Brain Edema in Acute Liver Failure

Abstract

Brain edema and the associated increase in intracranial pressure are potentially lethal complications of acute liver failure (ALF). Astrocyte swelling (cytotoxic edema) represents a significant component of the brain edema in ALF , and elevated blood and brain ammonia levels have been strongly implicated in its formation. We earlier showed in cultured astrocytes that oxidative stress (OS) and the mitochondrial permeability transition (mPT) play major roles in the mechanism of ammonia-induced astrocyte swelling. Glutamine , a byproduct of ammonia metabolism, has also been shown to induce OS , the mPT , and astrocyte swelling. Such effects of glutamine were suggested to be mediated by its hydrolysis in mitochondria , potentially yielding high levels of ammonia in this organelle and leading to OS and the mPT. L-histidine, an inhibitor of mitochondrial glutamine transport, was recently shown to mitigate OS , mPT , and cell swelling in cultured astrocytes treated with ammonia. The present study examined whether L-histidine similarly abolishes OS , the mPT , and brain edema in a rat model of ALF. Treatment of rats with thioacetamide caused a significant degree of brain edema , which was associated with induction of OS and the mPT. These changes were completely abolished by L-histidine , supporting a key role of mitochondrial glutamine transport and hydrolysis in the mechanism of the brain edema associated with ALF. Acute liver failure (ALF) is a life-threatening condition accounting for approximately 80% mortality in these patients.1,2 Such high mortality is in part attributable to the development of severe brain edema, leading to increased intracranial pressure and brain herniation. Currently, there is no effective treatment for the brain edema in ALF other than an emergency liver transplantation. 2,3Of several factors implicated in the development of ALF, ammonia is generally considered an important one as its levels in blood and brain correlate well with the degree of encephalopathy and brain edema. 4 -7

Astroglial NMDA receptors inhibit expression of Kir4.1 channels in glutamate-overexposed astrocytes in vitro and in the brain of rats with acute liver failure

“…Our results, however, negated this hypothesis. In the TAA-induced HE, His, administered at a dose that inhibited ONS in the cerebral cortex by counteracting mitochondrial damage (Rama Rao et al, 2010) and decreased the loss of whole-brain and mitochondrial GSH (Ruszkiewicz et al, 2013), did not rescue Glu-induced inhibition of Kir4.1 mRNA expression (Fig. 5B).…”

“…A number of recent studies have highlighted the contribution of ONS to the astrocytic dysfunction associated with HE in vivo (Rama Rao et al, 2010;Ruszkiewicz et al, 2013). Similarly emphasized is the ability of ammonia and other pathogenic factors operating in HE to induce ONS in cultured astrocytes, with activation of astrocytic NMDA receptors being considered as a possible intermediate step (Kruczek et al, 2011;Lachmann et al, 2013;Reinehr et al, 2007;Schliess et al, 2002;Zieliń ska et al, 2003) (for recent review, see Häussinger and Görg, 2010).…”

“…As repeatedly described in previous reports, this model faithfully reproduces basic symptoms of acuteto-subacute HE, including glutamatergic dysfunction and brain oedema (Hilgier et al, 1996;Rama Rao et al, 2010). The animals were sacrificed with carbon dioxide 72 h after the 1st TAA administration.…”

“…In contrast, i.p. administration of histidine (His) (100 mg/ml, 3 administrations at 24 h intervals), which attenuates the oxidative stressrelated symptoms of HE associated with glutamine accumulation (Rama Rao et al, 2010) and with a loss of intramitochondrial glutathione (GSH) (Ruszkiewicz et al, 2013), was ineffective in ameliorating the HE-induced decrease of Kir4.1 transcription (71.2 ± 12.1%, n = 11, *P < 0.01, Fig. 5B).…”

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

“…Here, it has been demonstrated, in vitro, that glutamine induces an opening of the mitochondrial transition pore and oxidative stress ( Jayakumar et al, 2004 andZiemińska et al, 2000). This has been supported in vivo (ALF rats) since the inhibition of the mitochondrial transport of glutamine attenuated oxidative stress, blocked the mitochondrial transition pore and prevented brain edema ( Rama Rao et al, 2010). Albrecht and Norenberg have proposed that the mitochondrial toxic effect of glutamine is due to its increased hydrolysis by glutaminase, resulting in ammonia liberation.…”