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New Insights About Albumin and Liver Disease
Joana R. Carvalho, Mariana Verdelho Machado
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mverdelhomachado@gmail.com

Correspondence and reprint request:
Department of Gastroenterology and Hepatology, Hospital Santa Maria, Lisbon, Portugal
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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Albumin structure&#46; Albumin has a single polypeptide sequence formed by 585 amino acids&#46; At position 34&#44; the cysteine residue is free and available for reaction with other molecules&#46; The protein has a heart-like shape&#44; possessing three homologous domains I-III&#44; each domain is divided into A and B subdomains&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Liver cirrhosis is the 14th most common cause of death&#44; being responsible for over a million deaths per year worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Survival significantly decreases when the disease progresses to a decompensated phase&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In fact&#44; survival of patients with decompensated cirrhosis is 2 to 4 years&#44; which is worse than survival associated with many oncologic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Ascites is the most frequent decompensation&#44; and once it develops&#44; about one half of the patients will be dead in 5 years&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The development of renal failure associates with further increase in mortality&#44; with more than 60&#37; of the patients being dead in one year&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">Advanced cirrhosis is associated with a decrease in plasmatic albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Patients with cirrhosis have impaired hepatocellular function and reduced albumin synthesis&#44; which can reach a 60-80&#37; reduction in advanced cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Protein levels further decrease due to the dilution effect from water and salt retention&#44; and to the sequestration of circulating albumin in extracellular space and ascitic fluid&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Importantly&#44; albumin is a major prognostic factor&#44; being a significant predictor of death in over a hundred studies in patients with cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Albumin is a component of the most important and widely used prognostic score in cirrhosis&#44; the Child-Pugh-Turcotte score&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">Recently&#44; a new concept of <span class="elsevierStyleItalic">effective albumin concentration</span> indicates that not only serum albumin decreases in liver cirrhosis&#44; but the quality of albumin also changes&#46; In fact&#44; in patients with liver cirrhosis&#44; albumin undergoes several reversible and irreversible posttranscriptional changes &#40;for example oxidation&#41; that change its properties&#46;<a class="elsevierStyleCrossRefs" href="#bib0055">11</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">Treatment with albumin has been widely used in liver cirrhosis due to its oncotic properties&#44; in order to expand plasma volume and to increase effective circulatory volume&#44; and hence to abrogate the cardiocirculatory changes associated with portal hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> However&#44; recently&#44; other potentially beneficial albumin functions have been reported&#44; such as its binding capacity&#44; anti-oxidant and anti-inflammatory properties&#44; modulation of hemostasis&#44; vasodilatation and acid base homeostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0075">15</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> There are three approved indications for the administration of human albumin solutions in cirrhosis&#58;<ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">&#8226;</span><p id="p0025" class="elsevierStylePara elsevierViewall">After large volume paracentesis to prevent paracentesis-induced circulatory dysfunction &#40;PICD&#41;&#59;</p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0030" class="elsevierStylePara elsevierViewall">Spontaneous bacterial peritonitis &#40;SBP&#41;&#59; and</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0035" class="elsevierStylePara elsevierViewall">Hepatorenal syndrome &#40;HRS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></li></ul></p><p id="p0040" class="elsevierStylePara elsevierViewall">Other proposed indications for albumin use in cirrhosis are still controversial&#44; such as&#58; bacterial infections other than SBP&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> hepatic encephalopathy<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and chronic ascites&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">In this article&#44; we aimed at reviewing the most relevant information and new insights about albumin and liver cirrhosis in a critical point of view&#44; highlighting consensual and controversial available data&#46;</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Structure and Function of Albumin</span><p id="p0050" class="elsevierStylePara elsevierViewall">Albumin is a 66&#46;5 kDa negatively charged protein with high solubility and stability&#44; encoded on chromosome 4&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> It has a single polypeptide sequence formed by 585 amino acids&#44; a relative abundance of charged amino acids lysine&#44; arginine&#44; glutamine and aspartic acid&#44; as well as&#44; one tryptophan and 35 cysteine residues&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Thirty-four of those 35 cysteine residues form 17 disulfide bridges that will determine the albumin structure&#44; leaving the cysteine-34 residue free and available for reaction with other molecules&#46; The secondary structure consists of 55&#37; a-helix and 45&#37; &#946;-structure&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> At the tertiary structure&#44; the protein has a heart-like shape&#44; possessing three homologous domains I-III<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure <span class="elsevierStyleSup">1</span></a>&#41;&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0055" class="elsevierStylePara elsevierViewall">Albumin is the most abundant protein in plasma&#44; with a concentration of 30&#8211;50 g&#47;L&#44; which corresponds to 50&#37; of all plasmatic proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Despite albumin&#8217;s plasmatic abundance&#44; the majority of albumin is not in circulation&#44; as 60&#37; is stored in the interstitial space&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> In fact&#44; although the half-life of albumin is about 17 days&#44; albumin only lasts 16&#8211;18 h in circulation&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The transcapillary escape of albumin can be reverted&#44; as albumin can eventually return into the plasma component via lymphatic return to maintain steady plasma concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">Albumin is predominantly synthesized in the liver&#44; although albumin mRNA was detected in extra-hepatic localizations&#44; such as pancreas&#44; kidney and brain&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Nahon&#44; <span class="elsevierStyleItalic">et al&#46;</span> found mature albumin mRNA in kidney&#44; pancreas&#44; heart and lung of newborn rats and in kidney and pancreas of adult rats&#46; Furthermore the authors described a cell population in the rat kidney that was found to actively transcribe albumin gene&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Moreover&#44; albumin protein and mRNA were found in mouse retina&#44; suggesting that albumin is also synthesized in the eye&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">Hepatic albumin synthesis rate is 150 mg&#47;kg&#47;day&#44; corresponding to 10&#8211;15 g per day&#44; and 10&#37; of hepatic protein synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Hepatic albumin synthesis can increase up to 4 times in response to