Pathogenesis Of Portal-systemic Encephalopathy Research Articles

There is nothin' like a Dame

HepatologyVolume 35, Issue 4 p. 983-985 Landmarks In HepatologyFree Access There is nothin' like a Dame Adrian Reuben, Adrian Reuben M.B.B.S., F.R.C.P. Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SCSearch for more papers by this author Adrian Reuben, Adrian Reuben M.B.B.S., F.R.C.P. Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SCSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2002.0350983Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Bloom H. Shakespeare. The Invention of the Human. New York: Riverhead Books, 1998; 255. 2 Summerskill WH. Aguecheek's disease. Gut 1978;19:468-469 and Lancet 1955; 2: 288– 289. 3 Shakespeare W. Twelfth Night. 1602. Act I Scene III. 4 Baló J, Korpássy B. The encephalitis of dogs with Eck fistula fed on meat. Arch Pathol 1932; 13: 80– 87. 5 Frerichs FT. A Clinical Treatise on Diseases of the Liver. Vol. 1, London: New Syndenham Soc., 1860. 6 Walshe JM. Observations on the symptomatology and pathogenesis of hepatic coma. Quart J Med 1951; 20: 421– 438. 7 Adams RD, Foley JM. The neurological disorder associated with liver disease. Res Publ Ass Nerve Ment Dis 1953; 32: 198– 237. 8 Adams RD, Foley JM. The neurological changes in the more common types of severe liver disease. Trans Am Neurol Assoc 1949; 74: 217– 219. 9 Hippocrates. The sacred disease. In: Adams F, (transl). The Genuine Works of Hippocrates. New York: W. Wood, 1929; 344. 10 Conn HO, Lieberthal MM. The Hepatic Coma Syndromes and Lactulose. Chapter 1: The syndrome of portal-systemic encephalopathy. Baltimore: Williams and Wilkins, 1979; 1– 45. 11 Matthews SA. Ammonia, a causative factor in meat poisoning in Eck fistula dogs. Am J Physiol 1922; 59: 459– 460. 12 McDermot WV Jr., Adams RD. Episodic stupor associated with an Eck fistula in the human with particular reference to metabolism of ammonia. J Clin Invest 1954; 33: 1– 9. 13 Phillips GB, Schwartz R, Gabuzda GJ Jr., Davidson CS. The syndrome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. N Engl J Med 1952; 247: 239– 246. 14 Sherlock S, Summerskill WHJ, White LP, Phear EA. Portal-systemic encephalopathy. Neurological complications of liver disease. Lancet 1954; 2: 453– 457. 15 White LP, Phear EA, Summerskill WHJ, Sherlock S. Ammonium tolerance in liver disease: observations based on catheterization of the hepatic veins. J Clin Invest 1955; 34: 158– 168. 16 Dawson AM, McClarey J, Sherlock S. Neomycin in the treatment of hepatic coma. Lancet 1957; 2: 1263– 1268. 17 Rossle M, Siegerstetter V, Huber M, Ochs A. The first decade of the transjugular intrahepatic porto-systemic shunt (TIPS): state of the art. Liver 1998; 18: 73– 89. MEDLINE 18 Conn HO, Lieberthal MM. The Hepatic Coma Syndromes and Lactulose. Chapter 2: Pathogenesis of portal-systemic encephalopathy. Baltimore: Williams and Wilkins 1979; 46– 121. 19 Editorial: Hepatic encephalopathy today. Lancet 1984; 1: 489– 491. MEDLINE 20 Mullen KD, Gacad R. Hepatic encephalopathy. Gastroenterologist 1996; 4: 188– 202. MEDLINE 21 Jones EA. Pathogenesis of hepatic encephalopathy. Clin Liver Dis 2000; 4: 467– 485. MEDLINE 22 Butterworth RF. Hepatic encephalopathy: a neuropsychiatric disorder involving multiple neurotransmitter systems. Curr Op Neurol 2000; 13: 721– 727. 23 Larsen FS, Blei AT. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol 1999; 31: 771– 776. MEDLINE 24 Amodio P, Del Piccolo F, Marchetti P, Angeli P, Iemmolo R, Coregano L, Merkel C, 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; 20: 1662– 1667. 25 Lockwood AH. “What's in a name?” Improving the care of cirrhosis. J Hepatol 2000; 32: 859– 861. MEDLINE Citing Literature Volume35, Issue4April 2002Pages 983-985 ReferencesRelatedInformation

