spahr et al. , evaluated patients without overt HE and examined the relationship among pallidal hyperintensity, blood Mn concentrations and extrapyramidal symptoms. These authors confirmed the recent reports of significantly elevated Mn blood levels in cirrhotic patients , correlating with the severity of MR hyperresonant globus pallidus MRI shows characteristic changes of symmetric pallidal hyperintensities in Tl-weighted images, but these do not correlate with the degree of hepatic encephalopathy  . Proton magnetic resonance spectroscopy (MRS) helps in an understanding of the pathogenesis of hepatic encephalopathy but does not help in the diagnosis of subclinical hepatic encephalopathy  . Position emission tomography (PET) is of academic interest and can be used to evaluate ammonia metabolism and investigate the neural response to drugs and other treatments  . Brain imaging integrated with computerized neuropsychological tests can also be used to evaluate the effectiveness of treatments for hepatic encephalopathy  .
| Prognosis and Complications|| |
The prognosis of patients with hepatic coma after acute liver failure depends on the extent and type of hepatic injury. Those who survive with medical management may make a good recovery. Others with fulminant hepatic failure may require liver transplantation. The survival probability of patients with hepatic cirrhosis who present with the first episode of hepatic encephalopathy is 42% at one year of follow-up and 23% at three years  . Complications of hepatic coma with cerebral edema include death due to transtentorial herniation. Chronic recurrent or persistent hepatic encephalopathy may lead to hepatocerebral degeneration with extrapyramidal disorders and dementia.
| Management|| |
Non-hepatic causes of altered mental function must be excluded. Consider checking the blood ammonia level in the initial assessment of a cirrhotic patient with altered mental status. Medications that depress central nervous system function, especially benzodiazepines, should be avoided. To decrease risk of worsening hepatic encephalopathy, patients with severe agitation may receive haloperidol or short acting opiates as alternative agents. It is particularly challenging to manage the patient who presents with coexisting alcohol withdrawal and hepatic encephalopathy. This patient may require therapy with benzodiazepines in conjunction with lactulose and other medical therapies for hepatic encephalopathy. Precipitants of hepatic encephalopathy, such as metabolic disturbances, gastrointestinal bleeding, infection and constipation should be corrected. Lactulose (betagalactosidofructose) is a nonabsorbable disaccharide. It may inhibit intestinal ammonia production by a number of mechanisms , . Lactulose is degraded by colonic bacteria to lactic acid and other acids, with resulting acidification of the gut lumen. This favors conversion of NH 3 to NH4 + and the passage of NH 3 from tissues into the lumen. Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli. Lactulose works as a cathartic, reducing colonic bacterial load. Initial lactulose dosing is 30m] orally once-twice per day. The dose may be increased as tolerated. Patients should be instructed to reduce lactulose dosing in the event of diarrhea, abdominal cramping, or bloating. Patients should take sufficient lactulose as to have 24 loose stools per day. Higher doses of lactulose may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to comatose patients who are unable to take the medication by mouth. The recommended dosing is 300ml lactulose plus 700 ml water, given as a retention enema every 4 hours as needed.
Neomycin and other antibiotics, such as metronidazole, oral vancomycin, paromomycin, and oral quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria , . Initial neomycin dosing is 250 mg onetwice per day. Doses as high as 4,000 mg per day may be administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and nephrotoxicity because of some systemic absorption. Ammonia-fixing strategies may be used in management. L-ornithine L-aspartate can stimulate ureagenesis and reduce blood ammonia levels. It has been found to be effective in treating hepatic encephalopathy in a number of European clinical trials. Sodium benzoate can interact with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 10mg daily can effectively control hepatic encephalopathy. Use of the medication is limited by the risk of salt overload and by its unpleasant taste. Diet may be modified in management. Some patients with hepatic encephalopathy are intolerant of diets high in protein. In the past, low protein diets were recommended routinely for cirrhotic patients in the hope of preventing exacerbations of hepatic encephalopathy. An obvious consequence was the worsening of pre-existing protein-calorie malnutrition. Protein restriction may play a role in the management of the patient with an acute flare of hepatic encephalopathy , . However, protein restriction is rarely justified in cirrhotic patients with chronic hepatic encephalopathy because malnutrition is a more serious clinical problem than hepatic encephalopathy for many of these patients. In the author's experience, the vast majority of patients with mild, chronic hepatic encephalopathy tolerate more than 60-80g protein per day. Furthermore, one recent study administered a protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation without inducing a flare of encephalopathy symptoms.
Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein, especially proteins derived from red meats. This may be due to increased content of dietary fiber, a natural cathartic, and decreased levels of aromatic amino acids. Aromatic amino acids, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen hepatic encephalopathy  .
| Conclusion|| |
Ammonia is the most prominent neurotoxin implicated in the pathophysiology of HE directly involving the ammonium ion as well as detoxification products of excess ammonia. The metabolic changes for glutamine detected by MRS would be consistent with the concept of an ammonia-induced alteration of brain neurotransmitter balance. On the other hand, the concept of ammonia toxicity does not explain the whole spectrum of hepatocerebral disease in acute and chronic liver failure. Manganese deposition is the most likely explanation for hyperresonant globus pallidus on MRI, loss of postsynaptic dopamine receptors, and extrapyramidal symptoms in patients with cirrhosis of the liver. However, recent studies reveal that MRI signal intensity, as well as alterations of MR spectra, do not reflect the proportion of hepatocerebral dysfunction. Extensive research involving longitudinal studies is needed to understand the interactions among ammonia detoxification, Mn accumulation, and cell volume disturbance indicated by MRI and MRS.
| Acknowledgment|| |
The author is grateful for Prof. Abdulkareem AI Aska for his suggestions and contributions and Lydia Gallardo for secretarial assistance.
| References|| |
|1.||Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry 1997; 63: 279-93. [PUBMED] [FULLTEXT]|
|2.||Adams RD, Foley JM. The neurological disorders associated with liver disease. Res New Merit Dis 1953, 32. 198-237. |
|3.||Sherlock S, Summerskill LP, Phear EA. Porto-systemic encephalopathy. Neurological complications of liver disease. Lancet 1954; 2: 453-7. |
|4.||Sherlock S. Hepatic encephalopathy: historical review up to 1975. In: Record C, Al-Mardini H (eds). Advances in hepatic encephalopathy and metabolism in liver disease. New Castle-Upon-Tyne, UK: Ipswich Book Company, 1997: 159-63. |
|5.||Chadwick J, Mann W. The medical works of Hippocrates. Oxford : Blackwell Scientific, 1950: 191. |
|6.||Wilson SA. Progressive lenticular degeneration, a familial nervous disease associated with cirrhosis of the liver. Brain 1912, 34: 295-309. |
|7.||Amodio P, Del Piccolo F, Marchetti P et al. Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 1999; 29: 1662-7. |
|8.||Takeuchi H. Hepatic encephalopathy acute type, chronic/recurrent type and mixed/terminal coma type. Ryoikibetsu Shokogun Shirizu. 2000; 29: 125-8. |
|9.||Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978; 75: 462-9. [PUBMED] |
|10.||Mullen KD, Dasarathy S. Hepatic encephalopathy. In: Schiff ER, Sorrell MF, Maddrey WC (eds). Schiffs Diseases of the Liver, 8th Philadelphia, Pa: Lippincott-Raven Publishers; 1999: 545-81. |
|11.||Colquhoun SD, Lipkin C, Connelly CA. The pathophysiology, diagnosis, and management of acute hepatic encephalopathy. Adv Intern Med 2001; 46: 155-76. [PUBMED] |
|12.||Lake JR, Sussman NL. Determining prognosis in patients with fulminant hepatic failure: when you absolutely, positively have to know the answer. Hepatology 1995; 21: 879-82. [PUBMED] |
|13.||Mullen KD, Gacad R. Hepatic encephalopathy. Gastroenterologist. 1996: 4: 188-202. |
|14.||Butterworth RF. The neurobiology of hepatic encephalopathy. Semin Liver Dis 1996; 16: 235-44. |
|15.||Butterworth RF. Pathogenesis of acute hepatic encephalopathy. Digestion 1998; 59: 16-21. [PUBMED] [FULLTEXT]|
|16.||Tagle M. Advances in the physiology and management of hepatic encephalopathy. Rev Gastroenterol Peru. 1996; 16: 97-8. |
|17.||Magiera M, Kucharz EJ, Chelmicka A. Hypothetical pathogenetic mechanisms of hepatic encephalopathy. Pol Arch Med Wewn. 1998; 100: 359-64 |
|18.||Basile AS, Jones EA, Skolnick P. The pathogenesis and treatment of hepatic encephalopathy: Evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991; 43: 27-71. [PUBMED] |
|19.||Zieve L. Pathogenesis of hepatic encephalopathy. Metab Brain Dis. 1987; 2: 147-65 |
|20.||Cordoba J, Salat D. The pathogenesis of hepatic encephalopathy. Gastroenterol Hepatol. 1999; 22: 247-57. |
