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Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy
Javier Vaquero1, Chuhan Chung1, Andres T. Blei1,
Corresponding author
a-blei@northwestern.edu

Address for correspondence:
1 Section of Hepatology. Department of Medicine. Lakeside VAMC and Northwestern University Feinberg School of Medicine
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Influence of cerebral blood flow on ammonia delivery to the brain&#46; The right panel shows calculated absolute values of ammonia delivery for different values of cerebral blood flow and levels of plasma ammonia&#46; In the left panel&#44; it is shown the percentage increase of ammonia delivery relative to the normal ammonia delivery to the brain &#40;calculated for normal ammonia plasma levels of 40 microM and cerebral blood flow of 40 mL&#47;100 g&#47; min&#41;&#46; With increased ammonia levels&#44; an increase in cerebral blood flow leads to disproportionate increases of ammonia delivery to the brain&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="txt0135" class="elsevierStylePara elsevierViewall">Abbreviations&#58;</p><p id="txt0035" class="elsevierStylePara elsevierViewall">Hepatic encephalopathy &#40;HE&#41;</p><p id="txt0040" class="elsevierStylePara elsevierViewall">Acute liver failure &#40;ALF&#41;</p><p id="txt0045" class="elsevierStylePara elsevierViewall">Portacaval anastomosis &#40;PCA&#41;</p><p id="txt0050" class="elsevierStylePara elsevierViewall">Cerebral blood flow &#40;CBF&#41;</p><p id="txt0055" class="elsevierStylePara elsevierViewall">Glial fibrillary acidic protein &#40;GFAP&#41;&#46;</p><p id="p0005" class="elsevierStylePara elsevierViewall">Supported by a Merit Review from the VA Research Administration and the Stephen B&#46; Tips Memorial Fund at Northwestern Memorial Hospital&#46; Dr&#46; Vaquero is supported by Fondo de Investigaci&#243;n Sanitaria &#40;BEFI&#47;FIS&#41;&#44; Madrid&#44; Spain&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">Hepatic encephalopathy &#40;HE&#41; is a frequent clinical complication of patients with acute and chronic liver disease&#44; and is defined as the presence of potentially reversible cerebral dysfunction in the absence of other known causes of brain disease&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Brain edema is defined as the excessive accumulation of intracellular and&#47;or extracellular fluid in brain tissue&#44; and is a deadly complication of patients with acute liver failure &#40;ALF&#41; in deep HE&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The development of these complications is an important event in the patient with liver disease&#46; In cirrhosis&#44; a first episode of encephalopathy signals a decreased survival and raises the need to evaluate liver transplantation in the appropriate candidate&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In fulminant hepatic failure&#44; the grade of hepatic encephalopathy is a strong predictor of outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Brain edema and intracranial hypertension remain a leading cause of death in ALF&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> despite important advances in intensive medical care&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">This review highlights links between HE and brain edema&#44; as well as discuss current concepts of the pathogenesis and pathophysiology of both complications&#46; A clinical perspective is emphasized&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Brain edema and intracranial hypertension in ALF</span><p id="p0020" class="elsevierStylePara elsevierViewall">Brain edema and intracranial hypertension are more common in patients with a fulminant presentation of ALF<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a><a class="elsevierStyleCrossRef" href="#f0005"><span class="elsevierStyleItalic">&#40;Figure 1&#41;&#44;</span></a> while their frequency decrease in subacute cases&#46; Conceptually&#44; it is important to distinguish brain edema from intracranial hypertension&#46; Even though brain edema leads to intracranial hypertension&#44; the latter will have effects <span class="elsevierStyleItalic">per</span> se in the brain that may or may not coincide with those that cause brain edema&#46; For this reason&#44; the investigation of the pathogenesis of brain edema has been frequently hampered by the presence of various degrees of intracranial hypertension in different studies&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">General anatomical and physiological basis of intracranial hypertension</span><p id="p0025" class="elsevierStylePara elsevierViewall">The cranium is a space with a fixed&#44; non-distensible volume&#46; Three different compartments are traditionally considered&#44; with the brain parenchyma being the largest &#40;approximately 80-90&#37; of intracranial volume in normal subjects&#41;&#44; followed by intravascular &#40;approximately 10&#37;&#41; and cerebrospinal fluid &#40;approximately 3-5&#37;&#41; compartments&#46; Cells constitute most of the volume of brain parenchyma&#44; with the extracellular fluid accounting just for 10-20&#37; of that volume&#46; This distribution is important as small increases in cell volume will lead to large increases in the total volume of the brain&#46;</p><p id="p0030" class="elsevierStylePara elsevierViewall">Intracranial hypertension is the result of an increase in volume in one or more of the previous compartments&#44; without equivalent reduction of the others &#40;Monro-Kelly doctrine&#41;&#46; The capacity of the brain to compensate an increase in volume without a corresponding increase of intracranial pressure is called Compliance &#40;&#916;V&#47;&#916;P&#41;&#46; Brain compliance has several important qualities <a class="elsevierStyleCrossRef" href="#f0010"><span class="elsevierStyleItalic">&#40;see figure 2&#41;</span></a>&#46; First&#44; compliance is lower when the increase in volume is acute&#44; which can leave no time for compensating mechanisms