Brain myo-inositol, an organic osmolyte, is decreased inositol are poorly understood. in cirrhotic patients with hepatic encephalopathy but myo-Inositol is a six-carbon polyol that participates in the appears unchanged in fulminant hepatic failure. An ossynthesis of intracellular signaling compounds of the phosmoregulatory response to the increase in brain glutaphatidylinositol group 5 and is a main organic osmolyte in mine may explain the decrease in brain myo-inositol; if the regulatory volume response to osmotic stress. 6 Besides this is the case, organic osmolytes may account for difhepatic encephalopathy, a decrease in brain myo-inositol has ferences in the development of brain edema seen in been noted in affective disorders 7 and in chronic hyponaacute or chronic liver failure. The response of myo-inositremia. 8 In the latter, the decrease of myo-inositol is accompatol and nine other organic osmolytes to the increase in nied by a reduction of other organic osmolytes, including glubrain glutamine at different time intervals after portacatamine, as part of the process of cellular regulatory volume val anastomosis (PCA) in the rat was studied. Organic decrease. This response is elicited by the osmotic gradient osmolytes were measured in brain tissue and cerebrobetween the intracellular and extracellular compartments. spinal fluid. Water in cerebral cortex was measured after During regulatory volume decrease, brain cells lose inorganic ammonia infusion with the gravimetric method. Six ions as well as organic osmolytes, such as amino acids, meweeks after PCA, despite an increase in brain glutamine thylamines, and inositols, to avoid cell swelling. 9 Whereas (PCA, 16.4 { 2 mmolrkg wt 01 rkg wt 01 ; sham, 5 { 1 changes in the concentration of electrolytes can result in se-mmolrL 01 rkg wt 01 ), the content of total organic osmovere neurophysiological consequences, the unique physical lytes did not increase (PCA, 44.1 { 3; sham, 43 { 4) beand chemical properties of organic osmolytes allow cells to cause of a decrease of other osmolytes (myo-inositol, 54%; withstand large changes in their concentration without detriurea, 39%; taurine, 33%; and glutamate, 8%). Brain myomental effects to cellular structure and function. 6 In hyponainositol was lower at 3 weeks (3.4 { 0.5 kg wt 01 ) than at tremia, up to one fourth of the osmotic response is dependent 1 day after PCA (4.7 { 0.5 kg wt 01 ). An ammonia infusion on organic osmolytes. 10 resulted in brain edema at both time points. In conclu-
In hepatic encephalopathy, the decrease in brain myo-inosion, the reduction in brain myo-inositol in PCA rats is sitol could occur as a compensatory response to the osmotic accompanied by the decrease of other organic osmogradient induced by the accumulation of glutamine in astrolytes, supporting the view that changes in myo-inositol cytes. If this is the case, other organic osmolytes should also reflect an osmoregulatory response. The decrease in decrease in response to the increase in glutamine. In patients brain myo-inositol is more marked as time elapses after with fulminant hepatic failure (FHF), the accumulation of PCA. In a model in which short-term and large doses of glutamine in the brain has been proposed as a mechanism ammonia were infused, the decrease in brain myo-inosito explain the development of brain edema. 11 Early studies tol did not prevent the development of brain swelling. using nuclear magnetic resonance-spectroscopy in human Understanding brain osmoregulatory mechanisms may FHF report an increase in brain glutamine but unchanged provide new insights into hepatic encephalopathy and values of myo-inositol. 12 We have postulated that differences brain edema in fulminant hepatic failure. (HEPATOLOGY in the concentration of organic brain osmolytes between acute 1996;24:919-923.)
and chronic liver failure could partly explain the lack of development of brain edema in chronic liver failure. 13 In this study, we have analyzed the response of brain myo-Brain glutamine is increased and myo-inositol is decreased inositol and nine other organic osmolytes to the increase in in cirrhotic patients with hepatic encephalopathy. 1,2 When brain glutamine induced by portacaval anastomosis (PCA) observed at nuclear magnetic resonance-spectroscopy, this in the rat. In a subsequent experiment, we evaluated the pattern is so common that it has been proposed as a tool influence of the duration of PCA on the decrease of myoto diagnose hepatic encephalopathy. 3 The increase of brain inositol. To determine the role of osmolar adaptation on the glutamine arises from the detoxification of ammonia, a propathogenesis of brain edema, we used the model of ammonia cess that is localized to glial cells. 4 However, the significance infusion in rats that underwent PCA. 14 Although we did not use a model of FHF, infusion of ammonia in rats that underwent PCA reproduces the high levels of brain glutamine observed in FHF and permits the study of brain edema without Abbreviations: FHF, fulminant hepatic failure; PCA, portacaval anastomosis; CSF, cerebrospinal fluid. other confounding factors. In accordance with previous stud-From the Department of Medicine, Veterans Administration Lakeside Medical Center ies, 15,16 measurement of key organic osmolytes in samples of and Northwestern