hypoalbuminemia&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> and stimulation by insulin&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> glucocorticoids&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> or growth hormone&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Conversely&#44; chronic &#40;but not acute&#41; acidosis<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and proinflammatory cytokines such as tumor necrosis factor &#40;TNF&#41;-a&#44; interleukin &#40;IL&#41;-6 and -1&#946; inhibit albumin synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Degradation of albumin can occur in any tissue&#44; but the majority occurs in the liver&#44; kidney and muscle&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Plasma albumin concentration is the result of the balance between albumin synthesis&#44; exchange between intravascular and interstitial compartments&#44; albumin degradation by catabolism&#44; and renal or intestinal loss&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">Serum albumin concentration has prognostic significance&#46; In the general population&#44; lower levels of albumin are associated with increased overall mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0205">41</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> The reverse is also true&#44; as in the normal albumin range&#44; albumin levels higher than 43 g&#47;L are associated with a 20&#37;&#8211;40&#37; decreased risk for all-cause mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Albumin contributes to 75&#37; of the plasmatic oncotic pressure&#44; which is disproportionally high since albumin only accounts for 50&#37; of plasma proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> That can be explained by albumin&#8217;s low molecular weight&#44; which results in high osmotic activity per gram&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Additionally&#44; the osmotic activity of albumin increases by its negative charge&#44; which holds osmotically active sodium cations &#40;Gibbs-Donnan effect&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">Albumin has other important functions namely its binding capacity&#44; anti-oxidant and anti-inflammatory properties&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> It has three essential functional domains&#58;<ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0085" class="elsevierStylePara elsevierViewall">A metal binding domain&#46;</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0090" class="elsevierStylePara elsevierViewall">Domains that bind to other substances&#44; and</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0095" class="elsevierStylePara elsevierViewall">A domain that confers stability&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></li></ul></p><p id="p0100" class="elsevierStylePara elsevierViewall">Albumin can bind to a variety of substances such as drugs&#44; long-chain fatty acids&#44; bilirubin&#44; bile acids&#44; endotoxin&#44; hormones&#44; and eicosanoids&#44; modulating their biologic activity&#44; distribution and clearance&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Moreover&#44; albumin has anti-oxidant properties as it binds to highly toxic reactive metal species&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> and its thiol groups from cysteine-34 residue act as potent scavengers of reactive oxygen species&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Albumin also has anti-inflammatory properties&#44; as it inhibits inflammatory mediators&#44; such as TNF-&#945; and C5a&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Albumin can inhibit inflammation through several mechanisms&#46; It inhibits TNF-&#945; expression directly through transcription down-regulation<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> and indirectly by preserving cellular glutathione and thus protecting cells against oxidant-mediated injury&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> which is a trigger for inflammatory responses&#46; TNF-&#945; down-regulation by albumin inhibits the activation of pro-inflammatory nuclear factor-kappa B &#40;NF-&#954;&#914;&#41; pathway<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> and recruitment of leukocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> further limiting inflammation &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure <span class="elsevierStyleSup">2</span></a>&#41;&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0105" class="elsevierStylePara elsevierViewall">Moreover&#44; albumin interferes with hemostasis inhibiting platelet aggregation and promoting vasodilation&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> for example through NO-albumin complexes&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> It may also play a role in acid-base homeostasis&#58; on one hand&#44; it behaves as a weak acid and&#44; on the other hand&#44; it can buffer non-volatile acids&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Lastly&#44; studies in animal models of liver cirrhosis&#44; also found that albumin exerts a positive cardiac inotropic effect counteracting the oxidative stress and TNF-&#945; effect in NF&#954;B-&#237;NOS pathway and b-receptor signalling&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Forms of Albumin in Liver Cirrhosis</span><p id="p0110" class="elsevierStylePara elsevierViewall">Albumin can undergo several posttranslational modifications &#40;PTM&#41; under physiological or pathological conditions&#44; such as oxidation&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> glycosylation&#44;<a class="elsevierStyleCrossRefs" href="#bib0290">58</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> truncation at the C- or N-terminus&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> dimerization<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> and carboxylation&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> These PTM result in important structural and functional heterogeneity of circulating albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">Oxidation of cysteine-34 residue is the most frequent PTM in albumin&#44; and is a result of oxidative-stress induced protein damage&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> In healthy subjects&#44; 70&#8211;80&#37; of albumin circulates in its reduced form&#44; dubbed mercaptoalbumin &#40;HMA&#41;&#44; which has a free sulfidril group at cysteine-34&#46;<a class="elsevierStyleCrossRefs" href="#bib0055">11</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Up to 25&#37; of circulating albumin suffers reversible oxidative modifications through reversible binding via mixed disulfide bridges between cysteine-34 and compounds containing sulfidril groups such as cysteine&#44; homocysteine and glutathione&#46; This reversible oxidized form of albumin is dubbed non-mercaptoalbumin type 1 &#40;HNA-1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> Finally&#44; up to 5&#37; of circulating albumin suffers complete and irreversible oxidation of cysteine-34 in sulfonic or sulfinic acid&#44; dubbed non-mercaptoalbumin type 2 &#40;HNA-2&#41;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure <span class="elsevierStyleSup">3</span></a>&#41;&#46; These oxidized forms of albumin show compromised anti-oxidant properties&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Oxidized albumin differs from native albumin pharmacokinetically and structurally&#44; negatively impacting its function&#46; Circulating life of oxidized albumin is lower than native albumin as a result of an increased plasma clearance by the liver and spleen&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Ligand-binding properties to endogeneous and exogenous ligands and anti-oxidant properties of oxidized albumin are compromised relative to reduced albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Furthermore&#44; oxidized albumin may itself have a noxious effect and exacerbate rather than ameliorate oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> In fact&#44; Luna&#44; <span class="elsevierStyleItalic">et al&#46;</span> showed that with aging&#44; oxidized albumin associates with