to develop&#46; Second&#44; when the increase in volume is continuous&#44; compliance decreases progressively with time&#44; leading ultimately to increased intracranial pressure&#46; Third&#44; when compliance is low&#44; a small increase in volume&#44; for example of cerebral blood volume&#44; can lead to large increases of intracranial pressure&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0035" class="elsevierStylePara elsevierViewall">In ALF&#44; intracranial hypertension is usually the manifestation of an increase in water content of brain tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> An increase of cerebral blood flow &#40;CBF&#41; is also a feature seen in many patients and in experimental models of ALF or hyperammonemia&#44; and can contribute to the increase of intracranial pressure via an increase in cerebral blood volume&#46; Cerebral imaging has shown a reduction of cerebrospinal fluid in ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Neuropathology of brain edema in acute liver failure</span><p id="p0040" class="elsevierStylePara elsevierViewall">Astrocyte swelling is a common finding in neuropathological studies of brain autopsy material from patients with ALF<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and from animal models of brain edema due to ALF&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Swelling is more prominent in foot processes than in cell bodies&#44; and affects predominantly astrocytes located in gray matter&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In accordance with this observation&#44; the increase in brain water content detected by the gravimetric technique in different animal models of ALF was also selective of cortical gray matter&#44; and was absent from subcortical&#44; mesencephalic or pontine white matter or in the cerebellum&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> This consistent alteration of astrocytes is in contrast with the ultrastructural preservation of neurons of the same brains&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">Tight junctions that characterize endothelial cells of brain capillaries were intact in all ultrastructural studies&#44; excluding a gross disruption of the blood-brain barrier in ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> However&#44; a significant vacuolization and enlargement of endothelial cells&#44; basement membrane and extracellular space was evident in some studies&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> suggesting increased permeability and pinocytic vesicular transport across the bloodbrain barrier&#46; Several functional studies have shown increased permeability to inulin&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> sucrose&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> GABA and analogues&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Trypan blue<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> or horseradish peroxidase<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> in different animal models of ALF and even in the rat 24 hours after portacaval anastomosis &#40;PCA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In contrast&#44; no abnormalities in the ultrastructure or permeability of the bloodbrain barrier are found in other studies&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Differences in methodology&#44; animal species&#44; models used or time of sampling &#40;before&#47;after intracranial hypertension has developed&#41; may be some of the reasons for the discrepancies&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis of brain edema in ALF</span><p id="p0050" class="elsevierStylePara elsevierViewall">For many years&#44; several hypotheses have tried to independently explain the occurrence of brain swelling in ALF&#46; In the last decade&#44; however&#44; we have witnessed a progressive convergence of previously excluding theories to a more rational context&#44; based on solid research observations&#46; A critical role for ammonia is now evident&#46; First&#44; hyperammonemia alone appears <span class="elsevierStyleItalic">sufficient</span> as a cause of brain edema&#44; as brain edema is seen in hyperammonemic patients with genetic disorders of urea cycle enzymes who do not have other alterations of liver function&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Also&#44; exposure to ammonia results in brain edema <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and astrocyte swelling <span class="elsevierStyleItalic">in vitro</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Second&#44; ammonia appears <span class="elsevierStyleItalic">necessary&#44;</span> as there are no reports of brain edema in ALF with normal ammonia levels&#44; and increased concentrations of ammonia in blood and brain are consistent findings in experimental ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Furthermore&#44; Clemmesen and cols have recently shown that cerebral herniation only occurred in their study in those patients with ALF and deep encephalopathy that had plasma ammonia levels above 150 micromols&#47;L&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">An osmotic disturbance</span><p id="p0055" class="elsevierStylePara elsevierViewall">An osmotic disturbance of the astrocyte as a result of ammonia is an observation that finds most support in clinical and experimental data&#46; The main pathway for detoxification of ammonia is through formation of glutamine as the brain lacks a complete urea cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The formation of glutamine from glutamate is catalyzed by glutamine synthetase&#44; an enzyme located mainly in astrocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> with the consumption of 1 molecule of ATP&#46; Because glutamine is a compound with osmotic properties&#44; its accumulation within the astrocyte has been proposed as one of the mechanism leading to astrocyte swelling&#46;</p><p id="p0060" class="elsevierStylePara elsevierViewall">The presence of increased