Journal of Hepatology
Volume 35, Issue 5 , Pages 661-662, November 2001

Images of the brain in chronic liver failure

Neuroscience Research Unit, Hôpital Saint-Luc, Centre Hospitalier de l'Université de Montréal, 1058 St. Denis Street, Montreal, Quebec, Canada H2X 3J4

See Article, pages 598–604

Article Outline

 

Recent advances in neuroimaging continue to provide new insights into the nature of the neuroanatomical substrates and the neurochemical mechanisms responsible for hepatic encephalopathy (HE). For example, positron emission tomography (PET) studies have shown that cirrhotic patients with mild encephalopathy manifest increased rates of brain ammonia uptake and metabolism [1], [2] and concomitant decreases in glucose utilization in regions of cerebral cortex which are associated with the processing of visual stimuli [3]. Magnetic resonance imaging (MRI) investigations, on the other hand, reveal bilateral T1-weighted signal hyperintensities in the globus pallidus of cirrhotic patients, a phenomenon which has been attributed to manganese deposition in this brain structure [4]. More information of a molecular nature is provided by studies using magnetic resonance spectroscopy (MRS), and the last 5 years have witnessed several studies using 1H (proton)-MRS for the study of pathophysiologic mechanisms implicated in HE in chronic liver failure. In all cases, a characteristic pattern of metabolite changes has been reported, consisting of an increase in the intensity of signals attributed to the protons of glutamate/glutamine, and a concomitant reduction in the intensity of signals attributable to the protons of choline-containing compounds and of myoinositol [5], [6].

In an important new study, Córdoba et al. [7] describe significant increases in glutamate/glutamine resonances in 1H-MRS which were significantly correlated with neuropsychologic deficits in a group of 24 non-alcoholic cirrhotic patients. These findings confirm those of a previous MRS study using higher field strengths and shorter echo times, by which it was possible to resolve the glutamate/glutamine complex resonance and to demonstrate that increases in the glutamine resonance specifically were found to correlate with severity of encephalopathy [8]. In the study by Córdoba et al. [7], liver transplantation led to normalization of glutamate/glutamine signals together with significant improvement in the neuropsychiatric status in these patients.

Increases of brain glutamine have consistently been reported in cirrhotic patients using either biochemical or spectroscopic methods of measurement [8], [9], and it has generally been assumed that this increase is the result of exposure of brain to increased concentrations of ammonia; the only effective route for ammonia removal by brain is via glutamine synthesis. Furthermore, it has been demonstrated that the rapid accumulation of intracellular glutamine is responsible for the astrocytic swelling which is characteristic of acute hyperammonemic syndromes, and intracellular glutamine accumulation has been proposed to explain the phenomenon of brain edema in acute liver failure [10]. However, pretreatment of animals with experimental acute liver failure with methionine sulfoximine, an inhibitor of glutamine synthesis in brain does not prevent brain edema in these animals [10]. The report by Córdoba et al. [7] may shed light on this issue. In their study, brain glutamate/glutamine concentrations were determined using 1H-MRS and, concomitantly, brain water accumulation was assessed by a technique known as magnetization transfer imaging (MTI), a technique which has the potential to provide a novel type of tissue contrast based on the transfer of magnetization between the free protons in water and those of macromolecules (the so-called ‘magnetization transfer ratio’ (MTR)). It is well established that water accumulation in the tissue results in a decrease in MTR. In the study by Córdoba et al. [7], reductions in MTR were found to be significantly negatively correlated with brain glutamate/glutamine resonances and with indices of neuropsychologic function. These correlations were lost and all parameters were found to be normalized following liver transplantation. The authors conclude that these findings indicate that mild HE in chronic liver failure is the consequence of water accumulation in brain caused by ammonia. Possible confounding causes of decreased MTR were entertained which included changes in plasma osmolarity, manganese accumulation and immunosuppressive medication. A correlation between plasma osmolarity and MTR changes was indeed observed, but possible contributions by manganese or immunosuppressants were discounted due to the lack of evidence of brain lesions and/or the time course of magnetic resonance changes due to manganese compared with those observed for MTR changes following liver transplantation.

It is tempting to relate the changes in MTR in this group of patients to the established neuropathology in human chronic liver failure, the cardinal feature of which is Alzheimer type II astrocytosis. Alzheimer type II changes consist of cellular and nuclear swelling, margination of chromatin and glycogen deposition [11]. In addition, astrocytes in chronic liver failure are known to express significantly less glial fibrillary acidic protein (GFAP) [12], a cytoskeletal protein which is intimately involved in cell volume regulation. Exposure of astrocytes in culture leads to decreased expression of GFAP and similar mechanisms have been proposed to explain the loss of GFAP expression in hyperammonemic syndromes, such as liver failure [13]. Loss of GFAP would be expected to result in increased visco-elastic properties of the cell, thus favoring cell swelling and alterations of microfilament proteins have been described in astrocytes of experimental animals following end-to-side portacaval anastomosis [14].

The MTI study of Córdoba et al. [7], showed a decrease in MTR, predominantly in white matter structures of the cerebral cortex. White matter lesions are common in chronic alcoholism. However, the observation of white matter changes in non-alcoholic cirrhotics is a novel finding, which opens the question as to the identity of the cells which undergo swelling due to water accumulation in these brains: astrocytes or oligodendrocytes (or both). In relation to this issue, it is noteworthy that neurofibrillary accumulations have previously been described in oligodendroglial processes in the brains of portacaval-shunted rats [15]. This issue deserves further study.

Finally, the findings consistent with low-grade cerebral edema in brain in cirrhosis open up the possibility that cell swelling may be implicated in the pathogenesis of HE. In favor of this possibility, in the study by Córdoba et al. [7], MTR changes were significantly correlated with neuropsychiatric disturbances, both of which normalized following liver transplantation. These findings are interesting in view of a growing body of evidence to suggest that cell swelling in the central nervous system may result in alterations of cell–cell signaling and, in this way, contribute to an imbalance between excitation and inhibition. For example, swelling of perineuronal astrocytes and the subsequent narrowing of the synaptic cleft would be expected to result in a decrease in diffusion (and consequently, increased concentrations) of neuronally-released neurotransmitters [16]. Cell swelling also impacts on signal transduction cascades, where the increase in cell volume per se may act as a second messenger leading to the induction of genes (and the proteins for which they encode) that regulate metabolic and neurotransmitter-related pathways in the brain. Such mechanisms have been proposed to explain the alterations of neuronal excitability that are characteristic of HE [17]. The further elucidation of these pathways, together with a knowledge of the consequences of their activation, should help to unravel the neurochemical mechanisms responsible for HE in patients with chronic liver failure. Elucidation of these mechanisms could ultimately lead to more rational pharmacotherapies for the disorder. These studies will undoubtedly continue to rely on state-of-the-art neuroimaging techniques.

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PII: S0168-8278(01)00225-2

Journal of Hepatology
Volume 35, Issue 5 , Pages 661-662, November 2001

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