endothelial damage through oxidative stress and increased apoptosis&#44; suggesting that oxidized albumin may be a cardiovascular risk factor&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a></p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0120" class="elsevierStylePara elsevierViewall">Mercaptoalbumin has a free sulfidril group at cysteine-34&#46; Non-mercaptoalbomin-1 results from reversible oxidative modifications through reversible binding via mixed disulfide bridges between cysteine-34 and compounds containing sulfidril groups such as cysteine &#40;Cys&#41;&#44; homocysteine &#40;HCY&#41; and glutathione &#40;GSH&#41;&#46; Non-mercaptoalbumin-2 is a result of complete and irreversible oxidation of cysteine-34 in sulfonic or sulfinic acid&#46;</p><p id="p0125" class="elsevierStylePara elsevierViewall">Liver cirrhosis&#44; particularly when decompensated&#44; associates with systemic inflammation and disturbed redox state&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> and hence associates with an increase in oxidized albumin forms HNA-1 and -2&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> Different groups found up to 50&#37; increase in the proportion of HNA-1 and 200&#37; of HNA-2 in patients with liver cirrhosis as compared with control healthy subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> An increase in the percentage of oxidized albumin associated with severity of liver cirrhosis &#40;as assessed by Child-Pugh-Turcotte class and MELD&#41; and clinical decompensation such as development of ascites&#44; HRS and bacterial infection&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> Finally&#44; oxidized albumin correlated with short and long-term mortality in patients with liver cirrhosis&#44; outperforming conventional prognostic tools such as MELD&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> Oettl&#44; <span class="elsevierStyleItalic">et al&#46;</span> found an optimal cut off of 12&#37; HNA-2 proportion for predicting 1-month and long-term mortality in patients admitted for decompensated cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> More pronounced changes in oxidized albumin were also found in acute on chronic liver failure &#40;ACLF&#41; and alcoholic hepatitis&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> conditions with dismal prognosis&#46;</p><p id="p0130" class="elsevierStylePara elsevierViewall">Other frequent PTM on albumin is ischemia-modified albumin &#40;IMA&#41; that consists in the functional alteration of the N-terminal portion of albumin molecule&#44; resulting in a reduced capacity to bind cobalt&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> It occurs as a result of oxidative stress-induced N-terminal biochemical degradation&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> IMA and IMA&#47;albumin ratio &#40;IMAr&#41; are increased in patients with cirrhosis&#44; particularly in association with bacterial infection and in patients who progress to ACLF&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a>&#44; <a class="elsevierStyleCrossRefs" href="#bib0410">82</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Corroborating the role of bacterial infection in the development of IMA&#44; animal models of liver cirrhosis show increased IMA levels after injection of lipopolysaccharide&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a> Importantly&#44; IMA and IMAr strongly correlate with prognostic tools such as MELD&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> In fact&#44; in patients with cirrhosis&#44; IMAr higher than 0&#46;02 strongly associates with mortality&#44; which places IMAr as a potential prognostic marker in advanced liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> Of notice&#44; neither albumin therapy nor molecular adsorbent recirculating system &#40;MARS&#41; has an effect on IMA&#47;IMAr&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a><a class="elsevierStyleCrossRef" href="#t0005">Table <span class="elsevierStyleSup">1</span></a> summarizes the available evidence of IMAr in liver disease&#46;</p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0135" class="elsevierStylePara elsevierViewall">Albumin dimerization is also increased in patients with cirrhosis&#44; particularly in patients with severe ACLF&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> Dimerization occurs at cysteine-34 and can be found with the native or truncated forms of albumin&#44; as homo or heterodimers&#46; Homodimeric N-terminal truncated albumin form proportion can independently stratify 1-year mortality in patients with ACLF&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a></p><p id="p0140" class="elsevierStylePara elsevierViewall">Many other different PTM in albumin were found increased in patients with liver cirrhosis&#44; such as cysteinylated&#44; glycated and truncated forms&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> As a consequence&#44; native&#44; non-modified albumin&#44; is significantly reduced in patients with cirrhosis&#44; particularly during clinical decompensation&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The absolute reduction of native albumin or the reduction in the proportion of native to total albumin were able to predict mortality in patients with liver cirrhosis&#44; outperforming total albumin concentration as a prognostic marker&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> Because modified albumin forms consistently present compromised function&#44; it is clinically more relevant to estimate the concentration of fully functional native albumin concentration than total albumin concentration&#44; and hence it has emerged the new concept of effective albumin concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a><a class="elsevierStyleCrossRef" href="#t0010">Table <span class="elsevierStyleSup">2</span></a> summarizes the modified forms of albumin in liver disease&#46;</p><elsevierMultimedia ident="t0010"></elsevierMultimedia></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Indications for Treatment with Albumin in Liver Cirrhosis</span><p id="p0145" class="elsevierStylePara elsevierViewall">Patients with cirrhosis present with absolute hypoalbuminemia&#44; which has been mainly attributed to a decreased synthetic capacity&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> but it is believed to be multifactorial&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a> In liver dysfunction&#44; albumin synthesis is decreased as a result of liver dysfunction and abnormal portal blood flow distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The decrease in effective intravascular blood volume frequently seen in cirrhosis&#44; leads to compensatory activation of the renin-angiotensin system and sympathetic nervous system&#44; and to increased release of antidiuretic hormone&#44; which culminates in sodium and water retention&#44; as well as&#44; in reduction of renal perfusion and glomerular filtration rate&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> This mechanism is responsible for the development of ascites and hepatorenal syndrome &#40;HRS&#41;&#46; Human albumin was first introduced in the management of cirrhotic patients with hypoalbuminemia and ascites in the 1950s&#44; due to its expanding volume capacities&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> However&#44; we now know that the beneficial effects of albumin surpass its oncotic properties&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0150" class="elsevierStylePara elsevierViewall">There are three approved indications for the administration of human albumin solution in patients with cirrhosis&#58;<ul class="elsevierStyleList" id="l0015"><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0155" class="elsevierStylePara elsevierViewall">After large volume paracentesis &#40;LVP&#41; to prevent paracentesis-induced circulatory dysfunction &#40;PICD&#41;&#46;</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">&#8226;</span><p id="p0160" class="elsevierStylePara elsevierViewall">Spontaneous bacterial peritonitis &#40;SBP&#41;&#46;</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">&#8226;</span><p