Journal of Hepatology
Volume 32, Issue 6 , Pages 1035-1038, June 2000

Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?

Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University-Düsseldorf, Germany

Article Outline

 

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease. Its pathogenesis is not understood, although there is agreement on the important role of neurotoxins, especially ammonia (1). In the brain of HE patients, neurons appear morphologically normal, but astrocytes exhibit signs of Alzheimer type II degeneration with nuclear enlargement, peripheral margination of chromatin and prominent nucleoli. Functional alterations in HE include selective alterations of blood-brain barrier permeability, changes in cerebral energy metabolism, an increased GABA-ergic tone and changes in several other neurotransmitter systems and their receptors (for reviews see 2., 3., 4., 5., 6., 7., 8.). However, previous hypotheses about the pathogenesis of HE were unable to explain all the facets of this clinical syndrome. Clearly, pathogenetic models have to explain the functional nature and reversibility of HE symptoms, and their precipitation by heterogeneous factors, such as infections, diuretics, sedatives, trauma, bleeding or high protein intake.

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Astrocytes and Hepatic Encephalopathy 

The finding that Alzheimer type II changes can be induced experimentally in cultured astrocytes upon exposure to ammonia prompted the idea that hepatic encephalopathy is a primary disorder of glial cells, with neuronal dysfunction being the consequence 9., 10.. Astrocytes are the only cell compartment in the brain containing glutamine synthetase (11) and are accordingly the major site of cerebral ammonia detoxification. They are important constituents of the bloodbrain barrier, and uptake of substances from the blood into the brain requires transastrocytic transport. In addition, astrocytes are highly regulated cells, which communicate directly with neurons (12) and participate in neurotransmitter processing, regulation of the ionic milieu in the brain and substrate provision for neurons (for reviews see 13., 14.. In acute liver failure astrocytes swell; clinically overt brain edema with increased intracranial pressure is frequent and critical for the patient's outcome. This was reviewed in a recent issue of the Journal of Hepatology (15). On the other hand, hepatic encephalopathy in chronic liver disease is not accompanied by clinical signs of cerebral edema. Nonetheless, recent in vivo proton-magnetic resonance-(MR)-spectroscopic (1H-MRS) studies suggest that disturbances of astrocyte cell volume homeostasis may be an early event in chronic HE in cirrhosis 16., 17..

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Evidence for a Disturbance of Cerebral Cell Volume Homeostasis in HE 

1H-MRS can be used to study metabolic abnormalities in the human brain in vivo and allows a myo-inositol signal to be picked up, which was recently identified to reflect an osmosensitive myo-inositol pool (16) of predominant glial origin 18., 19.. Indeed, myo-inositol is an organic osmolyte in astrocytes 20., 21., 22.. Such organic osmolytes play a role in cell volume regulation, in that they accumulate inside the cells in response to cell shrinkage, but are rapidly released in response to cell swelling via osmoregulated membrane channels (for reviews, see 23., 24.). In vivo 1H-MRS studies on the brain from cirrhotic patients with HE consistently show a depletion of myo-inositol which is accompanied by an increase in the glutamine/glutamate signal 16., 17., 25., 26., 27., 28.. Such alterations are also induced in the rat following portocaval shunting (26), are aggravated following institution of a transjugular intrahepatic portosystemic stent shunt (TIPS) (16) and may largely normalize following liver transplantation (27). There is a good correlation between the extent of these 1H-MRS-changes and the clinical severity of HE 16., 17., 27., 28. (Fig. 1). A high sensitivity and specificity of the myo-inositol signal for the diagnosis of HE in cirrhotics has been reported 27., 28., although these changes are observed already at preclinical stages of HE 16., 17., 27., 28..

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  • Fig. 1. 

    Parietal 1H-MR spectra from (A) a healthy person; patients with (B) posthepatitic cirrhosis and subclinical (latent) HE or (C) manifest grade I-II HE. Note the decrease in myo-inositol (Ino) signal and the decrease in the glutamine/glutamate (Glx) signal. Other peaks refer to choline (Cho), creatine (Crea) and N-acetylaspartate (NAA). From ref. (16).

