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Case Report
Hepatoxicity induced by clozapine: Case report and brief review
Hepatotoxicidad inducida por clozapina: reporte de caso y revisión breve de la literatura
Joshep Revilla-Zúñigaa,b,
Corresponding author
joshep.revilla.z@upch.pe

Corresponding author.
, Joise Cornejo-Del Carpioc, Lizardo Cruzadoa,b
a Instituto Nacional de Salud Mental Honorio Delgado-Hideyo Noguchi, Lima, Peru
b Universidad Peruana Cayetano Heredia, Lima, Peru
c Hospital Carlos Lanfranco La Hoz, Lima, Peru
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Clozapine is an atypical antipsychotic used preferentially in treatment-resistant schizophrenia&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It is reserved for this purpose because of its risk of agranulocytosis &#40;absolute neutrophil count &#60;500&#47;&#956;l&#41;&#44; which has a prevalence of around 0&#46;7&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> conditioning its use to be monitored with periodic blood cytology controls&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In general&#44; all antipsychotics can raise hepatic enzymes&#46; Of the typical antipsychotics&#44; chlorpromazine is most commonly associated with hepatotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In this case&#44; the injury type is cholestatic &#40;decreased bile flow&#44; which in this case does not imply any kind of obstruction&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Within the atypical group&#44; clozapine is the drug most associated with hepatotoxic effects&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Up to 60&#37; of patients have raised liver transaminases and 15&#37;&#8211;30&#37; have elevations up to two to three times the normal value&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> These elevations are often transient and asymptomatic&#44; but there are cases in which clozapine-induced hepatotoxicity can be severe&#44; as reported in different case series&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The following case describes a woman with a diagnosis of paranoid schizophrenia who was admitted to an accident and emergency department for nausea&#44; vomiting and jaundice&#44; apparently triggered by clozapine&#44; and who unfortunately had a fatal outcome due to hypovolemic shock&#46; Due to the scarcity of records in Spanish on clozapine-induced hepatotoxicity&#44; this report and review of the literature is relevant&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Case report</span><p id="par0020" class="elsevierStylePara elsevierViewall">This concerns a 39-year-old woman&#44; diagnosed with paranoid schizophrenia four years prior and with no family psychiatric history or drug use&#46; Relevant medical history included abdominal surgery at the age of eight years for hepatic trauma due to a traffic accident &#40;findings unknown&#41; and hepatitis A in childhood&#46; There is no record of subsequent liver problems&#46; Furthermore&#44; there was no additional consumption of any herbal or non-pharmaceutical product&#46; Her psychopharmacological history included previous treatment with risperidone&#44; haloperidol decanoate&#44; olanzapine and quetiapine&#46; Despite taking antipsychotic medication&#44; her psychotic symptoms had not progressed favourably&#44; so her treating doctor decided to start her on clozapine 200&#8239;mg from the first day of treatment&#46; The patient showed clinical improvement of positive symptoms after four weeks of treatment&#44; but suffered from orthostatic dizziness&#46; Two months before her admission &#40;eight weeks after taking clozapine&#41;&#44; morning sickness manifested&#44; but the psychotic symptoms were clinically stable&#44; so it was decided to reduce the clozapine dose to 150&#8239;mg&#47;day&#46; She also presented with sporadic vomiting one month before her admission&#46; Due to these discomforts&#44; she went to a gastroenterologist&#44; who performed an upper gastrointestinal endoscopy&#44; which revealed moderate erythematous chronic gastritis and bile reflux&#46; The patient discontinued clozapine eight days prior to admission due to the symptoms&#46; The patient was referred to the accident and emergency department of a general hospital for persistent nausea and vomiting&#44; as well as jaundice&#46; There is no information on when the jaundice started&#46; There was no weight alteration or hyporexia&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">On physical examination the patient was found to have dry oral mucous membranes&#44; with jaundiced &#40;&#43;&#43;&#47;&#43;&#43;&#43;&#41; sclerae&#44; skin and mucous membranes and epigastric and mesogastric pain on palpation&#46; There was no evidence of liver enlargement&#46; Axillary temperature was 37&#46;5&#8239;&#176;<span class="elsevierStyleSmallCaps">C</span>&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Her liver function tests on admission were glutamic oxaloacetic transaminase &#40;GOT&#41; 183&#8239;U&#47;l&#44; glutamic pyruvic transaminase &#40;GPT&#41; 268&#8239;U&#47;l&#44; with total bilirubin &#40;TBil&#41; of 3&#46;5&#8239;mg&#47;dl&#46; Her complete blood count showed white blood cells of 7970&#47;&#956;l&#44; with eosinophils of 40&#47;&#956;l &#40;normal&#44; 20&#8239;500&#47;&#956;l&#41; and C-reactive protein of 1&#46;3&#8239;mg&#47;dl&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Abdominal ultrasound findings on admission showed a liver with regular contours&#44; with increased parenchymal echotexture and no focal or diffuse lesions&#46; The