id="p0165" class="elsevierStylePara elsevierViewall">HRS&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a></p></li></ul></p><p id="p0170" class="elsevierStylePara elsevierViewall">There are other controversial proposed indications for albumin expansion&#44; such as non-BSP infections&#44;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> ascites<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and encephalopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a></p><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Prevention of paracentesis-induced circulatory dysfunction</span><p id="p0175" class="elsevierStylePara elsevierViewall">After LVP&#44; intra-abdominal pressure abruptly drops&#44; which increases venous return to the right atrial pressure&#44; with consequent increase in cardiac output and stroke volume&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> However&#44; this transient increase in cardiac output induces an excessive drop in peripheral vascular resistance&#44; while increasing intrahepatic vascular resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a> As a consequence&#44; blood is sequestrated into the peripheral circulation resulting in a decrease in effective circulating volume and in arterial pressure&#46;<a class="elsevierStyleCrossRefs" href="#bib0500">100</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a> Interestingly&#44; this impairment in effective blood volume does not associate with an increase in transvascular escape of albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> A persistent reactivation of renin angiotensin aldosterone system &#40;RAAS&#41; occurs as a counteracting mechanism that can last for months&#44;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> which can result in recurrence of ascites&#44; hyponatremia&#44; HRS and decreased survival&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0520">104</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> Paracentesis-induced circulatory dysfunction &#40;PICD&#41; has been defined as at least 50&#37; increase in plasma renin activity up to level higher than 4 ng&#47;mL&#47;h at the 6th day after paracentesis&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> PICD occurs in one third of patients submitted to LVP and does not revert spontaneously&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a></p><p id="p0180" class="elsevierStylePara elsevierViewall">The first study showing a benefit of albumin administration in the prevention of PICD was performed&#44; more than 30 years ago&#44; by Gines&#44; <span class="elsevierStyleItalic">et al</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> Albumin infusion abrogated an increase in plasma renin activity after paracentesis&#44; and prevented hyponatremia and deterioration in renal failure&#46; The rational for the use of albumin is expansion of plasma volume avoiding a decrease in effective blood volume&#44; which occurs in the absence of an increase in albumin transvascular escape&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">102</span></a> One decade later&#44; the same group showed that this strategy of albumin infusion would only be beneficial when more than 5 liters of ascites are removed &#40;decreasing by 50&#37; the risk of PICD&#41;&#44; since for lower volume paracentesis the risk of PICD is similar to the spontaneous deterioration in untreated cirrhotics with ascites&#44; i&#46;e&#46; about 10&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> Since then&#44; several studies and different meta-analysis compared the efficacy of albumin <span class="elsevierStyleItalic">vs&#46;</span> other volume expanders such as dextran&#44; gelatin&#44; hydroxyethyl starch and hypertonic saline&#46; In 2012&#44; a meta-analysis of 17 trials comprising 1&#44;225 patients&#44; showed that albumin was superior to the other strategies&#44; decreasing in 57&#37; to 75&#37; the risk for PICD&#44; in 42&#37; the risk for hyponatremia and in 36&#37; the risk for mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a> Subsequent meta-analysis confirmed the superiority of albumin in reducing PICD and hyponatremia&#44; while showing insufficient evidence for mortality prevention&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">108</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">109</span></a> However&#44; the strength of most recent meta-analysis has been questioned since they included different albumin protocols as well as studies comparing albumin with no treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a></p><p id="p0185" class="elsevierStylePara elsevierViewall">According to AASLD and EASL guidelines&#44; LVP is the first-line therapy in patients with large ascites &#40;grade 3 ascites&#41; and should be performed together with the administration of albumin to prevent PICD&#44; when more than 5 liters of ascites are removed&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> The recommended dose of albumin is 8 g&#47;L of ascitic fluid removed&#44; which was the most frequently used dose in clinical trials&#46; Two small studies compared the standard albumin dose with half the dose &#40;4 g&#47;L of ascitic fluid removed&#41; and found no difference in adverse outcomes&#58; prevalence of PICD&#44; hyponatremia&#44; renal impairment&#44; ascites recurrence or 6 months survival&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">111</span></a> For the time being&#44; however&#44; this dose cannot be recommended because these findings have not yet been replicated&#46;</p><p id="p0190" class="elsevierStylePara elsevierViewall">A different strategy studied to prevent PICD is the administration of vasoconstrictors&#44; since the decrease in effective blood volume is a direct consequence of excessive peripheral vasodilation&#46; The level of evidence is still low&#44; however while midrodine seems less effective than albumin&#44;<a class="elsevierStyleCrossRefs" href="#bib0560">112</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> small studies did not demonstrate differences between noradrenaline<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">116</span></a> or terlipressin<a class="elsevierStyleCrossRefs" href="#bib0580">116</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> as compared with albumin infusions&#46;</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Treatment of bacterial spontaneous peritonitis</span><p id="p0195" class="elsevierStylePara elsevierViewall">About one third of patients with SBP develop renal dysfunction<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">119</span></a> due to a rapidly progressive impairment in systemic hemodynamics as a consequence of activation of vasodilation systems by proinflammatory cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">120</span></a> These patients present worse outcomes including decreased survival&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">101</span></a></p><p id="p0200" class="elsevierStylePara elsevierViewall">The first randomized study assessing the effect of albumin administration in renal function and mortality&#44; in patients with SBP&#44; was performed in 1999&#46; This study included 126 patients&#44; which were treated either with antibiotics alone or in association with human albumin solution at a dose of 1&#46;5 g&#47;kg of body weight at the time of diagnosis&#44; followed by 1 g&#47;kg of body weight on the third day&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">121</span></a> In the group not treated with albumin&#44; 33&#37; of the patients developed renal impairment as compared with only 10&#37; in the albumin group&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">121</span></a> Furthermore&#44; albumin administration associated with a 50&#37; decrease in 3 months mortality &#40;41&#37; <span class="elsevierStyleItalic">vs&#46;</span> 21&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">121</span></a> Other studies replicated these results&#46; In fact&#44; a meta-analysis of 4 studies including 288 patients&#44; showed 80&#37; reduction in the risk of renal impairment &#40;30&#46;6&#37; <span class="elsevierStyleItalic">vs&#46;</span> 