|21.||Douglass A, Al Mardini H, Record C. Amino acid challenge in patients with cirrhosis: a model for the assessment of treatments for hepatic encephalopathy. J Hepatol. 2001; 34: 658-64. |
|22.||Seery J P, Aspinall RJ, Taylor-Robinson SD. Diagnosis and treatment of chronic hepatic encephalopathy. Hosp Med. 1998; 59: 200-4. |
|23.||Norenberg MD. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996; 16: 245-53. [PUBMED] |
|24.||Norenberg MD. Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis 1998; 13:319-35. [PUBMED] [FULLTEXT]|
|25.||Cooper AJ, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev 1987, 67: 440-519. [PUBMED] [FULLTEXT]|
|26.||Butterworth RF, Pomier-Layrargues G (eds). Hepatic Encephalopathy. Pathophysiology and Treatment. Clifton, NJ, Humana Press 1989; 159-76. |
|27.||Ma KC. Alzheimer-type I astrogliopathy (AIA) and its implications for dynamic plasticity of astroglia: A historical review of the significance of AIA. J Neuropathol Exp Neurol. 2001. |
|28.||Albercht J, Dolinska M. Glutamine as a pathogenic factor in hepatic encephalopathy. J Neurosci Res. 2001; 65: 1-5. |
|29.||Feher J, Pronai L. Lactufose and its derivatives: Treatment of hepatic encephalopathy and other possible indications for its use orv Hetil 1993; 134: 1417-9 |
|30.||Cohn R, Castell DO. The effect of acute hyperammonemia on the electroencephalogram. J Lab Clin Med 1966; 68: 195205. [PUBMED] |
|31.||Arikan K, Coskun T, Guvener B, Oran O. Effects of ammonia on pentylenetetrazole-induced seizure threshold. Metab Brain Dis. 1999; 14: 223-30. |
|32.||Huizenga JR, Gips CH, Tangerman A. The contribution of various organs to ammonia formation: A review of factors determining the arterial ammonia concentration. Ann Clin Biochem 1996:33:23-30. |
|33.||lIes JF, Jack JJB. Ammonia: Assessment of its action on postsynaptic inhibition as a cause of convulsions. Brain 1980; 103: 555-78. |
|34.||Flannery DB, Hsia E, Wolf B. Current status of hyperammonemia syndromes. Hepatology 1982; 2: 495-506. |
|35.||Ha JH, Basile AS. Modulation of ligand binding to components of the GABA A receptor complex by ammonia: Implications for the pathogenesis of hyperammonemic syndromes. Brain Res 1996; 720: 35-44. [PUBMED] [FULLTEXT]|
|36.||Hertz L, Yu AC, Kala G, Schousboe A. Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation. Neurochem Int. 2000; 37: 83-102. |
|37.||Wiltfang J, Nolte W, von Heppe J, Bahn E, Pilz J, Hajak G, Ruther E, Ramadori G. Sleep disorders and portal-systemic encephalopathy following transjugular intrahepatic portosystemic stent shunt in patients with liver cirrhosis. Relation to plasma tryptophan. Adv Exp Med Biol. 1999, 467: 169-76. |
|38.||Basile AS, Jones EA. Ammonia and GABAergic neurotransmission: Interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology 1997: 25: 103-5. |
|39.||Capocaccia L, Cangiano C, Cascino A, Calcaterra V, Cardelli P, Rossi Fanelli F. Influence of phenylethanolamine on octopamine plasma determination in hepatic encephalopathy. Clin Chim Acta. 1979; 93: 371-6. |
|40.||Szerb JC, Butterworth RF. Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog Neurobiol 1992; 9: 135-53. |
|41.||Oja SS, Saeansaari P, Wysmyk U et al Loss of GABA B binding sites in the cerebral cortex of rats with acute hepatic encephalopathy. Brain Res 1993; 629: 355-7. |
|42.||Albrecht J, Dolinska M. Glutamine as a pathogenic factor in hepatic encephalopathy. J Neurosci Res. 2001; 65: 1-5. |
|43.||Norenberg MD, Huo Z, Neary JT et al. The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: Relation to energy metabolism and glutamatergic neurotransmission. Glia 1997; 21: 124-33. |
|44.||Norenberg MD, Itzhak Y, Bender AS. The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy. Adv Exp Med Biol 1997: 420: 95-111. |
|45.||Laccetti M, Manes G, Uomo G, Lioniello M. Rabitti PG. Balzano A. Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study. Dig Liver Dis. 2000; 32: 335-8. |
|46.||Venturini I, Corsi L, Avallone R, Farina F, Bedogni G, Baraldi C, Baraldi M, Zeneroli ML. Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand J Gastroenterol. 2001; 36: 423-5. |
|47.||Elkjaer JM, Jensen TU, Emborg J. Treatment of hepatic encephalopathy with flumazenil. Ugeskr Laeger 2000, 162: 4681-4. |