brain glutamine levels in animal models and patients with ALF or hyperammonemia has been confirmed in multiple studies&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> An increased brain efflux of glutamine has been observed in patients with ALF compared to cirrhotic and healthy controls&#44; which was higher in those who subsequently died of cerebral herniation&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The increase of brain glutamine seems to be an early event&#44; as evidenced by the 2-fold increase seen just 24 hours after performance of portacaval anastomosis in the rat&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Inhibition of glutamine formation results in amelioration of ammonia-induced swelling in the rat brain <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and in isolated astrocytes <span class="elsevierStyleItalic">in vitro</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">Accumulation of glutamine alone&#44; however&#44; does not provide a complete explanation for the development of brain edema&#46; Mild hypothermia<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and indomethacin administration&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> for example&#44; reduce brain swelling and intracranial hypertension in ammonia-infused PCA rats&#44; <span class="elsevierStyleItalic">despite</span> similar increases of glutamine in brain&#46; Other elements must be present to account for the development of brain swelling&#46; One possibility would be the involvement of other organic osmoles&#44; such as alanine&#46; Alanine&#44; which can be generated from transamination of glutamine&#44; is also increased in the rat brain of ALF models&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Notably&#44; whereas glutamine increases rapidly in the early stages of HE and remains elevated to the same extent at coma stages&#44; alanine continues to progressively rise in parallel with worsening encephalopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Other organic osmoles&#44; such as myo-inositol or taurine&#44; seem to be unchanged or slightly decreased in experimental models of ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">The role of the blood-brain barrier</span><p id="p0070" class="elsevierStylePara elsevierViewall">An alteration of the blood-brain barrier could explain a <span class="elsevierStyleItalic">vasogenic</span> theory for brain edema in ALF&#46; Notably&#44; functional abnormalities of the blood-brain barrier have been described in various experimental models&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However&#44; if an alteration of the blood-brain barrier permeability were the <span class="elsevierStyleItalic">initial</span> and <span class="elsevierStyleItalic">critical</span> event&#44; it could hardly explain the selective swelling of astrocytes and the alterations in aminoacids and organic osmoles described above&#46; Furthermore&#44; no beneficial effects of corticosteroid therapy&#44; a measure supposed to improve blood-brain barrier permeability&#44; were seen in patients with ALF and intracranial hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Alterations of blood-brain barrier permeability&#44; if present&#44; appear to play more a secondary and&#47;or facilitating role&#44; than being the central determinant of brain water accumulation in ALF&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Alterations of brain glutamate</span><p id="p0075" class="elsevierStylePara elsevierViewall">Glutamate is the main excitatory neurotransmitter of the brain&#44; participating in more than 80&#37; of synapses&#46; Total brain glutamate levels were found to be decreased in ALF<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and in hyperammonemia&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> However&#44; levels of extracellular brain glutamate are increased in patients<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> and experimental models<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> of ALF&#44; as measured via brain microdialysis &#40;a technique that allows monitoring of extracellular space composition&#41;&#46; The increase of extracellular glutamate probably results from the impairment of glutamate re-uptake by astrocytes&#44; given that decreased expression of astrocytic glutamate transporters as well as decreased astrocytic glutamate re-uptake have been shown in various experimental models&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> An increased release of glutamate is also possible&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">A role for glutamate in the pathogenesis of brain edema in ALF is suggested by 1&#41; glutamate induces astrocytes swelling when injected into the brain or in isolated preparations<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> 2&#41; brain extracellular glutamate correlates positively with severity of HE and brain water content in some ALF models&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> and 3&#41; administration of glutamate antagonists has been reported to increase survival<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> and to ameliorate brain edema<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> in rodents with acute ammonia intoxication&#46; Despite these observations&#44; the exact role of glutamate in the production of brain edema in ALF requires further investigation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Oxidative and nitrosative stress</span><p id="p0085" class="elsevierStylePara elsevierViewall">A potential role for oxidative and nitrosative stress in the pathogenesis of brain edema in ALF is being increasingly explored&#46; In the clinical setting&#44; treatment with the antioxidant N-acetylcysteine was associated with less frequent progression to coma and brain edema in patients with ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> These effects&#44; however&#44; were thought to arise from an improved brain