In view of the role of myo-inositol as an organic osmolyte in astrocytes, these MRS findings are highly suggestive of a disturbance of cell volume homeostasis in brain (16), in the sense of a cellular (cytotoxic, but not vasogenic (29)) edema, and may be explained by an osmotically active intracellular accumulation of glutamine in response to hyperammonemia and counteraction of the resulting astrocyte swelling by myo-inositol depletion. In line with this, cultured astrocytes swell under the influence of ammonia (30) in a methionine sulfoximine-sensitive way (10) and the above-mentioned 1MRS changes are also found in hyperammonemic Reye's syndrome. Also in the portocaval-shunted rat in vivo, ammonia induces brain edema and intracranial hypertension in a largely methionine sulfoximine-sensitive way (31). Further, 15N-ammonia positron emission tomography studies (32) on human brain from encephalopathic patients showed an increased cerebral metabolic rate for ammonia, consistent with an enhanced cerebral ammonia uptake in HE and detoxification by glutamine synthesis. However, ammonia may not be the only mechanism by which astrocyte swelling is triggered in HE, because astrocyte swelling also occurs in vitro under the influence of hyponatremia 33., 34., some neurotransmitters 33., 35., tumor necrosis factor-α (36), and benzodiazepines 10., 35.. It should be emphasized that myo-inositol is just one indicator of astrocyte swelling in HE. In fact, recent data suggest that besides myo-inositol other well-known organic osmolytes such as taurine 19., 22. and α-glycerophosphorylcholine 22., 37. are depleted in order to counteract astrocyte swelling in HE.

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Functional Consequences of Low-grade Astrocyte Swelling 

In all cell types studied so far, the cellular hydration state was identified as an independent signal which regulates cell function and gene expression (for reviews see 24., 38.). Multiple osmosignalling pathways have been identified which provide the link between cell hydration and cell function (39). In hepatocytes, i.e. the best studied cell type in this respect, small increases of cell water content (i.e. less than 10%), stimulate glycogen and protein synthesis, amino acid transport, biliary excretion, decrease proteolysis and glycogen breakdown and exert multiple effects on cytoskeletal proteins and gene expression (38). Thus, small increases in astrocyte water content, as may occur in HE, could already have important functional consequences despite the absence of clinically overt increases of intracranial pressure. This is suggested by recent evidence. Swelling of astrocytes in culture activates extracellular regulated protein kinases (Erks) (34), i.e. members of the MAP-kinase family with multiple functions, in a phosphatidylinositol-3-kinase-dependent way, elevates intracellular calcium concentration (40), upregulates the peripheral type benzodiazepine receptor (PBR) at the level of agonist binding (41) and mRNA (R. Fischer & Häussinger, D., unpublished) and affects multiple ion channels and amino acid transport (33). Further, astrocyte swelling increases the pH in endocytotic vesicles (42) through an Erk-dependent osmosignalling pathway (R. Fischer & D. Häussinger, unpublished result). Several key findings in HE can thus at least in part be explained as a result of increased astrocyte hydration. Given the important role of a low endosomal pH for receptor/ligand sorting, the marked endosomal alkalinization in response to astrocyte swelling is expected to affect receptor densities and neurotransmitter processing. Likewise, swelling-induced changes of the activity of plasma membrane transporters may underlie the selective changes in “blood-brain barrier” permeability, which are observed in HE. The increased deposition of glycogen in astrocytes in animal models of chronic HE (10) may also be explained by cell swelling, because swelling of hepatocytes increases glycogen synthesis and inhibits glycogenolysis (for review (38)). Increased expression of PBR in response to astrocyte swelling augments the synthesis of neurosteroids, which are potent modulators of neuronal GABAA receptor activity (10). Thus, the interaction between astrocyte swelling, PBR expression and increased neurosteroid synthesis may explain the increased GABA-ergic tone found in HE.

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Pathogenetic Model 

In view of the above, it is hypothesized that one major pathogenetic event in the development of HE in chronic liver disease is an increase in astrocyte hydration, i.e. a low-grade cerebral edema without a clinically overt increase in intracranial pressure, but sufficient to trigger multiple alterations of astrocyte function (Fig. 2). This may finally result in a disturbance of glioneuronal communication and the clinical picture of HE. Since astrocyte swelling is induced not only by ammonia, but also by hyponatremia, benzodiazepines or inflammatory cytokines, such a model would explain why rather heterogeneous conditions (e.g. bleeding, electrolyte disturbances, sedatives, infections) can precipitate HE in the cirrhotic patient. Thus, multiple factors would act synergistically on the common pathogenetic endpath, i.e. glial swelling with its functional consequences. Noncirrhotics may tolerate such precipitating factors without developing HE symptoms, because their osmolyte systems for counteraction of cell swelling are not exhausted. In cirrhosis, however, organic osmolytes are largely depleted in order to compensate for glial glutamine accumulation and there may be little room for action of these volume-regulatory mechanisms against further challenges of cell volume. Thus, the 1H-MRS findings in nonencephalopathic cirrhotics may describe an early stage of a largely compensated disturbance of astrocyte volume homeostasis with few consequences yet for astrocyte hydration and function. This situation, however, can decompensate rapidly in response to precipitating factors, and hydration-dependent alterations of glial function will become clinically apparent. This labile situation may explain the rapid kinetics of HE episodes and why severe brain edema with fatal outcome can occasionally develop in endstage cirrhotics (43). Thus similarities exist with respect to the pathogenesis of HE in chronic liver disease and acute liver failure, but differences in the kinetics, extent and counterregulation of glial swelling may be responsible for differences in the clinical picture of acute versus chronic HE, respectively.

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  • Fig. 2. 

    Proposed mechanism through which various precipitating factors can induce hepatic encephalopathy. This model views a disturbance of astrocyte hydration (lowgrade cerebral edema) as a key event and one (not the only) major mechanism leading to astrocyte dysfunction and the clinical picture of HE.

At present, no new therapeutic options can be deduced from this hypothesis, but all established therapeutic measures for HE are directed against factors which also augment astrocyte swelling. One may also speculate that the respiratory alkalosis which is frequently found in cirrhotic patients, may represent a beneficial adaptation, because hypocapnia is known to decrease astrocyte hydration. It is hoped that these considerations may stimulate future research in the field of HE.

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References 

  1. Butterworth RF, Giguere JF, Michaud J, Lavoie J, Layrargue GP. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol. 1987;6:1–12
  2. Lockwood AH. Hepatic Encephalopathy. Boston: Butterworth-Heinemann; 1992;
  3. Ferenci P, Püspök A, Steindl P. Current concepts in the pathogenesis of hepatic encephalopathy. Eur J Clin Invest. 1992;22:573–581
  4. Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997;337:473–479
  5. Jalan R, Seery JP, Taylor-Robinson SD. Pathogenesis and treatment of chronic hepatic encephalopathy. Aliment Pharmacol Ther. 1996;10:681–697
  6. Basile AS, Jones EA. Ammonia and GABA-ergic neurotransmission: interrelated factors in the pathogenesis of hepatic encephalopathy. Hepatology. 1997;25:1303–1305
  7. Butterworth RF. The neurobiology of hepatic encephalopathy. Semin Liver Dis. 1996;16:235–244
  8. Norenberg MD. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liv Dis. 1996;16:245–253
  9. Norenberg MD, Neary JT, Bender AS, Dombro RS. Hepatic encephalopathy: a disorder in glial-neuronal communication. In:  Yu ACH,  Hertz L,  Norenberg MD,  Sykova E,  Waxman SG editor. Progress in Brain Research. Amsterdam: Elsevier Publ BV; 1992;p. 261–269
  10. Norenberg MD, Itzhak Y, Bender AS, Baker L, Aguila-Mansilla HN, Zhou BG, et al.  In:  Häussinger D,  Jungermann K editor. Liver and Nervous System. Lancaster, England: Kluwer Acad Publ; 1998;p. 276–293
  11. Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in the brain. Science. 1977;195:1356–1358
  12. Nedergaard M. Direct signalling from astrocytes to neurons in cultures of mammalian brain cells. Science. 1994;263:1768–1771
  13. In:  Murphy S editors. Astrocytes - Pharmacology and Function. San Diego: Academic Press; 1993;
  14. In:  Kimelberg H,  Ransom BR editor. Neuroglia. New York: Oxford University Press; 1995;
  15. Blei AT, Larsen FS. Pathophysiology of cerebral edema in fulminant hepatic failure. J Hepatol. 1999;31:771–776
  16. Häussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, et al.  Proton magnetic resonance spectroscopic studies on human brain myo-inositol in hypoosmolarity and hepatic encephalopathy. Gastroenterology. 1994;107:1475–1480
  17. Laubenberger J, Häussinger D, Bayer S, Gufler H, Hennig J, Langer M. Proton magnetic resonance spectroscopy of the brain in symptomatic and asymptomatic patients with liver cirrhosis. Gastroenterology. 1997;112:1610–1616
  18. Brand A, Leibfritz D. Metabolic markers in glial cells for differentiation of brain tissue. Abstr Commun 11th Ann Meet Soc MR Med. 1992;649
  19. Zwingmann C, Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR spectroscopy studies on NH4Cl-induced metabolic alterations and detoxification processes in primary astrocytes and glioma cells. Dev Neurosci. 1998;20:417–426
  20. Paredes A, McManus M, Kwon HM, Strange K. Osmoregulation of Na+-inositol cotransporter activity and mRNA levels in brain glial cells. Am J Physiol. 1992;263:C1282–C1288
  21. Isaacks RE, Bender AS, Kim CY, Norenberg MD. Effect of osmolarity and anion channel inhibitors on myo-inositol efflux in cultured astrocytes. J Neurosci Res. 1999;57:866–871
  22. Cordoba J, Gottstein J, Blei AT. Glutamine, myo-inositol and organic brain osmolytes after portacaval anastomosis in the rat: implications for ammonia-induced brain edema. Hepatology. 1996;24:919–923
  23. Burg MB. Molecular basis of osmotic regulation. Am J Physiol. 1995;268:F983–F996
  24. Lang F, Busch GL, Ritter M, Völkl H, Waldegger S, Gulbins E, et al.  Functional significance of cell volume regulatory mechanisms. Physiol Rev. 1998;78:247–306
  25. Kreis R, Farrow NA, Ross BD. Diagnosis of hepatic encephalopathy by proton magnetic resonance spectroscopy. Lancet. 1990;336:635–636
  26. Moats RA, Lien YH, Filippi D, Ross BD. Decrease in cerebral inositols in rats and humans. Biochem J. 1993;295:15–18
  27. Ross BD, Danielsen ER, Bluml S. Proton magnetic resonance spectroscopy: the new gold standard for diagnosis of clinical and subclinical hepatic encephalopathy. Dig Dis. 1996;14(suppl 1):30–39
  28. Ross BD, Jacobson S, Villamil F, Korula J, Kreis R, Ernst T, et al.  Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities. Radiology. 1994;193:457–463
  29. Kimelberg HK. Current concepts of brain edema. J Neurosurg. 1995;83:1051–1059
  30. Norenberg MD, Baker L, Norenberg LOB, Blicharska J, Bruce-Gregorius JH, Neary JT. Ammonia-induced astrocyte swelling in primary culture. Neurochem Res. 1991;16:833–836
  31. Blei AT, Olafsson S, Therrien G, Butterworth RF. Ammonia-induced brain edema and intracranial hypertension in rats after portocaval anastomosis. Hepatology. 1994;19:1437–1444
  32. Lockwood AH, Yap EWH, Wong HE. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metabol. 1991;11:337–341
  33. Kimelberg HK, O'Connor ER, Kettenmann H. Effects of cell swelling on glial function. In:  Lang F,  Häussinger D editor. Interactions in Cell Volume and Cell Function. Heidelberg, Germany: Springer Verlag; 1993;p. 158–186
  34. Schliess F, Sinnig R, Fischer R, Schmalenbach C, Häussinger D. Calcium-dependent activation of Erk-1 and Erk-2 following hypoosmotic astrocyte-swelling. Biochem J. 1996;320:167–171
  35. Bender AS, Norenberg MD. Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J Neurosci Res. 1998;54:673–680
  36. Bender AS, Rivera IV, Norenberg MD. Tumor necrosis factor α induces astrocyte swelling. Trans Am Neurochem. 1992;23:113
  37. Bluml S, Zuckerman E, Tau J, Ross BD. Proton-coupled 31P magnetic resonance spectroscopy reveals osmotic and metabolic disturbances in human hepatic encephalopathy. J Neurochem. 1998;71:1564–1576
  38. Häussinger D. The role of cellular hydration in the regulation of cell function. Biochem J. 1996;313:697–710
  39. Häussinger D, Schliess F. Osmotic induction of signalling cascades: role in regulation of cell function. Biochem Biophys Res Commun. 1999;255:551–555
  40. Fischer R, Schliess F, Häussinger D. Characterization of the hypoosmotically-induced Ca2+ response in primary astrocytes. Glia. 1997;20:51–58
  41. Itzhak Y, Bender AS, Norenberg MD. Effect of hypoosmotic stress on peripheral-type benzodiazepine receptors in cultured astrocytes. Brain Res. 1994;644:221–225
  42. Busch GL, Wiesinger H, Gulbins E, Wagner HJ, Hamprecht B, Lang F. Effect of astroglial swelling on pH of acidic intracellular compartments. Biochim Biophys Acta. 1996;1285:212–218
  43. Donovan JP, Schafer DF, Shaw BW, Sorell MF. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet. 1998;351:719–721

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Journal of Hepatology
Volume 32, Issue 6 , Pages 1035-1038, June 2000

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