The astrocytic (“peripheral-type”) benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy

An increasing body of evidence supports the notion that activation of astrocytic (peripheral-type) benzodiazepine receptors contributes to the pathogenesis of the central nervous system symptoms which are characteristic of portal-systemic encephalopathy (PSE). Binding site densities for the PTBR ligand [ 3H-PK11195] are increased in autopsied brain tissue from PSE patients as well as in the brains of animals with experimental chronic liver failure. In the case of the animal studies, increased PTBR sites resulted from increased PTBR gene expression. Exposure of cultured astrocytes to ammonia or manganese (two neurotoxic agents which under normal circumstances are removed by the hepatobiliary system and which are found to accumulate in brain in PSE) results in increased densities of [ 3H-PK11195] binding sites. Activation of PTBR is known to result in increased cholesterol uptake and increased synthesis in brain of neurosteroids some of which have potent positive allosteric modulator properties on the GABA-A receptor system. Accumulation of such substances in the brain in chronic liver failure could explain the neural inhibition characteristics of PSE.

An investigation of the relationship between the liver and brain using an isolated perfused rat brain preparation

The pathogenesis of portal-systemic encephalopathy (PSE) and hepatic encephalopathy (HE), disorders of the brain attributed to abnormal liver function, are poorly understood. This study was conducted to examine if a fundamental, and possibly exclusive, homeostatic interrelationship exists between the liver and brain that might deteriorate during liver failure to result in the syndrome of PSE and HE. An isolated organ perfusion circuit was devised to accommodate an isolated rat brain and an isolated rat liver preparation perfused concomitantly. The survival time of the brain preparation was measured by the maintenance of the spontaneous electroencephalocorticogram and was extended from a median survival time of 35 min (range 22 to 53 min), when perfused alone, to 210 min (range 172 to 480 min), when perfused simultaneously with a liver. Also, concomitant perfusion with an isolated rat liver reduced perfusate glucose concentrations from 200 mg% to a range between 45 to 60 mg%. These data support our hypothesis that a homeostatic interrelationship exists between the liver and brain that is independent of other metabolic influences; disturbance of this relationship may contribute towards the syndrome of PSE and HE.

Role of manganese in the pathogenesis of portal-systemic encephalopathy.

Amongst the potential neurotoxins implicated in the pathogenesis of hepatic encephalopathy, manganese emerges as a new candidate. In patients with chronic liver diseases, manganese accumulates in blood and brain leading to pallidal signal hyperintensity on T1-weighted Magnetic Resonance (MR) Imaging. Direct measurements in globus pallidus obtained at autopsy from cirrhotic patients who died in hepatic coma reveal 2 to 7-fold increases of manganese concentration. The intensity of pallidal MR images correlates with blood manganese and with the presence of extrapyramidal symptoms occurring in a majority of cirrhotic patients. Liver transplantation results in normalization of pallidal MR signals and disappearance of extrapyramidal symptoms whereas transjugular intrahepatic portosystemic shunting induces an increase in pallidal hyperintensity with a concomitant deterioration of neurological dysfunction. These findings suggest that the toxic effects of manganese contribute to extrapyramidal symptoms in patients with chronic liver disease. The mechanisms of manganese neurotoxicity are still speculative, but there is evidence to suggest that manganese deposition in the pallidum may lead to dopaminergic dysfunction. Future studies should be aimed at evaluating the effects of manganese chelation and/or of treatment of the dopaminergic deficit on neurological symptomatology in these patients.

Proton magnetic resonance spectroscopy in portal-systemic encephalopathy.