microcirculation&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> In our lab&#44; treatment with N-acetylcysteine ameliorated ammonia- induced brain edema in PCA rats&#44; despite the lack of differences in CBF or haemodynamics compared to placebo- treated controls&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> Ammonia&#44; which has been reported to increase the formation of free radicals both <span class="elsevierStyleItalic">in vivo</span><a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> and <span class="elsevierStyleItalic">in vitro</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> could be one potential source for oxidative stress&#46; An ammonia-induced increase of hemeoxygenase-1 gene expression&#44; which is considered the best gene-marker of oxidative stress&#44; also supports this assumption&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> Regarding nitrosative stress&#44; increased expression and activity of neuronal nitric oxide synthase<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> and increased brain nitric oxide production<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> have been shown in experimental models of hyperammonemia&#46; Evidence for nitrosative stress arises also from cellular studies&#44; where exposure of isolated astrocytes to ammonia resulted in increased nitration of protein tyrosine residues&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> Astroglial protein tyrosine nitration was also found in brains from rats after acute ammonia intoxication or after portacaval anastomosis&#44; indicating the possible <span class="elsevierStyleItalic">in vivo</span> relevance of those findings&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">Even though of considerable interest&#44; further <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> work is needed in order to clarify the role of oxidative and nitrosative stress in the pathogenesis of brain edema in ALF&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Energy failure</span><p id="p0095" class="elsevierStylePara elsevierViewall">Malfunction of the Na&#43;&#44; K&#43;-ATPase pump by a substance not cleared by the failing liver&#44; which would lead to accumulation of intracellular sodium&#44; was initially suspected&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> This was not confirmed in subsequent studies&#46; Depletion of brain ATP could not be demonstrated with preserved concentrations of high energy phosphates &#40;phosphocreatine&#44; ATP&#41; in various experimental models of ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> Thus&#44; brain energy failure is considered to be an improbable pathogenic event&#44; at least prior to the development of intracranial hypertension&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Cerebral blood flow and the pathogenesis of brain edema and intracranial hypertension in ALF</span><p id="p0100" class="elsevierStylePara elsevierViewall">In patients with ALF&#44; a wide spectrum of values of CBF has been reported&#44; ranging from abnormally low to abnormally high levels&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a> Even though differences in methodology could explain some of the discrepancies&#44; intra- individual variations have been noted&#46; Thus&#44; the wide spectrum of CBF in ALF is more likely to reflect a real situation where CBF is subjected to the influence of multiple factors&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> such as disease severity&#44; systemic haemodynamics or extrahepatic complications&#46; Despite these variations&#44; it is now well accepted that cerebral oxidative metabolism is preserved in ALF&#44;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> with CBF usually higher than the metabolic needs of the brain &#40;the so-called luxury perfusion&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a></p><p id="p0105" class="elsevierStylePara elsevierViewall">In the following paragraphs&#44; we will examine how the normal coupling between CBF and brain metabolism is altered in ALF&#44; and how changes of CBF can influence the development of intracranial hypertension and brain edema in ALF&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Loss of CBF autoregulation in ALF</span><p id="p0110" class="elsevierStylePara elsevierViewall">In normal conditions&#44; CBF varies according to the metabolic requirements of the brain&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> increasing or decreasing in parallel with brain activity&#46; This autoregulation occurs independently of changes in mean arterial pressure or cardiac output&#44; whenever blood pressure varies within the limits of 60 to 160 mmHg&#46; Landmark studies by Larsen and cols have clearly shown that CBF autoregulation is lost in patients with ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> The loss of autoregulation can be explained by the presence of vasodilatation of cerebral arterioles&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> Maneuvers that induce vasoconstriction of cerebral vessels&#44; such as hyperventilation leading to hypocapnia&#44; can restore CBF autoregulation in ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> Restoration of autoregulation can also be achieved by moderate hypothermia<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a> and liver transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Influence of CBF on brain edema in ALF</span><p id="p0115" class="elsevierStylePara elsevierViewall">In patients with ALF&#44; cerebral hyperemia has been associated with deeper coma&#44; increased brain edema and higher mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a> Furthermore&#44; interventions that abrogate an increase in CBF&#44; such as hypothermia or indomethacin administration&#44; have been shown effective for controlling or delaying the development of brain edema and intracranial hypertension in humans<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> as well as in animal models of ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In the PCA rat with ammonia infusion&#44; we have shown a predictable and selective rise of CBF that occur prior to the development of brain edema&#44; in the setting of normal systemic haemodynamics&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> Three more observations in this model suggest an important role for a high CBF in the pathogenesis of brain edema&#58; 1&#41; there is a striking positive correlation between CBF and brain water content&#44; 2&#41; abrogation of the increase in CBF by indomethacin or hypothermia results in amelioration of brain edema&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> and 3&#41; the increase in CBF does not occur when brain edema is prevented via the inhibition of glutamine formation with methioninesulfoximine&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> Why CBF increases in this model has not been elucidated&#44; and even though a role of nitric oxide was initially suggested&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> subsequent studies did not confirm this contention&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">The mechanism by which CBF can influence brain edema deserves further attention&#46; The flux of water&#47;solutes across the blood-brain barrier is determined by the terms of the Starling equation&#44; as recently discussed&#58;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">Water flux &#61; L<span class="elsevierStyleInf">p</span> x A x &#91;&#916;P - &#931;&#963; &#40;i&#41; x &#916;&#960;<span class="elsevierStyleInf">i</span>&#93;</p><p id="p0130" class="elsevierStylePara elsevierViewall">where L<span class="elsevierStyleInf">p</span> is the filtration coefficient of the capillary membrane&#44; A is the capillary membrane area&#44; &#916;P is the hydrostatic pressure gradient between the lumen of the capillary and the interstitial tissue&#44; &#963; &#40;i&#41; is the reflection coefficient of substance i over the capillary membrane&#44; and &#916;&#960;<span class="elsevierStyleInf">i</span>&#44; is the osmotic pressure gradient created by the concentration gradient of substance i between blood and tissue&#46;</p><p id="p0135" class="elsevierStylePara elsevierViewall">Changes in CBF and cerebral autoregulation in ALF could favour water flux into the brain by affecting mainly several components of the Starling equation&#46; First&#44; a higher hydrostatic pressure gradient &#40;&#916;P&#41; is a normal result of an increase in CBF if no new capillaries are opened&#46; Also&#44; given that autoregulation is lost in ALF as a consequence of cerebral arteriolar vasodilatation&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> variations in systemic arterial pressure will greatly influence the hydrostatic pressure in the capillaries&#46; Second&#44; an increase in CBF would result in increased ammonia delivery to the brain&#46; This could worsen &#916;&#960;<span class="elsevierStyleInf">i</span> by inducing further accumulation of intracellular glutamine and increase of brain tissue osmolarity&#44; which would favour the flux of water into the brain&#46; Finally&#44; an increase in CBF could lead to a larger capillary membrane area &#40;A&#41; if new capillaries were opened &#40;capillary recruitment&#41;&#44; but the relevance of such mechanism in the brain is controversial&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a></p><p id="p0140" class="elsevierStylePara elsevierViewall">Subtle alterations in the permeability of blood-brain barrier&#44; that would affect L<span class="elsevierStyleInf">p</span> and &#963; &#40;i&#41;&#44; have been previously discussed&#46; The net consequence of an increase in blood flow is to raise ammonia delivery to the brain&#46; Indeed&#44; small increases in blood flow will greatly increase ammonia delivery to the brain in a hyperammonemic state <a class="elsevierStyleCrossRef" href="#f0015"><span class="elsevierStyleItalic">&#40;Figure 3&#41;</span></a>&#46;</p><elsevierMultimedia ident="f0015"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Clinical pathophysiology of the brain edema and intracranial hypertension</span><p id="p0145" class="elsevierStylePara elsevierViewall">All clinicians recognize that multiple factors can potentially influence the development of HE&#46; Thus&#44; it is not surprising that a wide array of factors can affect the expression of brain edema and intracranial hypertension in the clinical setting&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> We will examine several physiological variables&#44; applying concepts previously reviewed&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Infection</span><p id="p0150" class="elsevierStylePara elsevierViewall">Infection is a well-known precipitant of hepatic encephalopathy in chronic liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> In ALF&#44; more than 80&#37; of patients present evidence of infection&#44;<a class="elsevierStyleCrossRef" href="#bib0480">96</a> and increased levels of circulating cytokines are a consistent finding&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">97</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> A correlation between infection or the systemic inflammatory response syndrome &#40;SIRS&#41; and presence of severe HE has been reported in ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> Furthermore&#44; infection was an independent predictor of progression from mild to severe HE in a study of the US Acute Liver Failure Study Group&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> The mechanisms by which infection could precipitate or worsen HE are not well understood but are likely to be diverse&#44; with effects on the periphery &#40;deterioration of liver function&#44; alteration of haemodynamics&#41; and effects on the brain&#46; Receptors for some cytokines such as IL-1 have been described in brain capillaries&#44; suggesting that cytokines could exerts their effects in the brain even without crossing the blood-brain