bile ducts and common bile duct were of normal calibre and without gallstones&#46; The kidney ultrasound was normal&#46; Her serology tests for hepatitis B and C were negative&#46; She was diagnosed with an emetic syndrome and jaundice syndrome until clozapine-induced hepatotoxicity was ruled out&#44; and she was admitted&#46; Nasogastric feeding tube placement was indicated but&#44; despite this indication&#44; nausea and vomiting persisted for 13 days and the vomiting was bilious in content&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Fifteen days after admission&#44; oral tolerance was tested with a liquid diet because she had gone two days without vomiting&#44; but the nausea continued&#44; so the nasogastric feeding tube was reinserted due to the reappearance of vomiting&#46; Other tests performed were&#58; thyrotropin&#44; 1&#46;36&#8239;&#956;IU&#47;ml &#40;normal&#44; 0&#46;3&#8211;4&#46;5&#8239;&#956;IU&#47;ml&#41;&#59; free T4&#44; 16&#46;8&#8239;pg&#47;ml &#40;normal&#44; 8&#46;9&#8211;17&#46;2&#8239;pg&#47;ml&#41;&#59; IgG&#44; 1236&#8239;mg&#47;dl &#40;normal&#44; 656&#8211;1351&#8239;mg&#47;dl&#41;&#59; ANA&#44; 1&#47;100 pattern DFS70 positive&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the evolution of liver function during hospitalisation&#46; As can be seen&#44; GOT and GPT were three times higher than the upper limit of normal in the patient one month after hospitalisation&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Other tests ordered were an abdominal CT scan one month after hospitalisation&#44; which showed a liver of normal size&#44; shape and location&#44; with decreased density in the simple phase &#40;without intravenous contrast&#41; and with contrast&#59; no focal lesions or bile duct dilatation were found&#44; with a common bile duct of preserved calibre&#46; The gallbladder was described as collapsed&#44; with perivesical oedema and no gallstones&#46; The conclusion was mild diffuse hepatopathy and perivesical oedema&#46; Due to the suspicion of intestinal obstruction&#44; she underwent an intestinal transit X-ray&#44; which could not be completed due to vomiting induced by the contrast medium&#44; and an upper gastrointestinal tract endoscopy&#44; which showed a regular amount of mucous and bile in the stomach&#44; the antrum with a mucosa of whitish mottled appearance&#44; congestive&#44; without erosions&#44; and a congestive pylorus&#46; It was concluded&#58; antral congestive gastropathy and bile reflux&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">From the time the patient was admitted&#44; oral intolerance due to nausea and vomiting and jaundice persisted until day 42 of hospitalisation&#44; when greenish vomiting appeared&#46; Her glucose level was found to be 45&#8239;mg&#47;dl with a prothrombin time of 20&#8239;s&#46; One day later&#44; her condition was complicated by encephalopathy and refractory multi-organ failure due to an upper gastrointestinal haemorrhage&#46; The cause could not be determined due to the torpid progression of the patient&#44; who died one day after the onset of the disease&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0055" class="elsevierStylePara elsevierViewall">Drug-induced hepatotoxicity refers to any damage to liver function from the ingestion of drugs&#44; herbs or dietary supplements and ranges from asymptomatic raised liver enzymes to acute liver failure&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Drug-induced hepatotoxicity can be classified as follows&#58; direct&#44; idiosyncratic or indirect&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The direct&#44; or intrinsic&#44; mechanism is known to be related to accumulation of the drug after ingestion&#44; as well as direct damage of its metabolites in the liver&#46; It is dose-dependent and predictable&#44; and the latency period is short &#40;1&#8211;5 days&#41; after high therapeutic doses or supratherapeutic doses&#44; such as in the case of intentional or accidental overdose&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The idiosyncratic mechanism is the most common mechanism and is neither dose-dependent nor predictable&#44; relying on the uniqueness of the individual&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> This type of hepatotoxicity results from immune-mediated liver injury or direct cell damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> Hepatotoxicity by this mechanism is initiated by exposure of the hepatocyte to some form of stress&#44; although there are also other factors that sensitise this cell and amplify cell damage&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Protective mechanisms are involved&#44; such as glutathione&#44; which has the function of scavenging reactive oxygen species<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and the activation of anti-oxidative genes and their proteins mediated by the nuclear factor-erythroid 2 related factor 2 &#40;Nrf2&#41; protective pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Impairment of these protective mechanisms can lead to hepatocyte damage &#40;protein dysfunction&#44; impaired regulation of drug transporters&#44; mitochondrial toxicity and lysosomal damage&#41;&#46; The formation of reactive drug metabolites and covalent binding can lead to immune activation of T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In the idiosyncratic mechanism&#44; a hypersensitivity syndrome may occur&#44; characterised by the emergence of rash&#44; eosinophilia and the development of autoantibodies&#44; and manifests after a short latency