8&#46;3&#37;&#41; and 66&#37; reduction in the risk of mortality &#40;35&#37; <span class="elsevierStyleItalic">vs&#46;</span> 16&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">122</span></a></p><p id="p0205" class="elsevierStylePara elsevierViewall">More recent studies tried to select a high-risk population of patients with SBP in order to limit albumin administration&#46; Sigal&#44; <span class="elsevierStyleItalic">et al</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a> studied 38 episodes of SBP and defined high-risk patients the ones who presented plasma bilirubin &#62; 68&#46;4 <span class="elsevierStyleItalic">&#181;</span>mol&#47;l &#40;4 mg&#47;dL&#41;&#44; creatinine &#62; 88&#46;4 <span class="elsevierStyleItalic">&#181;</span>mol&#47;l &#40;1 mg&#47;dL&#41; or blood urea nitrogen &#62; 30 mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a> Low-risk patients were not treated with albumin&#44; and none developed renal failure nor died&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">123</span></a> Another study analyzed 216 episodes of SBP during a 7-year period and did not treat with albumin low-risk patients&#44; while in the high risk patients albumin was given at the discretion of the attending physician&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> Low-risk patients presented much lower risk of renal failure &#40;4&#46;7&#37; <span class="elsevierStyleItalic">vs&#46;</span> 18&#46;6&#37;&#41; or inhospital mortality &#40;3&#46;1&#37; <span class="elsevierStyleItalic">vs&#46;</span> 28&#46;8&#37;&#41; as compared with high-risk patients treated with albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a></p><p id="p0210" class="elsevierStylePara elsevierViewall">Since the recommended dose comes from arbitrary doses used in the first study performed in 1999&#44;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">121</span></a> a more recent pilot study included 46 patients with SBP and compared the standard albumin dose with a reduced protocol of 1 g&#47;kg at admission and 0&#46;5 g&#47;kg of albumin on the third day&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a> No significant differences were found between albumin doses in respect to development of renal failure and HRS&#44; in-hospital mortality and mortality up to 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a></p><p id="p0215" class="elsevierStylePara elsevierViewall">A small study in high-risk patients with SBP compared 4 different strategies&#58; administration of albumin&#44; terlipressin&#44; terlipressin plus albumin or midrodine&#46; Though they did not find different outcomes in the albumin or terlipressin groups&#44; patients treated with midrodine developed higher circulatory dysfunction&#44; higher incidence of renal failure and a non-significant trend towards higher mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">126</span></a></p><p id="p0220" class="elsevierStylePara elsevierViewall">Until further development&#44; evidenced-based current guidelines recommend that patients with ascitic fluid polymorphonuclear leukocyte counts &#62; 250 cells&#47;mm<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and clinical suspicion of SBP who also have a serum creatinine &#62; 1 mg&#47;dL&#44; blood urea nitrogen &#62; 30 mg&#47;dL&#44; or total bilirubin &#62; 4mg&#47;dL should receive 1&#46;5 g albumin per kg body weight within 6 h of detection and 1&#46;0 g&#47;kg on the third day&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a></p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Prevention of hepatorenal syndrome</span><p id="p0225" class="elsevierStylePara elsevierViewall">In patients with advanced cirrhosis and portal hypertension there is a reduction in the effective arterial blood volume as a result of splanchnic arterial vasodilation and cardiac dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> RAAS is activated&#44; as a compensatory response&#44; and&#44; over time&#44; severe intrarenal vasoconstriction&#44; renal hypoperfusion and&#44; ultimately&#44; renal failure can develop&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> HRS is defined as a functional renal failure&#44; unresponsive to plasma volume expansion that occurs in patients with end-stage liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> There are two types of HRS&#58; type 1&#44; a rapid deterioration of renal function&#44; defined as an increase in serum creatinine to a value twice the baseline and &#62; 2&#46;5 mg&#47;dL within 2 weeks&#59; type 2&#44; a slow and gradual deterioration of renal function with serum creatinine above 1&#46;5 mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> Current guidelines recommend the administration of both vasoconstrictors and human albumin in the treatment of HSR&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a></p><p id="p0230" class="elsevierStylePara elsevierViewall">The evidence for the use of albumin comes from a small study that included 21 patients with HRS &#40;16 with type 1 HRS&#44; 5 with type 2 HRS&#41; that compared treatment with terlipressin alone versus terlipressin with albumin&#44; until complete response was achieved &#40;defined as serum creatinine level &#60; 1&#46;5 mg&#47;dL&#41; or for 15 days&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a> Albumin administration was the only predictive factor of complete response&#46; In fact&#44; treatment with albumin was associated with a 3-fold increase in complete response &#40;77&#37; in patients receiving terlipressin and albumin <span class="elsevierStyleItalic">vs&#46;</span> 25&#37; in those receiving terlipressin alone&#44; p &#61; 0&#46;03&#41;&#46; Importantly&#44; complete response was associated with improved survival&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a></p><p id="p0235" class="elsevierStylePara elsevierViewall">The efficacy of this combined therapy results from the vasoconstriction effect induced by terlipressin on the splanchnic vascular district and the expansion caused by albumin&#44; which together improves effective hypovolemia and ultimately restores renal perfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a>&#44;<a class="elsevierStyleCrossRefs" href="#bib0645">129</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">131</span></a></p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Controversial indications for albumin therapy in cirrhosis</span><p id="p0240" class="elsevierStylePara elsevierViewall">The beneficial effect of human albumin was also assessed in patients with cirrhosis and bacterial infections other than SBP&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In fact&#44; non-SBP infections also associate with an increased risk for renal failure&#44; which occurs in more than one third of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">132</span></a> However&#44; the risk seems to be particularly significant in sub-diaphragmatic infections&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">133</span></a> Guevara&#44; <span class="elsevierStyleItalic">et at</span>&#46; evaluated 110 patients with cirrhosis and non SBP infections &#40;such as respiratory&#44; urinary and skin infections&#41; and found a trend to lower frequency of type 1 HRS in patients treated with antibiotics and albumin compared to those treated only with antibiotics&#44; after 14 days&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a> Importantly&#44; although no differences between the two groups were found on 3 months survival&#44; when adjusted for factors with independent prognostic value&#44; treatment with albumin was an independent predictive factor for survival&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a> A more recent clinical trial on 193 Child-Pugh-Turcotte B or C cirrhotic patients with non-SBP infection found albumin treatment to delay&#44; rather than to prevent&#44; renal failure&#46; No effect of albumin was seen on 3-months mortality&#44; and 8&#37; of patients developed pulmonary edema after albumin infusion&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a> Therefore&#44; until more robust evidence is provided&#44; there is not enough evidence to support albumin administration