|48.||Mullen KD, Szauter KM, Kaminsky-Russ K. "Endogenous" benzodiazepine activity in physiological fluids of patients with hepatic encephalopathy. Lancet 1990; 2: 81-83. |
|49.||Ikeda S, Sera Y, Yoshida M, Ohshiro H, Uchino S, Oka Y, Lee KJ, Kotera A. Manganese deposits in patients with biliary atresia after hepatic porto-enterostomy. J Pediatr Surg.2000;35.450-3. |
|50.||Rose C, Butterworth RF, Zayed J, Normandin L, Todd K, Michalak A, Spahr L, Huet PM, Pomier-Layrargues G. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterol 1999; 117: 640-4. |
|51.||Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H Neuropsychological characterization of hepatic encephalopathy. J Flepatol. 2001, 34: 768-73. |
|52.||Basile AS, Ostrowski NL, Gammal SH et al. The GABA A receptor complex in hepatic encephalopathy: Autoradiographic evidence for the presence of an endogenous benzodiazepine receptor ligand. Neuropsychopharmacol 1990, 3:61-71. |
|53.||Danbolt NC. Glutamate uptake. Pro-, Neurobiol 2001, 65: 1105. |
|54.||Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol. 2001; 34: 768-73. |
|55.||Proctor SP, Letz R, White RF. Validity of a computerassisted neurobehavioral test battery in toxicant encephalopathy. Neurotoxicology 2000; 21: 703-14. [PUBMED] |
|56.||Thomas MA, Huda A, Guze B, Curran J, Bugbee M, Fairbanks L, Ke Y, Oshiro T, Martin P, Fawzy F. Cerebral 1 H MR spectroscopy and neuropsychologic status of patients with hepatic encephalopathy. AJR Am J Roentgenol 1998,171:1123-30. [PUBMED] |
|57.||Kullmann F, Hollerbach S, Holstege A, Scholmerich J. Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials.J Hepatol. 1995; 22: 101-10. |
|58.||Butterworth RF, Pomier-Layrargues G (eds). Hepatic Encephalopathy. Pathophysiology and Treatment. Clifton, NJ, Humana Press, 1989; 355-87. |
|59.||Geissler A, Lock G, Frond R et al. Cerebral abnormalities in patients with cirrhosis detected by proton magnetic resonance spectroscopy and magnetic resonance imaging. Hepatology 1997; 25: 48-5417 |
|60.||Hauser RA, Zefiewicz T, Rosemurgy AS et al. Manganese intoxication and chronic liver failure. Ann Neurol 1994; 36: 871-5. |
|61.||Laubenberger J, Haussinger D, Bayer S et al. Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology 1997, 112: 1610-16. |
|62.||Spahr L, Butterworth RF, Fontaine S et al. Increased blood manganese in cirrhotic patients: Relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms. Hepatology 1996, 24: 1116-20. |
|63.||Kostler H. Proton magnetic resonance spectroscopy in portal-systemic encephalopathy. Metab Brain Dis 1998, 13. 291-301. |
|64.||Lockwood AH. Positron emission tomography in the study of hepatic encephalopathy. Metab Brain Dis 1998, 13: 3039. [PUBMED] [FULLTEXT]|
|65.||Watanabe A. Cerebral changes in hepatic encephalopathy. J Gastroenterol Hepatol 1998; 13: 752-60 [PUBMED] |
|66.||Bustamante J, Rimola A, Ventura PJ et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30: 890-5. |
|67.||Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci. 2000, 45 1549-52. |
|68.||Banares R, Carneros JA, Rincon D. New treatments of hepatic encephalopathy. Gastroenterol Hepatol 1998; 21: 196-202. |
|69.||Curioso WH, Monkemuller KE. Neomycin should not be used to treat hepatic encephalopathy. BMJ. 2001, 323: 333. |
|70.||Miglio F, Valpiani D, Rossellini SR, Ferrieri A. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin 1997; 13: 593-601. |
|71.||Amodio P, Caregaro L, Patteno E, Marcon M, Del Piccolo F, Gatta A. Vegetarian diets in hepatic encephalopathy: facts or fantasies? Dig Liver Dis. 2001, 33: 492-500. |
|72.||Soulsby CT, Morgan MY. Dietary management of hepatic encephalopathy in cirrhotic patients: survey of current practice in United Kingdom. BMJ 1999; 318: 1391. [PUBMED] [FULLTEXT]|
|73.||Jalan R, Seery JP, Taylor-Robinson SD. Pathogenesis and treatment of chronic hepatic encephalopathy. Aliment Pharmacol Ther 1996, 10: 681-97. [PUBMED] |
Abdulkader Mohammed Daif
Department of Medicine/Neurology King Khalid University Hospital, P. 0. Box 7805, Riyadh 11472
Source of Support: None, Conflict of Interest: None
[Table - 1]
| Article Access Statistics|
| Viewed||10493 |
| Printed||214 |
| Emailed||6 |
| PDF Downloaded||0 |
| Comments ||[Add] |