period &#40;one to six weeks&#41;&#46; Although this mechanism is not fully understood&#44; it is postulated that the hypersensitivity reaction is type I due to an increase in immunoglobulin E&#44; angioedema and skin rash in some cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> Another hypothesis is the stimulation of T-lymphocytes&#44; with a subsequent increase in interleukin 5&#44; which promotes the production of eosinophils&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Based on laboratory findings&#44; the idiosyncratic mechanism can be classified as hepatocellular&#44; cholestatic and mixed<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Hepatocellular pattern&#58; GPT &#8805;3 times the upper limit of normal and a GPT&#47;alkaline phosphatase &#40;ALP&#41; ratio&#8239;&#8805;5 times&#46; It is the most common manifestation of idiosyncratic liver injury&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Cholestatic pattern&#58; ALP&#8239;&#8805;2 times the upper limit of normal and a GPT&#47;ALP ratio&#8239;&#8804;2 times&#46; This pattern is related to bile secretion impairment&#44; such as that caused by chlorpromazine&#44; which leads to cholestasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;22</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Mixed pattern&#58; GPT&#8239;&#8805;3 times the upper limit of normal&#44; ALP&#8239;&#8805;2 times the upper limit of normal and a GPT&#47;ALP ratio &#60;5 and &#62;2 times&#46;</p></li></ul></p><p id="par0095" class="elsevierStylePara elsevierViewall">The third mechanism described is indirect liver injury through increased risk of metabolic syndrome&#44; which in turn increases the risk of non-alcoholic fatty liver disease&#44; characterised by hepatic accumulation of triglycerides&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Antipsychotics&#44; especially atypical agents&#44; are associated with weight gain&#44; hyperphagia&#44; hyperglycaemia&#44; insulin resistance&#44; type 2 diabetes mellitus and dyslipidaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Of the atypical antipsychotics&#44; clozapine is the one most associated with impaired liver function&#44; usually raised transaminases&#44; pointing to liver injury with a hepatocellular pattern&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It should be noted that&#44; in addition to clozapine&#44; another of the most hepatotoxic antipsychotics is chlorpromazine&#44; while the least hepatotoxic are aripiprazole and ziprasidone&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5&#44;25</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the main antipsychotics and their hepatotoxicity classification&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Raised liver function tests with clozapine are dose-dependent and usually occur at 200&#8211;400&#8239;mg&#47;day&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Raised liver enzyme levels to clinically significant ranges occurs 5&#8211;8 weeks after starting clozapine&#44; with a mean time of 34&#46;2 days&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> Raised transaminase levels normalise spontaneously without clozapine dose reduction in about half of patients at approximately nine weeks&#46; When clozapine is reduced or stopped&#44; hepatic enzymes return to normal in 4&#8211;6 weeks&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;29&#44;30</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">While there is no specific scale to assess the severity of clozapine-induced liver injury&#44; the severity of drug-induced liver injury in general is shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Regarding clozapine dosage&#44; the literature recommends starting with 12&#46;5&#8239;mg&#47;day&#44; with gradual increases of 25&#8211;50&#8239;mg&#47;day up to 300&#8239;mg&#47;day after 2&#8211;3 weeks&#44; to reduce dangerous adverse effects such as orthostatic hypotension&#44; seizures&#44; myocarditis and neuroleptic malignant syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Clinical guidelines are not specific about monitoring hepatic enzymes&#46; The Maudsley Prescribing Guidelines in Psychiatry<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> recommend a baseline liver function test and another at 4&#8211;6 months of clozapine treatment&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Moreover&#44; in the event of clinical symptoms such as general malaise&#44; fever&#44; abdominal pain&#44; nausea&#44; vomiting&#44; rash&#44; dark urine or jaundice&#44; hepatic enzymes should be checked and clozapine discontinued if GPT&#44; GOT and GGT values are above three times the normal value or ALP or total bilirubin are &#62;2 times the normal value&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;34&#8211;36</span></a> Acute fulminant hepatic failure has been described&#44; which fortunately is extremely rare&#44; with only two cases &#40;0&#46;001&#37;&#41; published&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In our case&#44; the diagnosis of clozapine-induced hepatotoxicity was based on the patient&#8217;s clinical history and the ruling out of other possible causes&#46; Although the patient had a positive ANA test&#44; the reported DFS70 pattern &#40;fine and dense mottling&#44; molecular weight 70&#8239;kDa&#41; is found in healthy individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The patient was admitted with GPT values six times the upper limit of normal&#44; GOT five times the upper limit of normal and total bilirubin in the jaundice range&#44; with no