Localized proton magnetic resonance spectroscopy (MRS) with short echo times provides unique information of human cerebral metabolism. Studies on patients with portal-systemic encephalopathy (PSE) have been performed to clarify the pathogenesis of this disease and to find a method which allows an objective diagnosis. Spectra of patients with PSE show typical abnormalities. Regional variations of these spectral changes are observed. The metabolic changes correlate with the grade of encephalopathy but the dependence on the Child-Pugh score is controversial. No causal dependence between MRS findings and abnormalities in magnetic resonance imaging is evident. Differences in magnetic resonance spectra in patients compared to controls vanish after liver transplantation, but increase after TIPS. The results of proton magnetic resonance spectroscopy are important for an understanding of the pathogenesis of PSE, but do not aid in the diagnosis of subclinical hepatic encephalopathy.

Elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy.

Brain tissue levels of the two serotonin metabolites 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured in porta-caval shunted rats, an in vivo model of portal-systemic encephalopathy. An intraperitoneal challenge of L-tryptophan (280 mg/kg body weight) to sham-operated rats was also instituted to increase the brain serotonin metabolism in these rats. The results revealed significant increases in 5-hydroxytryptophol (by 31% and 5-HIAA (by 87%) brain levels in porta-caval shunted rats as compared to sham-operated controls. The brain 5-hydroxytryptophol-to-5-HIAA ratio was lower in the porta-caval shunted rats. The 5-hydroxytryptophol levels in sham rats after the L-tryptophan challenge were intermediate between the porta-caval shunted and sham rats but not statistically significant for either group. These results suggest that increased brain 5-hydroxytryptophol levels might be associated with the pathogenesis of portal-systemic encephalopathy. Further, the elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy are probably a result of the increased brain serotonin metabolism prevailing in this condition rather than changes in the brain redox potential.

Neuropsychiatric implications of brain tryptophan perturbations appearing in hepatic encephalopathy.

The metabolic encephalopathies exhibit CNS-symptoms that rapidly may alter in location of brain region of engagement, indicating a continuous fluctuation of the level of which brain functions are disturbed. This is particularly obvious in chronic conditions, such as chronic or latent hepatic encephalopathy (HE), where the fluctuating level of consciousness may be a dangerous sudden developing symptom in a person otherwise appearing to have normal brain functions. If these individuals are occupied with e.g. driving vehicle in traffic or working in heavy industrial practice, such chronic portal-systemic encephalopathy (PSE) (Sherlock et al., 1954) may be a particular hazard to both themselves and others. Unfortunately, the pathogenesis of PSE is still unknown. Hence, the delineation of the pathogenesis for HE/PSE, and therapeutic modalities developing therefrom, is highly warrented. Numerous pathogenetic mechanisms and etiological factors for PSE have been suggested (Conn and Liebertahl, 1979).

Selective Alterations of Extracellular Brain Amino Acids in Relation to Function in Experimental Portal‐Systemic Encephalopathy: Results of an In Vivo Microdialysis Study

Portal-systemic encephalopathy (PSE) is characterized by neuropsychiatric symptoms progressing through stupor and coma. Previous studies in human autopsy tissue and in experimental animal models of PSE suggest that alterations in levels of brain amino acids may play a role in the pathogenesis of PSE. To assess this possibility, levels of amino acids were measured using in vivo cerebral microdialysis in frontal cortex of portacaval-shunted rats administered ammonium acetate (3.85 mmol/kg, i.p.) to precipitate severe PSE. Sham-operated rats served as controls. Portacaval shunting resulted in significant increases of levels of extracellular glutamine (threefold, p < 0.001), alanine (38%, p < 0.01), aspartate (44%, p < 0.05), phenylalanine (170%, p < 0.001), tyrosine (140%, p < 0.001), tryptophan (63%, p < 0.001), leucine (75%, p < 0.001), and serine (60%, p < 0.001). Administration of ammonium acetate to sham-operated animals led to a significant increase in extracellular glutamine and taurine content, but this response was absent in shunted rats. The lack of taurine release into extracellular fluid following ammonium acetate administration in portacaval-shunted rats could relate to the phenomenon of brain edema in these animals. Ammonium acetate administration resulted in significant increases in the extracellular concentrations of phenylalanine and tyrosine in both sham-operated and portacaval-shunted rats. Severe PSE was not accompanied by significant increases in extracellular fluid concentrations of glutamate, aspartate, GABA, tryptophan, leucine, or serine, suggesting that increased spontaneous release of these amino acids in cerebral cortex is not implicated in the pathogenesis of hepatic coma.