barrier&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Necrotic liver</span><p id="p0155" class="elsevierStylePara elsevierViewall">Improvement of brain edema and control of intracranial pressure after total hepatectomy has been reported in patients with ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> An increased release of cytokines from the necrotic liver suggests an inflammatory element in the intracranial hypertension of ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> However&#44; confounding factors were present in these studies&#44; such as the use of extracorporeal detoxification methods or mild hypothermia&#44; clouding the assessment of the effect of hepactectomy <span class="elsevierStyleItalic">per se</span>&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Temperature</span><p id="p0160" class="elsevierStylePara elsevierViewall">Temperature is a component of the systemic inflammatory response syndrome&#46; Whereas hypothermia has been shown to exert beneficial effects in decreasing brain edema and intracranial pressure in patients<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> and animal models&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> of ALF&#44; hyperthermia is a deleterious event&#46; Hyperthermia was shown to precede surges of intracranial pressure in patients with ALF&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> to increase cerebral blood flow in dogs&#44;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a> and to increase blood-brain barrier permeability in some animal models&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> Fever should be vigorously treated in patients with ALF&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Agitation</span><p id="p0165" class="elsevierStylePara elsevierViewall">Episodes of agitation often precede surges of intracranial pressure in patients with ALF&#44;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> making the prevention and treatment of agitation an important aspect in the management of these patients&#46; Agitation may reflect increase extra-cellular brain glutamate levels&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Propofol is the preferred approach to handle this situation&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Arterial pressure and cerebral blood flow</span><p id="p0170" class="elsevierStylePara elsevierViewall">Changes in arterial pressure will influence CBF and intracranial pressure in the patient with ALF that has a loss of cerebral autoregulation and poor brain compliance&#46; In this setting&#44; even small increases of arterial pressure may lead to increased cerebral blood volume and intracranial hypertension&#46; On the other hand&#44; a decrease of arterial pressure in the patient with intracranial hypertension could lead to brain hypoxia&#46; Thus&#44; monitoring of intracranial pressure and of jugular bulb oxygen saturation has been proposed to tailor the treatment with vasoactive drugs in ALF patients&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> Cerebral perfusion pressure &#40;mean arterial pressure minus intracranial pressure&#41; must be maintained above 40 mmHg to avoid tissue hypoxia&#46; Jugular bulb oxygen saturations lower than 55&#37; are indicative of cerebral ischemia&#44; while saturations greater than 85&#37; indicate decreased metabolic demands of the brain or&#44; more commonly&#44; cerebral hyperemia&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Glucose and lactate</span><p id="p0175" class="elsevierStylePara elsevierViewall">Even though cerebral energy metabolism seems to be preserved until the last stages of the disease&#44; brain metabolism of glucose is altered in ALF&#46; In a preliminary report&#44; hyperglycemia above 12 mM &#40;200 mg&#47;dL&#41; was shown to be associated with intracranial hypertension in patients with ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> Brain edema from other etiologies is known to worsen if hyperglycemia is present&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">111</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> However&#44; mild hyperglycemia was not associated with worsening of brain edema in the ischemic rat model of ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">113</span></a> Thus&#44; the consequences of hyperglycemia in ALF are still unclear&#46;</p><p id="p0180" class="elsevierStylePara elsevierViewall">Lactate is increased in the plasma of patients with ALF<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a> and was initially interpreted to be the result of tissue hypoxia&#46; Subsequent studies showed increased lactate production in the brain<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> and led the authors to postulate a pathological supply dependency of oxygen to the brain&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> Increased production of lactate by the brain has been further confirmed in various experimental models of ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> However&#44; cerebral oxidative metabolism is preserved in patients with ALF&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> Two recent reports provide important insight and cast doubt on the &#8220;hypoxic&#8221; mechanistic explanation&#46; First&#44; Tofteng and cols&#46; have shown an increase in extracellular lactate in patients with ALF and deep HE by means of brain microdialysis&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Notably&#44; increases in extracellular glucose and lactate preceded surges of intracranial pressure without a rise in extracellular glutamate&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> No change in lactate&#47;pyruvate ratio and no evidence of tissue hypoxia were detected in most subjects&#46; Based on these findings&#44; the authors proposed that lactate may be implicated in the cerebral vasodilatation and surges of intracranial pressure in ALF&#46; Second&#44; Zwingman and cols&#46; showed a selective increase of de novo synthesis of lactate from glucose in the brains