evidence of obstruction by stones&#46; This is considered severe liver injury&#46; The presentation was hepatocellular based on the marked increase in GPT&#44; ultrasound findings and subsequent ALP controls&#44; which did not show values &#62;2 times the upper limit of normal&#46; Despite discontinuing clozapine&#44; hepatic enzymes did not normalise and there was no clinical improvement&#46; Liver function tests should have normalised within one month of stopping clozapine&#46; It is hypothesised that the history of childhood abdominal trauma and the initial dose of clozapine 200&#8239;mg&#47;day without prior titration were related to hepatotoxicity&#46; Although the patient experienced one of the most common gastrointestinal adverse effects of clozapine &#8211; nausea &#8211; from the first month of treatment&#44; the persistence of nausea and the occurrence of vomiting should raise red flags and prompt immediate testing of hepatic enzymes&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">The reported case concerns clozapine-induced hepatotoxicity&#46; This conclusion was reached on the basis of presenting symptoms&#44; ruling out other possible causes&#44; the physical examination and laboratory findings&#46; According to the literature reviewed&#44; this is the third case with a fatal outcome&#46; After having reviewed the literature&#44; we recommend&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0145" class="elsevierStylePara elsevierViewall">Liver panel testing should be taken into consideration before starting clozapine&#46; The next check-up should be after 4&#8211;6 months of treatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0150" class="elsevierStylePara elsevierViewall">If the patient exhibits clinical symptoms with clozapine&#44; such as jaundice&#44; fever&#44; rash&#44; malaise&#44; nausea and vomiting&#44; the liver panel should be checked for raised hepatic enzymes&#46; If they are &#62;3 times the normal value&#44; clozapine should be discontinued&#46; Otherwise&#44; the clozapine dosage can be continued and the liver panel can be continuously assessed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0155" class="elsevierStylePara elsevierViewall">Progressive titration of clozapine is recommended&#44; starting at 12&#46;5&#8239;mg&#47;day&#46; It should be increased by 25&#8211;50&#8239;mg&#47;day to 300&#8239;mg&#47;day after 2&#8211;3 weeks&#46;</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Antipsychotics are drugs that can produce transient elevations of hepatic enzymes&#46; Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia and there is evidence that it can produce elevations of hepatic transaminases&#44; expression of liver damage in a hepatocellular pattern&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Case report and non-systematic review of the relevant literature&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case presentation</span><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">A 39-year-old woman with a diagnosis of paranoid schizophrenia attended the emergency department of a general hospital for nausea&#44; vomiting and jaundice that appeared after the initiation of clozapine&#46; There was no clinical improvement during hospitalisation&#44; and death occurred after 44 days&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Literature review</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Clozapine can increase the liver enzyme levels transiently and asymptomatically&#59; however&#44; there are clinical criteria that recommend the withdrawal of the antipsychotic&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">This is the third case reported in the literature of a fatal outcome of clozapine-induced hepatotoxicity&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Los antipsic&#243;ticos son medicamentos que pueden producir elevaciones transitorias de las enzimas hep&#225;ticas&#46; La clozapina es un antipsic&#243;tico at&#237;pico usado en el tratamiento de la esquizofrenia refractaria a los antipsic&#243;ticos convencionales y existe evidencia que puede producir elevaciones de las transaminasas hep&#225;ticas&#44; expresi&#243;n de da&#241;o hep&#225;tico con patr&#243;n hepatocelular&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Reporte de caso y revisi&#243;n no sistem&#225;tica de la literatura relevante&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Presentaci&#243;n del caso</span><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Una mujer de 39 a&#241;os con diagn&#243;stico de esquizofrenia paranoide acudi&#243; a un servicio de urgencias de un hospital general por n&#225;useas&#44; v&#243;mitos e ictericia que apareci&#243; tras el inicio de clozapina&#46; No hubo mejor&#237;a cl&#237;nica de la paciente durante la hospitalizaci&#243;n&#44; que falleci&#243; a los 44 d&#237;as de su ingreso&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Revisi&#243;n de la literatura</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">La clozapina puede elevar las cifras de funci&#243;n hep&#225;tica de manera transitoria y asintom&#225;tica&#46; Hay criterios cl&#237;nicos para recomendar la suspensi&#243;n de este antipsic&#243;tico&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Este caso es el tercero en la literatura que registra un desenlace fatal tras un cuadro de hepatotoxicidad inducido por clozapina&#46;</p></span>"