in non-SBP infections&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a></p><p id="p0245" class="elsevierStylePara elsevierViewall">Albumin was also proposed for the treatment of hepatic encephalopathy&#46; A study that included 56 patients with cirrhosis and hepatic encephalopathy&#44; compared 2 strategies to expand plasma volume&#58; albumin infusion &#40;N &#61; 26&#41; or expansion with a crystalloid &#40;N &#61; 30&#41;&#46; Both strategies associated with similar resolution of hepatic encephalopathy&#44; however&#44; there was significant improvement on 3-months survival in the albumin-treated group&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> A recent study on 120 patients with hepatic encephalopathy treated with either lactulose alone or lactulose plus albumin found that the association with albumin correlated with a 50&#37; increase in the resolution rate of encephalopathy as well as 50&#37; decrease in mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a> Further studies are needed before recommendations for albumin administration in hepatic encephalopathy can be made&#46;</p><p id="p0250" class="elsevierStylePara elsevierViewall">Lastly&#44; Romaneli&#44; <span class="elsevierStyleItalic">et al&#46;</span> evaluated the effect of albumin administration &#40;albumin plus diuretics <span class="elsevierStyleItalic">vs&#46;</span> diuretics alone&#41; in the treatment of patients with ascites&#44; with a median follow-up of 84 months&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In this trial&#44; albumin-treated patients had lower probability of ascites recurrence &#40;51&#37; <span class="elsevierStyleItalic">vs&#46;</span> 94&#37;&#44; P &#60; 0&#46;0001&#41; and significantly greater cumulative survival rate &#40;Breslow test &#61; 7&#46;05&#44; p &#61; 0&#46;0078&#41;&#46; Interestingly&#44; the difference in survival was only evident after 16 months of therapy&#46; More recently&#44; Bernardi&#44; <span class="elsevierStyleItalic">et al&#46;</span> presented in EASL 2017 a study on the long-term effect of weekly albumin administration versus standard of care in more than 400 patients with cirrhosis and ascites&#46; Albumin treatment not only reduced in half the necessity of paracentesis and the risk for refractory ascites&#44; but it was also associated with a decreased risk for other complications such as SBP and renal failure&#46; Also&#44; chronic albumin treatment was associated with a 38&#37; reduced mortality risk &#40;<a class="elsevierStyleCrossRef" href="#t0015">Table <span class="elsevierStyleSup">3</span></a>&#41;&#46;</p><elsevierMultimedia ident="t0015"></elsevierMultimedia></span></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Conclusion</span><p id="p0255" class="elsevierStylePara elsevierViewall">Albumin is the most abundant plasmatic protein&#46; Liver cirrhosis associates with decreased levels of albumin as well as disturbed albumin function&#46; Currently&#44; there are three well established indications for albumin infusion in patients with liver disease&#58;<ul class="elsevierStyleList" id="l0020"><li class="elsevierStyleListItem" id="u0050"><span class="elsevierStyleLabel">&#8226;</span><p id="p0260" class="elsevierStylePara elsevierViewall">Prevention of cardiocirculatory and renal dysfunction after LVP&#46;</p></li><li class="elsevierStyleListItem" id="u0055"><span class="elsevierStyleLabel">&#8226;</span><p id="p0265" class="elsevierStylePara elsevierViewall">Treatment of SBP&#46;</p></li><li class="elsevierStyleListItem" id="u0060"><span class="elsevierStyleLabel">&#8226;</span><p id="p0270" class="elsevierStylePara elsevierViewall">Treatment of HRS &#40;<a class="elsevierStyleCrossRef" href="#t0005">Table <span class="elsevierStyleSup">1</span></a>&#41;&#46;</p></li></ul></p><p id="p0275" class="elsevierStylePara elsevierViewall">Colloidal albumin properties&#44; and its impact on osmotic pressure&#44; have been the rational for using albumin in these situations&#46; Recently&#44; however&#44; potential beneficial effects of albumin surpass its oncotic effect&#44; since it has been acknowledged its pleotropic nature&#44; with important binding capacity to toxic substances and drugs&#44; anti-inflammatory effects&#44; modulation of hemostasis and acid-base homeostasis&#44; among other properties&#46; Therefore&#44; further indications for albumin infusions in cirrhotic patients are under evaluation&#46;</p><p id="p0280" class="elsevierStylePara elsevierViewall">A relevant new concept is that of effective albumin concentration&#46; Patients with advanced liver disease present posttranslational modifications on albumin such as oxidized HNA-1&#47;2 and ischemia modified albumin&#44; which perturb albumin function&#46; Accordingly&#44; not only a decrease in total albumin concentration&#44; but specifically a decrease in native unmodified albumin &#40;at expense of an increase in modified albumin forms&#41; has important prognostic value&#44; associating with decreased short and longterm mortality&#44; in patients with liver cirrhosis&#46; In the near future&#44; determination of modified forms of albumin may enter clinical practice&#44; similarly to determination of modified glycated hemoglobin in patients with diabetes mellitus&#46; Also&#44; the paradigm may shift from albumin replacement to albumin modification strategies in the treatment of patients with liver cirrhosis&#46;</p><p id="p0285" class="elsevierStylePara elsevierViewall">Albumin in liver cirrhosis is a hot topic for research&#44; with expected exciting breakthroughs in the near future&#46;</p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Abbreviations</span><p id="p0290" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0025"><li class="elsevierStyleListItem" id="u0065"><span class="elsevierStyleLabel">&#8226;</span><p id="p0295" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CLF&#58;</span> acute on chronic liver failure&#46;</p></li><li class="elsevierStyleListItem" id="u0070"><span class="elsevierStyleLabel">&#8226;</span><p id="p0300" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HMA&#58;</span> human mercaptoalbumin&#46;</p></li><li class="elsevierStyleListItem" id="u0075"><span class="elsevierStyleLabel">&#8226;</span><p id="p0305" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HNA-1&#58;</span> human non-mercaptoalbumin type 1&#46;</p></li><li class="elsevierStyleListItem" id="u0080"><span class="elsevierStyleLabel">&#8226;</span><p id="p0310" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HNA-2&#58;</span> human non-mercaptoalbumin type 2&#46;</p></li><li class="elsevierStyleListItem" id="u0085"><span class="elsevierStyleLabel">&#8226;</span><p id="p0315" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HRS&#58;</span> hepatorenal syndrome&#46;</p></li><li class="elsevierStyleListItem" id="u0090"><span class="elsevierStyleLabel">&#8226;</span><p id="p0320" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">IMA&#58;</span> ischemia-modified albumin&#46;</p></li><li class="elsevierStyleListItem" id="u0095"><span class="elsevierStyleLabel">&#8226;</span><p id="p0325" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">IMAr&#58;</span> IMA&#47;albumin ratio&#46;</p></li><li class="elsevierStyleListItem" id="u0100"><span class="elsevierStyleLabel">&#8226;</span><p id="p0330" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">LVP&#58;</span> large volume paracentesis&#46;</p></li><li class="elsevierStyleListItem" id="u0105"><span class="elsevierStyleLabel">&#8226;</span><p id="p0335" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">MARS&#58;</span> molecular adsorbent recirculating system&#46;</p></li><li class="elsevierStyleListItem" id="u0110"><span class="elsevierStyleLabel">&#8226;</span><p id="p0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">NF-kB&#58;</span> nuclear factor-kappa B&#46;</p></li><li class="elsevierStyleListItem" id="u0115"><span class="elsevierStyleLabel">&#8226;</span><p id="p0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PICD&#58;</span> paracentesis-induced circulatory dysfunction&#46;</p></li><li class="elsevierStyleListItem" id="u0120"><span class="elsevierStyleLabel">&#8226;</span><p id="p0350" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PTM&#58;</span> posttranslational modifications&#46;</p></li><li class="elsevierStyleListItem" id="u0125"><span class="elsevierStyleLabel">&#8226;</span><p id="p0355" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">RAAS&#58;</span> renin angiotensin aldosterone system&#46;</p></li><li class="elsevierStyleListItem" id="u0130"><span class="elsevierStyleLabel">&#8226;</span><p id="p0360" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SBP&#58;</span> spontaneous bacterial peritonitis&#46;</p></li></ul></p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Financial Support</span><p id="p0365" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:10 [
        0 => array:3 [
          "identificador" => "xres1207238"
          "titulo" => "Abstract"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abs0010"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1124284"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "s0005"
          "titulo" => "Introduction"
        ]
        3 => array:2 [
          "identificador" => "s0010"
          "titulo" => "Structure and Function of Albumin"
        ]
        4 => array:2 [
          "identificador" => "s0015"
          "titulo" => "Forms of Albumin in Liver Cirrhosis"
        ]
        5 => array:3 [
          "identificador" => "s0020"
          "titulo" => "Indications for Treatment with Albumin in Liver Cirrhosis"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "s0025"
              "titulo" => "Prevention of paracentesis-induced circulatory dysfunction"
            ]
            1 => array:2 [
              "identificador" => "s0030"
              "titulo" => "Treatment of bacterial spontaneous peritonitis"
            ]
            2 => array:2 [
              "identificador" => "s0035"
              "titulo" => "Prevention of hepatorenal syndrome"
            ]
            3 => array:2 [
              "identificador" => "s0040"
              "titulo" => "Controversial indications for albumin therapy in cirrhosis"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "s0045"
          "titulo" => "Conclusion"
        ]
        7 => array:2 [
          "identificador" => "s0050"
          "titulo" => "Abbreviations"
        ]
        8 => array:2 [
          "identificador" => "s0055"
          "titulo" => "Financial Support"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-03-21"
    "fechaAceptado" => "2018-05-14"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1124284"
          "palabras" => array:4 [
            0 => "Liver cirrhosis"
            1 => "Albumin"
            2 => "Effective albumin concentration"
            3 => "Posttranslational changes"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">Decompensated liver cirrhosis has a dismal prognosis&#44; with an overall survival of 2-4 years&#44; which is worse than for many oncological diseases&#46; Albumin is an important tool in the management of patients with cirrhosis&#44; since it decreases for less than half the risk for post-paracentesis cardiocirculatory dysfunction and mortality associated with spontaneous bacterial infection&#44; as well as&#44; it triplicates the response to terlipressin in patients with hepatorenal syndrome&#46; Recently&#44; research on albumin has been a hot topic&#44; with important new insights such as the characterization of the pleiotropic effects of albumin &#40;which surpass its oncotic properties&#41; and the concept of effective albumin concentration&#46; In fact&#44; patients with liver cirrhosis present posttranslational modifications on albumin that compromises its function&#46; Those modified albumin forms were proved to have prognostic value and its knowledge may change the paradigm of albumin treatment&#46; In this review&#44; we critically summarize the latest evidence on the potential benefits of albumin in patients with end-stage liver disease&#46;</p></span>"
      ]
    ]
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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Albumin structure&#46; Albumin has a single polypeptide sequence formed by 585 amino acids&#46; At position 34&#44; the cysteine residue is free and available for reaction with other molecules&#46; The protein has a heart-like shape&#44; possessing three homologous domains I-III&#44; each domain is divided into A and B subdomains&#46;</p>"
        ]
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      1 => array:7 [
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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Anti-inflammatory properties of albumin&#46; Albumin preserves cellular glutathione&#44; protecting cells against oxidant-mediated injury and down-regulation of the activation of the oxidant-sensitive transcription protein complex NF-&#954;B&#46;</p>"
        ]
      ]
      2 => array:7 [
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Albumin forms&#46; Mercaptoalbumin has a free sulfidril group at cysteine-34&#46; Non-mercaptoalbomin-1 results from reversible oxidative modifications through reversible binding via mixed disulfide bridges between cysteine-34 and compounds containing sulfidril groups such as cysteine &#40;Cys&#41;&#44; homocysteine &#40;HCY&#41; and glutathione &#40;GSH&#41;&#46; Non-mercaptoalbumin-2 is a result of complete and irreversible oxidation of cysteine-34 in sulfonic or sulfnic acid&#46;</p>"
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          "leyenda" => "<p id="np0005" class="elsevierStyleSimplePara elsevierViewall">IMA expressed as absorbance units &#40;ABSU&#41; estimated using cobalt binding test &#40;ABT&#41;&#46; IMAr normalized for albumin in g&#47;dL&#46; ACLF&#58; acute on chronic liver failure&#46; CPT&#58; Child-Pugh-Turcotte class&#46; IMA&#58; ischemia-modified albumin&#46; IMAr&#58; IMA&#47;albumin ratio&#46; PELD&#58; pediatric end-stage liver disease class&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IMAr in healthy controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">IMAr in patients with liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Correlation between IMAr and severity of liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Correlation between IMAr and mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Effect of treatment on IMAr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Jalan R&#44; 2009<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; 80 controls &#8226; 12 alcoholic cirrhosis &#8226; 22 ACLF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;10 &#177; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; in cirrhosis &#40;0&#46;21 &#177; 0&#46;01&#41; &#8226; &#8593;&#8593; In ACLF &#40;0&#46;30 &#177; 0&#46;02&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; With MELD &#40;r &#61; 0&#46;81&#44; p &#60; 0&#46;007&#41; &#8226; Not with CPT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; ROC 0&#46;8 &#40;p &#60; 0&#46;001&#41; &#8226; Cutoff 0&#46;20 with 83&#37; Se and 67&#37; Sp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MARS did not change IMAr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chen CY&#44; 2011<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; 51 controls &#8226; 25 chronic hepatitis &#8226; 24 cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;100 &#177; 0&#46;014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; in hepatitis &#40;0&#46;125 &#177; 0&#46;037&#41; &#8226; &#8593;&#8593; In cirrhosis &#40;0&#46;198 &#177; 0&#46;056&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; With MELD &#40;r &#61; 0&#46;462&#44; p &#61; 0&#46;023&#41; &#8226; With CPT &#40;r &#61; 0&#46;531&#44; p &#61; 0&#46;008&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albumin therapy did not change IMAr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cakir M&#44; 2012<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; 33 controls &#8226; 33 children with chronic liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;126 &#177; 0&#46;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; in chronic liver disease &#40;0&#46;152 &#177; 0&#46;046&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; With PELD &#40;r &#61; 0&#46;503&#44; p &#61; 0&#46;03&#41; &#8226; With fibrosis &#40;r &#61; 0&#46;400&#44; p &#61; 0&#46;021&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; ROC 0&#46;82 &#40;p &#61; 0&#46;013&#41; &#8226; Cutoff 0&#46;156 with 83&#37; Se and 82&#37; Sp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Giannone FA&#44; 2015<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; 44 controls &#8226; 127 cirrhosis hospitalized&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;090 &#177; 0&#46;024&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; in cirrhosis &#40;0&#46;154 &#177; 0&#46;058&#41; &#8226; &#8593;&#8593; In infection &#40;OR 2&#46;411&#41; &#8226; No association with etiology or ACLF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Not with MELD &#8226; With CPT &#40;r &#61; 0&#46;204&#44; p &#61; 0&#46;021&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No association with 1-year mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kumar PA&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; 28 controls &#8226; 43 chronic liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;074 &#177; 0&#46;0283&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; in chronic liver disease &#40;0&#46;203 &#177; 0&#46;097&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; With MELD &#40;r &#61; 0&#46;3495&#44; p &#61; 0&#46;046&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yavuz F&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; 28 controls &#8226; 43 chronic hepatitis B &#40;31 advanced fibrosis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;060 &#177; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; in chronic liver disease &#40;0&#46;080 &#177; 0&#46;040&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; With fibrosis&#58; AUROC for Advanced fibrosis 0&#46;797 &#40;p &#60; 0&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Evidence of IMAr in liver disease&#46;</p>"
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        "identificador" => "t0010"
        "etiqueta" => "Table 2"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Albumin form&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Biological function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Evidence in liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">References&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oxidized&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8595; Antioxidant properties&#46; &#8226; &#8595; Binding to endogenous ligands and drugs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; 50&#37; HNA-1 and &#8593; 200&#37; HNA-2 in liver cirrhosis&#46; &#8226; Associates with CPT and MELD&#46; &#8226; Associates with ascites&#44; HRS and bacterial infection&#46; &#8226; Associates with mortality&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8595; Heavy metals binding &#8226; &#8595; Free-radical scavenging ability&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; IMA and IMAr &#8593; in liver cirrhosis and ACLF&#46; &#8226; Associates with fibrosis&#46; &#8226; Associates with CPT and MELD&#46; &#8226; Associates with bacterial infection&#46; &#8226; Associates with mortality&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a>&#44; <a class="elsevierStyleCrossRefs" href="#bib0410">82</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glycosylated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8595; 50&#37; binding to albumin and 95&#37; binding to fatty acids&#46; &#8226; &#8595; Binding to copper&#46; &#8226; &#8595; Antioxidant properties&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; In liver cirrhosis&#46; &#8226; Associates with CPT&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dimers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Useful as a biomarker&#46; &#8226; Binding ability seems preserved&#46; &#8226; May have &#8593; plasma circulating life&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593; In liver cirrhosis&#46; &#8226; &#8593; Associates with mortality&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a>&#44; <a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Indication&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">After LVP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 g&#47;L for removed ascites &#40;&#62; 5 L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SBP<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;5 g&#47;kg day 1 &#40;within 6 h of detection&#41; and 1&#46;0 g&#47;kg on day 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">European and American Guidelines&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 g&#47;kg day 1&#44; 20&#8211;40 g id day 2&#8211;15 &#43; terlipressin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-SBP infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Controversial&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ascites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">ACLF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
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                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(14)60121-5"
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                        "tituloSerie" => "Lancet"
                        "fecha" => "2014"
                        "volumen" => "383"
                        "paginaInicial" => "1749"
                        "paginaFinal" => "1761"
                        "link" => array:1 [ …1]
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The burden of liver disease in Europe&#58; a review of available epidemiological data"
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                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2012.12.005"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2013"
                        "volumen" => "58"
                        "paginaInicial" => "593"
                        "paginaFinal" => "608"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
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              "etiqueta" => "3&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New concepts on the clinical course and stratification of compensated and decompensated cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jhep.2005.10.013"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "2006"
                        "volumen" => "44"
                        "paginaInicial" => "217"
                        "paginaFinal" => "231"
                        "link" => array:1 [ …1]
                        "itemHostRev" => array:3 [ …3]
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            3 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Natural history of patients hospitalized for management of cirrhotic ascites"
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                        0 => array:2 [ …2]
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                    0 => array:2 [
                      "doi" => "10.1016/j.cgh.2006.08.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Gastroenterol Hepatol"
                        "fecha" => "2006"
                        "volumen" => "4"
                        "paginaInicial" => "1385"
                        "paginaFinal" => "1394"
                        "link" => array:1 [ …1]
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            4 => array:3 [
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              "etiqueta" => "5&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Renal failure and cirrhosis&#58; a systematic review of mortality and prognosis"
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                        0 => array:2 [ …2]
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                  "host" => array:1 [
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                      "titulo" => "Natural history and prognostic indicators of survival in cirrhosis&#58; a systematic review of 118 studies"
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            6 => array:3 [
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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