of rats with acute ischemic liver failure&#44; by means of proton and carbon-13 NMR spectroscopy&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> In contrast to the levels of glutamine&#44; which increased in the precoma stage but did not subsequently rise&#44; the increase in lactate correlated with the severity of encephalopathy&#46; Based on these findings&#44; the authors suggested that alterations of cellular glucose-and energy metabolism rather than the intracellular &#40;astrocytic&#41; accumulation of glutamine were the major cause of HE and brain edema in that model&#46; Further studies to investigate the role of glucose and lactate in HE and brain edema are needed&#44; and could have important repercussions in the clinical management of these patients&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Water and electrolyte abnormalities</span><p id="p0185" class="elsevierStylePara elsevierViewall">Sodium concentration is the main factor determining plasma osmolarity under normal conditions&#46; Hyponatremia is common in cirrhosis and water&#47;electrolyte abnormalities are a common precipitant of HE&#46; The relatively high frequency of central pontyne myelinolysis in hyponatremic cirrhotic subjects after liver transplantation<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">116</span></a> is probably a reflection of the profound alteration of osmoregulation and osmo-compensation in the brain of these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a> Extreme care should be taken in the correction of hyponatremia before&#44; during and after liver transplantation&#46;</p><p id="p0190" class="elsevierStylePara elsevierViewall">The consequences of hyponatremia were studied in experimental models&#46; In the rat with portacaval anastomosis&#44; induction of chronic hyponatremia by 1-desamino-8-Darginine vasopresin treatment decreased the levels of brain organic osmolytes&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> Infusion of ammonia resulted in the expected rise of glutamine and a reduction of taurine and myo-inositol&#44; the main organic osmolytes in both normonatremic and hyponatremic rats&#46; Importantly&#44; infusion of ammonia resulted in a higher degree of brain edema in hyponatremic compared to normonatremic rats&#44; despite an attenuated rise of glutamine in the former&#46; These observations suggest that chronic hyponatremia makes the brain more vulnerable to an ammonia-induced osmotic disturbance with subsequent brain swelling&#46; In contrast&#44; increasing plasma osmolarity by infusion of hypertonic saline has been observed to reduce intracranial hypertension in ALF&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> its use is being evaluated in ongoing clinical trials&#46;</p><p id="p0195" class="elsevierStylePara elsevierViewall">Alterations of potassium could also influence HE by altering normal ammonia metabolism&#46; Hypokalemia increases renal ammoniagenesis and seems to result in both increased urinary excretion and venous secretion of ammonia as seen in humans with chronic potassium depletion&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">119</span></a> Serum potassium and urine flow significantly correlated with kidney ammonia production&#44; with serum potassium accounting for 61&#46;4&#37; of variations in ammonia production&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Ammonia metabolism</span><p id="p0200" class="elsevierStylePara elsevierViewall">A highly orchestrated interorgan metabolism and trafficking of ammonia and glutamine is present in physiological conditions&#46; Chronic and acute liver failure result in hyperammonemia and leads to an important disturbance of normal body nitrogen homeostasis &#40;for review see&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">120</span></a> Different clinical factors influence <span class="elsevierStyleItalic">per se</span> the plasma levels or the effects of ammonia in the brain in liver failure&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Muscle wasting</span><p id="p0205" class="elsevierStylePara elsevierViewall">Even though glutamine synthetase activity in skeletal muscle is low&#44; its relative increased mass compared to other organs that contain this enzyme makes the muscle one of the main glutamine synthesizing organs&#46; Due to the increased plasma ammonia levels in liver failure&#44; the muscle becomes an important ammonia detoxifying organ&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">121</span></a> Avoidance of muscle wasting in cirrhosis and stimulation of ammonia metabolism in the muscle are important potential therapeutic targets in chronic and acute liver failure&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Gastrointestinal bleeding</span><p id="p0210" class="elsevierStylePara elsevierViewall">Gastrointestinal bleeding is a known precipitant of HE&#46; Blood in the digestive tract has been shown to be a potent stimulus for the intestinal production of ammonia&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">122</span></a> In the rat with portacaval anastomosis&#44; simulated gastrointestinal bleeding led to increased levels of ammonia and glutamine in the brain and to worsening of hepatic encephalopathy&#44;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a> indicating a mechanistic association&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Acid-base abnormalities</span><p id="p0215" class="elsevierStylePara elsevierViewall">Ammonia can occur in blood as ammonium ion &#40;NH<span class="elsevierStyleInf">4</span><span class="elsevierStyleSup">&#43;</span>&#41; or as ammonia gas &#40;NH<span class="elsevierStyleInf">3</span>&#41;&#46; The ammonia gas form is lipophilic and diffuses easily across cell membranes&#44; whereas the ammonium ion is non-diffusible and crosses membranes only by carrier-mediated processes&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> At physiological pH&#44; most ammonia is in the ion form and only 1&#37; is present as ammonia gas&#46; Circumstances