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                  \t\t\t\t">GOT &#40;normal&#44; 5&#8211;35&#8239;U&#47;l&#41;&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">183&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">162&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">48&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">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&#46;9&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GPT &#40;normal&#44; 5&#8211;45&#8239;U&#47;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \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">255&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">251&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">99&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">152&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">91&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GGT &#40;normal&#44; 5&#8722;49 U&#47;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="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">77&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><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">97&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">122&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">129&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total bilirubin &#40;normal&#44; 0&#46;2&#8211;1&#46;2&#8239;mg&#47;dl&#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">3&#46;5&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">1&#46;8&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;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;2&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">3&#46;0&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alkaline phosphatase &#40;normal&#44; 30&#8211;120&#8239;U&#47;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="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><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><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">216&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">224&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">199&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C-reactive protein &#40;normal&#44; 0&#8211;0&#46;7&#8239;mg&#47;dl&#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">1&#46;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">&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">0&#46;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">0&#46;49&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelets &#40;normal&#44; 150&#8211;400&#8239;&#215;&#8239;109&#47;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">301&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">175&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">225&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">235&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
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A&#58; the drug causes clinically apparent direct or idiosyncratic liver injury&#46; More than 50 cases have been reported&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">B&#58; the drug is very likely to cause clinically apparent idiosyncratic liver injury&#46; Between 12 and 50 cases have been reported&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">C&#58; the drug is likely to cause idiosyncratic liver injury&#46; Fewer than 12 cases have been reported&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">D&#58; it is a rare cause of liver injury&#46; Fewer than 3 cases have been reported&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">E&#58; there is no evidence that the drug has caused liver injury&#46; There may be single case reports&#44; but they are largely unconvincing&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">E&#42;&#58; the drug has not been proven to cause liver injury&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">X&#58; it is unknown if the drug has caused liver injury&#46; Applies to drugs that are newly introduced or rarely used in clinical medicine&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Modified from Chalasani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and Bj&#246;rnsson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number of cases&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fatal injury&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Category&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Typical</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Chlorpromazine&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">&#62;100&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&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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Haloperidol&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">25&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&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">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Atypical</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Clozapine&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">27&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&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">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Olanzapine&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">28&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&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">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Quetiapine&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">11&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&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">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Risperidone&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">6&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&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">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ziprasidone&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">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">0&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">D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Aripiprazole&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">&#8211;&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">&#8211;&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">E&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Antipsychotics and hepatotoxicity&#46;</p>"
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        "etiqueta" => "Table 3"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Taken from Yu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p>"
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            0 => array:2 [
              "tabla" => array:1 [
                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">Severity&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="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Description&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grade 0&#58; no liver injury&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">Tolerance to the drug without any hepatotoxic reaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grade 1&#58; mild liver injury&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">Raised serum levels of GPT and&#47;or alkaline phosphatase&#44; total bilirubin &#60;2&#46;5 times the upper limit of normal&#44; INR&#8239;&#60;&#8239;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " 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">There may be fatigue&#44; asthenia&#44; nausea&#44; anorexia&#44; right upper abdominal pain&#44; jaundice&#44; pruritus&#44; rash or weight loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grade 2&#58; moderate liver injury&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">Raised GPT and&#47;or alkaline phosphatase&#44; with total bilirubin &#8805;2&#46;5 times the upper limit of normal or INR&#8239;&#8805;&#8239;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " 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">The symptoms described can be exacerbated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grade 3&#58; severe liver injury&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">Raised serum levels of GPT and&#47;or alkaline phosphatase&#44; total bilirubin &#8805;5 times the upper limit of normal&#44; with or without INR&#8239;&#8805;&#8239;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grade 4&#58; acute liver failure&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">Evidence of coagulation abnormalities indicated by INR&#8239;&#8805;&#8239;1&#46;5 or prothrombin activity &#60;40&#37;&#44; signs of hepatic encephalopathy and total bilirubin &#8805;10 times the upper limit of normal or daily elevation &#8805;1&#8239;mg&#47;dl within 26 weeks after the onset of drug-induced liver injury Ascites and dysfunction of other organs may occur&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Grade 5&#58; lethal&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">Death due to drug-induced liver injury or need for liver transplantation for survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Severity of drug-induced liver injury&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:39 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy of clozapine in the treatment of atypical antipsychotic refractory schizophrenia&#58; a pilot study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46; Narendran"
                            1 => "C&#46;M&#46; Young"
                            2 => "C&#46;A&#46; Pristach"
                            3 => "M&#46;T&#46; Pato"
                            4 => "A&#46;M&#46; Valenti"
                            5 => "A&#46;R&#46; Fass"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Clin Psychopharmacol"
                        "fecha" => "2003"
                        "paginaInicial" => "103"
                        "paginaFinal" => "104"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "More than 25 years of genetic studies of clozapine-induced agranulocytosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;A&#46;J&#46; de With"
                            1 => "S&#46;L&#46; Pulit"
                            2 => "W&#46;G&#46; Staal"
                            3 => "R&#46;S&#46; Kahn"
                            4 => "R&#46;A&#46; Ophoff"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/tpj.2017.6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacogenomics J"
                        "fecha" => "2017"
                        "volumen" => "17"
                        "paginaInicial" => "304"
                        "paginaFinal" => "311"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28418011"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Psychotropic drugs and liver disease&#58; a critical review of pharmacokinetics and liver toxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "D&#46; Telles-Correia"
                            1 => "A&#46; Barbosa"
                            2 => "H&#46; Cortez-Pinto"
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Article information
ISSN: 25303120
Original language: English
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