Current theories on the pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver disease. Several hypotheses have emerged following the development of appropriate animal models of HE and following studies using postmortem brain tissue from HE patients. It was originally suggested that primary energy failure was responsible for HE; however, there is now mounting evidence that the pathogenetic defect involves neurotransmission failure. Specific neurotransmitter systems implicated in the pathogenesis of portal-systemic encephalopathy (PSE) include the excitatory amino acid glutamate as well as neuroactive and/or neurotoxic biogenic amine metabolites. Although it has been proposed that alterations in the gamma-aminobutyric acid (GABA) system may play a pathogenic role in HE associated with both chronic and acute liver failure, there is now overwhelming evidence to the contrary. On the other hand, there is evidence to suggest that a subgroup of patients with HE have increased blood and CSF concentrations of substances that bind to GABA-related benzodiazepine receptors in brain. Alterations of both the glutamatergic and serotoninergic neurotransmitter systems in PSE likely result from the metabolic consequences of chronic exposure of brain to toxic levels of ammonia. In addition to its effects on glutamatergic and serotoninergic systems during chronic liver disease, ammonia has been intimately associated with the brain edema invariably observed in acute liver failure. It is evident that, regardless of the type of liver failure, effective reductions of ammonia levels remains the strategy of choice in the prevention of encephalopathy. The further elucidation of neurotransmitter alterations in HE could result in novel "downstream" neuropharmacologic approaches to its prevention and treatment.

Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy

Increased brain and CSF lactate have been described in human and experimental portal-systemic encephalopathy (PSE). Using a recently described cisterna magna catheter technique, CSF lactate was measured in relation to deterioration of neurological status in portacaval shunted rats administered ammonium acetate to precipitate severe PSE. Loss of righting reflex (precoma stage of PSE) was accompanied by 2-3 fold increased CSF lactate and onset of coma by 4-fold increases of lactate (p less than 0.001 compared to either sodium acetate treated portacaval shunted rats or sham-operated controls administered ammonium acetate). The most likely explanation for increased CSF lactate is ammonia-induced inhibition of malate-aspartate shuttle and/or inhibition of tricarboxylic acid cycle flux in brain. Similar mechanisms could be involved in the pathogenesis of PSE in patients with chronic liver disease.

Amino acid imbalance following portal diversion in the rat: The relevance of nutrition and of hepatic function

End-to-end portacaval transposition has previously been shown to produce less hepatocellular dysfunction than end-to-side portacaval shunt in the rat. Liver weight is also significantly reduced after portacaval shunt compared to portacaval transposition and these differences are not abolished by pair-feeding. Histological evidence of CNS damage is also reduced in transposed rats compared to shunted animals. This study examines the amino acid and hormone changes in these models. The characteristic amino acid changes of chronic liver disease (decreased branched-chain and elevated aromatic amino acids) are reproduced in portacaval shunt rats, but not in portacaval transposition. The differences between these groups in the branched-chain amino acids, but not those in the aromatic amino acids, are reduced by pair-feeding. Insulin and glucagon are elevated to a similar extent in both groups. These findings add further support to a role for peripheral amino acid imbalance in the pathogenesis of portal-systemic encephalopathy. Normal liver function, maintained by replacement of portal inflow with systemic blood, appears to minimize both CNS damage and amino acid changes.

URINARY AND SERUM OCTOPAMINE IN PATIENTS WITH PORTAL-SYSTEMIC ENCEPHALOPATHY

Urinary excretion and serum concentrations of octopamine were studied in seventeen controls, thirty-three patients with portal-systemic encephalopathy, and thirteen patients with liver disease without encephalopathy. No differences were detected between control subjects and patients without encephalopathy. Urinary excretion and serum concentrations of octopamine were significantly higher in patients with encephalopathy compared with those without encephalopathy. The presence and grade of portal-systemic encephalopathy seemed to correlate more closely with the serum-octopamine concentrations than with urinary octopamine excretion. It is postulated that octopamine may be involved in the pathogenesis of portal-systemic encephalopathy.