that alter blood pH could&#44; thus&#44; be pathogenically important&#46; Metabolic or respiratory alkalosis&#44; produced for example by diuretics or hyperventilation&#44; could increase the gaseous form of ammonia&#44; facilitating in this way its entry into the brain&#46; However&#44; the global effect of an altered pH in ammonia metabolism is difficult to evaluate&#44; because the consequences can be different in different organs&#46; Thus&#44; whereas alkalosis can favour ammonia detoxification by improving urea synthesis in the liver&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a> it may increase ammonia production in the kidney&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">126</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> Similarly&#44; whereas metabolic acidosis increases gut release of ammonia&#44; it increases ammonia uptake in the liver and the muscle&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Sedatives</span><p id="p0220" class="elsevierStylePara elsevierViewall">The role of sedatives as precipitants of HE is well recognized&#46; Recent reports implicate endogenous benzodiazepine- like compounds in the pathogenesis of HE and brain edema&#46; In isolated astrocytes&#44; different benzodiazepines induced protein tyrosine nitration<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">130</span></a> and free radical production<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">131</span></a> in a manner similar to that produced by ammonia<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> and exacerbated ammonia-induced astrocyte swelling&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">132</span></a> Sedation is difficult to avoid in the agitated patient with ALF&#44; but benzodiazepines should be avoided&#46;</p></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conclusion</span><p id="p0225" class="elsevierStylePara elsevierViewall">Hepatic encephalopathy of chronic liver disease and brain edema of acute liver failure have been considered two distinct and unrelated clinical entities for many years&#46; Even though their pathogenesis is still not fully resolved&#44; a new paradigm has progressively developed where both entities are different elements of a continuous spectrum&#46; Hepatic encephalopathy and brain edema seem to share common pathogenic roots&#44; with a key role of ammonia and a critical involvement of the astrocyte in both complications&#46; The study of one helps to understand the other&#58; whereas ALF facilitates the study of causal relationships in a firmer manner&#44; chronic liver failure gives the opportunity to study brain compensating mechanisms&#46; This integrated view provides also a better perspective to judge the pathophysiological relevance that other factors may have in the manifestation of the disease&#46;</p></span></span>"
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          "titulo" => "Brain edema and intracranial hypertension in ALF"
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        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Hepatic encephalopathy and brain edema are important complications in the course of a patient with acute liver failure&#46; Presumed unrelated for many years&#44; increasing evidence suggests that an increase in brain water is seen in all forms of hepatic encephalopathy&#46; Ammonia&#44; traditionally linked to the pathogenesis of hepatic encephalopathy&#44; plays an important role in the increase in brain water&#46; In acute liver failure&#44; an osmotic disturbance in the astrocyte&#44; in combination with an alteration of cerebral blood flow results in overt brain edema and intracranial hypertension&#46; In cirrhosis&#44; magnetic resonance techniques indicate the presence of a brain osmotic disturbance&#46; Several clinical factors modulate the development of brain swelling&#46;</p></span>"
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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Rapid development of brain edema in a patient with fulminant hepatic failure&#46; On the right&#44; the TC scanner made at admission was normal&#46; On the left&#44; the TC scanner performed 8 hours later shows evident signs of brain edema&#46;</p>"
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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Relation between increase of volume and intracranial pressure &#40;compliance&#41;&#46; Continuous increases of volume leads to progressively larger increases of intracranial pressure&#46; Even though the increase of volume is the same in A and B&#44; the lower brain compliance results in higher increases of pressure in B&#46; The curve will be steeper when the insult is acute&#44; due to a lesser capacity of compensation&#46;</p>"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Influence of cerebral blood flow on ammonia delivery to the brain&#46; The right panel shows calculated absolute values of ammonia delivery for different values of cerebral blood flow and levels of plasma ammonia&#46; In the left panel&#44; it is shown the percentage increase of ammonia delivery relative to the normal ammonia delivery to the brain &#40;calculated for normal ammonia plasma levels of 40 microM and cerebral blood flow of 40 mL&#47;100 g&#47; min&#41;&#46; With increased ammonia levels&#44; an increase in cerebral blood flow leads to disproportionate increases of ammonia delivery to the brain&#46;</p>"
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                      "titulo" => "Hepatic encephalopathy&#8212;definition&#44; nomenclature&#44; diagnosis&#44; and quantification&#58; final report of the working party at the 11th World Congresses of Gastroenterology&#44; Vienna&#44; 1998"
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                      "doi" => "10.1053/jhep.2002.31250"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
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ISSN: 16652681
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos