Recent Advances in Hepatotoxicity of Non Steroidal Anti-inflammatory Drugs
Read
2708
Timeswas read the article
556
Total PDF
2152
Total HTML
Share statistics
array:24 [ "pii" => "S1665268119301504" "issn" => "16652681" "doi" => "10.5604/01.3001.0010.8633" "estado" => "S300" "fechaPublicacion" => "2018-03-01" "aid" => "70027" "copyright" => "Fundación Clínica Médica Sur, A.C." "copyrightAnyo" => "2018" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2018;17:187-91" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 164 "formatos" => array:3 [ "EPUB" => 20 "HTML" => 77 "PDF" => 67 ] ] "itemSiguiente" => array:19 [ "pii" => "S1665268119301516" "issn" => "16652681" "doi" => "10.5604/01.3001.0010.8634" "estado" => "S300" "fechaPublicacion" => "2018-03-01" "aid" => "70028" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2018;17:192-204" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 669 "formatos" => array:3 [ "EPUB" => 12 "HTML" => 500 "PDF" => 157 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Fontan-Associated Liver Disease: A Review" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "192" "paginaFinal" => "204" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 205 "Ancho" => 544 "Tamanyo" => 15902 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Regenerative nodular hyperplasia in FALD. <span class="elsevierStyleBold">A</span>. Hepatic congestion and reduced cardiac output cause a decrease in portal blood flow predominantly in periphery of the liver, resulting in focal ischemia. <span class="elsevierStyleBold">B</span>. Extinction of the parenchyma secondary to ischemia triggers an arteria vasodilatory response that stimulates the proliferation of healthy hepatocytes resulting in nodular regenerative hyperplasia <span class="elsevierStyleBold">(B)</span>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luis Téllez, Enrique Rodríguez-Santiago, Agustín Albillos" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Luis" "apellidos" => "Téllez" ] 1 => array:2 [ "nombre" => "Enrique" "apellidos" => "Rodríguez-Santiago" ] 2 => array:2 [ "nombre" => "Agustín" "apellidos" => "Albillos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301516?idApp=UINPBA00004N" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301516/v1_201905140709/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268119301498" "issn" => "16652681" "doi" => "10.5604/01.3001.0010.8631" "estado" => "S300" "fechaPublicacion" => "2018-03-01" "aid" => "70026" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2018;17:182-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 225 "formatos" => array:3 [ "EPUB" => 17 "HTML" => 136 "PDF" => 72 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Nonalcoholic Fatty Liver Disease Progresses into Severe NASH when Physiological Mechanisms of Tissue Homeostasis Collapse" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "182" "paginaFinal" => "186" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 462 "Ancho" => 656 "Tamanyo" => 32200 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue by inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance (up-arrows). Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory adipokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue (down-arrows). SFRP5: secreted frizzled-related protein 5. UCP1: uncoupling protein 1. FGF21: fibroblast growth factor 21. TNF a: tumor necrosis factor a. IL1 and IL6: interleukin 1 and 6. MCP-1: mono-cyte chemotactic protien-1.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Silvia Sookoian, Carlos J. Pirola" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Silvia" "apellidos" => "Sookoian" ] 1 => array:2 [ "nombre" => "Carlos J." "apellidos" => "Pirola" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301498?idApp=UINPBA00004N" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301498/v1_201905140709/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "titulo" => "Recent Advances in Hepatotoxicity of Non Steroidal Anti-inflammatory Drugs" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "187" "paginaFinal" => "191" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Lucy Meunier, Dominique Larrey" "autores" => array:2 [ 0 => array:3 [ "nombre" => "Lucy" "apellidos" => "Meunier" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "Dominique" "apellidos" => "Larrey" "email" => array:1 [ 0 => "dom-larrey@chu-montpellier.fr" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">**</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Liver and Transplantation Unit, Montpellier School of Medicine, Montpellier, France" "etiqueta" => "*" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "IRB-INSERM-1183, Montpellier, France" "etiqueta" => "**" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">INTRODUCTION</span><p id="p0005" class="elsevierStylePara elsevierViewall">Non-steroidal-anti-inflammatory drugs (NSAIDs) are among the most used drugs worldwide. Their indications are multiple, mainly to treat various inflammatory diseases or to relief acute pain or fever in various acute or chronic situations.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Consequently, their use is very variable regarding the administration route (orally, parenterally, percutaneously, suppository), the duration of administration (from single dose to long term treatment), the variable dosage according to the type of indication (low to high dose), as monotherapy or in combination with other drugs (for instance, paracetamol). This variability leads frequently to automedication beside the prescription by a care professional. NSAIDs make a heterogenous pharma-co-therapeutic class of drugs, with variable side-effects, gastro-duodenal, intestinal, cutaneous, renal et hepatic. They are responsible for about 10% of cases of drug-induced liver injury.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Ninety-nine % of reported cases of hepatotoxicity are caused by seven NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The estimated incidence of NSAID-induced hepatotoxicity is variable, ranging from 0.29 to 9 per 100,000 patients per year.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However, considering the quantity of consummed NSAIDs, hepatotoxicity is a rare event.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">The specific clinical aspects of liver injuries and the involved mechanisms of each class of NSAIDS are presented below as well as the recent advances for the diagnosis and prediction of hepatotoxicity.</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">HEPATOTOTOXICITY OF THE DIFERENT CLASS OF NSAIDS<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></span><p id="p0015" class="elsevierStylePara elsevierViewall">NSAIDs are classified into families according to their molecular structure: acetic acid derivatives, propionic acid derivatives, salicylates, enolic acid derivatives (Oxicams) and selective COX-2 inhibitors (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>).</p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0020" class="elsevierStylePara elsevierViewall">The review regards cases reported with variable dates of publications and methods of causality assessment. The accuracy of causality assessment is obviously a key -point.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The Roussel-Uclaf Causality Assessment Method Method (RUCAM) developed more than 20 years ago to assess rigorously causlity in suspected drug-induced liver injury has been recently refinied to help clinicians and health authorities.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The RUCAM has been choosed as the reference method in recent international guidelines for DILI evaluation.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Indeed, RUCAM is based on the importance of various types of suspected DILI.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The limitations of RUCAM is that it has not been designed for suspected chronic DILI, which is mostly an unrecognized preexisting liver disease.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Consequently, aiming to provide a fair presentation, we indicate the drugs, cases or series presented in this review which have been assessed with the RUCAM assessement.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Propionic acid derivatives</span><p id="p0025" class="elsevierStylePara elsevierViewall">In this class, the two most hepatotoxic compounds are ibuprofen and naproxen.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Ketoprofen causes lower hepatotoxicity with an increase in transaminases over three times the upper limit of normal in less than 1% of patients and a single case of fulminant hepatitis indexed in LiverTox.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> They mostly cause acute hepatocellular or cholestatic hepatitis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Much less commonly, there are also cases of cholestasis with prolonged course and vanishing bile duct syndrome for ibuprofen.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The mechanism of toxicity is primarily metabolic-idiosyncratic.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> NSAIDs of this class are also responsible for microvesicular steatosis due to an inhibitory effect of the carboxylic radical on mitochondria.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In contrast with cyclins or cordarone, microvesicular steatosis remains benign and are is not accompanied by acute hepatic insufficiency.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Crosshepatotoxicity may occur within NSAIDs of this class as reported between naproxen and fenoprofen.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Acetic acid derivatives</span><p id="p0030" class="elsevierStylePara elsevierViewall">In this class, there are two of the most hepatotoxic NSAIDs: diclofenac and sulindac. They cause acute hepatocellular or cholestatic hepatitis. The mechanism of toxicity is primarily idiosyncratic.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Genetic factors have been demonstrated for diclofenac.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> It is mainly metabolized by CYP2C9, of which there are several polymorphisms but which do not seem to be associated with hepatotoxicity.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In contrast, allelic variants for the genes encoding the enzymes involved in the metabolism of diclofenac UGT2B7, CYP2C8, and ABCC2 have been associated with increased risk of hepatotoxicity, particularly for patients with at least one UGT2B7 allele ⋆ 2 (OR 8.5).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Similarly, allelic variants for cytokine receptors involved in the immune and inflammatory reaction (Interleukins 4 and 10) are associated with the hepatic toxicity of diclofenac.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Some cases of cross-hepatotoxicity between indomethacin and sulindac have been reported.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Salicylates<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></span><p id="p0035" class="elsevierStylePara elsevierViewall">The only NSAID in this class is acetylsalicylic acid, one of the most widely used analgesic and antipyretic treatments in the world. It acts as an irreversible inhibitor of COX 1. Its mechanism of toxicity is dose-depending. While most cases are asymptomatic, cases of severe hepatitis for doses between 1800 and 3200 mg per day (blood level of 25 mg/dL).<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Reye’s syndrome is a particular form of toxicity of acetylsalicylic acid: in children, taking aspirin during a viral infection (chicken pox, influenza) can lead to severe hepatitis with severe microvesicular steatosis.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Enolic acid derivatives (Oxicams)<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></span><p id="p0040" class="elsevierStylePara elsevierViewall">Among the NSAIDs in the class, the most hepatotoxic is piroxicam. It is more frequently acute cholestatic than hepatocellular hepatitis. The mechanism of toxicity is unknown. An idiosyncratic immunoallergic toxicity and toxic metabolites are mentioned first.</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Selective COX-2 inhibitors<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></span><p id="p0045" class="elsevierStylePara elsevierViewall">Rare cases of idiosyncratic acute hepatitis secondary to celecoxib have been described. The mechanism is idiosyncratic and immunoallergic, especially in patients with a history of sulfonamide allergy. Lumiracoxib, another NSAID in this class, was withdrawn from the market in 2007 after more than 20 cases of severe acute hepatitis occurred in Europe and Australia.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> However, a genetic study revealed a strong association between HLA variant DRB1 ⋆ 1501-DQB1 ⋆ 0602-DRB5 ⋆ 0101-DQA1 ⋆ 0102 and hepatotoxicity (OR 7.5).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Lumiracoxib is one of the best examples of the link between genetics and hepatotoxicity.</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Sulfonanilides<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></span><p id="p0050" class="elsevierStylePara elsevierViewall">The only NSAID in the class is nimesulide, a preferred inhibitor of COX 2.</p><p id="p0055" class="elsevierStylePara elsevierViewall">This is mainly acute hepatocellular hepatitis. The mechanism of toxicity is metabolic-idiosyncratic.</p></span></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">SYNTHESIS OF NSAID HEPTATOTOXICITY</span><p id="p0060" class="elsevierStylePara elsevierViewall">In total, NSAID- hepatotoxicity varies from one molecule to another with a variable level of evidence. The majority (99%) of reported cases of hepatotoxicity are attributed to seven NSAIDs (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> For diclofenac, ibuprofen and nimesulide, the causality assessment has been made using the RUCAM;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> for sulindac, naproxen, piroxicam, the causality has been assessed individually without unspecific method of assessment which may lower the level of evidence. For acetylsalicylic acid, hepatotoxicity is described for long with many cases. The role of this drug in the onset of Reye syndrome is well-documented with a comprehensive mechanism. The clinical phenotype is mostly acute liver injury with variable severity from mild and transient increase of transaminases to fulminant hepatitis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Uncommonly, microvesicular steatosis may occur with proprionic acid derivatives with a fair level of evidence since the lesion is reproducible in animals.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Most acute liver injuries associated with NSAIDs appear as idiosyncrasic reaction with or without immunoallergic reactions.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Their mechnisms are only partially elucidated for most of them.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The diagnosis of NSAID hepatotoxicity is frequently difficult because of the absence of specific clinical features.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> It relies mainly on the elimination of other causes and on chronological criteria.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Apart few specific situations, liver biopsy is generally useless.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This reinforce the interest of using specific causality assessment methods. There is no specific treatment of liver injury apart to stop the administration of the offending drug. In case of past liver injury caused by a NSAID, drugs of the same chemical family should be avoided to prevent cross-hepatotoxicity.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In contrast, there is no contra-indication to use a NSAID of another chemical family.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">NEW BIOLOGICAL MARKERS OF DRUG-INDUCED LIVER INJURY<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>></span><p id="p0065" class="elsevierStylePara elsevierViewall">There is an important need to get new markers for diferent steps of idiosyncratic DILI: a) the recognition of real liver injury and its type; the severity of liver injury; the causality of liver injury and the role of DILI and early diagnosis compared to current diagnositc rules (reviewed in reference 13). Recently, new biomarkers of hepatotoxicity have been developed to contribute to an early diagnosis of DILI and predict the severity of liver injury as compared to current diagnostic rules (reviewed in reference 17). The new biomarkers include GLDH (Glutamate dehydrogenase) and SDH (Sorbitol dehydrogenase) proposed as marker for hepatocyte necrosis;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Cytokeratin 18: (caspase-cleaved CytoKeratin-18), a cytoskeletal protein that is very abundant at the hepatic but nonspecific level. Keratin may be a prognostic marker for liver injury because it is markedly higher in patients who have died or transplanted after paracetamol overdose compared to patients who have spontaneously recovered. It has been proposed as marker for apoptosis,<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> HMGB1 (high mobility group box 1), a chromatin binding protein that is passively released by necrotic cells and participates in the activation of the immune system as is the case in some idiosyncratic hepatitis;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> (receptor-1) proposed as marker for immune activation.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Other proposed biomarkers included M-30 (apoptosis), M-65 (apoptosis/necrosis), and microRNA-192 (unspecified liver damage),<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> MCSFR1 (macrophage colony stimulating factor receptor 1): a highly increased marker in cases of idiosyncratic hepatotoxicity secondary to an analgesic, flupirtine;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> osteopontin: a protein associated with the case of severe drug hepatitis associated with a poor prognosis;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> bile acids: the increase of certain bile acids (glycochenodeoxycholic acid, taurochenodeoxycholic acid, taurocholic acid) has been demonstrated in some cases of hepatotoxicity (flupirtine) even in the absence of biological cholestasis.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Despite potentially promising, these new biomarkers exhibit some limitations as recently stressed.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Indeed, ideally, a biomarker of DILI should not only be the signature of a liver injury but also identify the offending drug or, at least, a class of chemical entities.</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">GENETIC FACTORS<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></span><p id="p0070" class="elsevierStylePara elsevierViewall">Many links between drug and genetic hepatotoxicity have been established. In the NSAID category, the best example is lumiracoxib, currently withdrawn from the market, and its association between hepatic toxicity and HLADQA1*0102.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The delay in obtaining the results and their cost did not make it possible to use the search for these genetic factors before the prescription of drugs. They are currently used retrospectively to improve understanding of the mechanisms of toxicity. In the coming years, the availability easy-to use genetic tests might facilitate the diagnosis and help to predict the risk of hepatotoxicity of drugs, including NSAIDs.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> However, the usefulness of genetict testing for the diagnosis and prediction of drug-induced liver injury is still a matter of discussion.</p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">CONCLUSIONS</span><p id="p0075" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">•</span><p id="p0080" class="elsevierStylePara elsevierViewall">NSAIDs are one of the main causes of acute hepatitis especially hepatocellular type.</p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">•</span><p id="p0085" class="elsevierStylePara elsevierViewall">The incidence of severe cases is low but it is one of the most prescribed pharmaco-therapeutic classes in the world.</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">•</span><p id="p0090" class="elsevierStylePara elsevierViewall">Most of NSAID induced acute liver injuries are associated with idiosycratic patterns and only partially understood mechanisms with the exception of aspirin.</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">•</span><p id="p0095" class="elsevierStylePara elsevierViewall">In case of hepatitis, the reintroduction of the incriminated NSAID or of the same class must be proscribed. Another class of NSAIDs can be used.</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">•</span><p id="p0100" class="elsevierStylePara elsevierViewall">New tools to help diagnosis and predict NSAID-related hepatotoxicity are forthcoming in a near future.</p></li></ul></p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1190040" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0010" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1109518" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "s0005" "titulo" => "INTRODUCTION" ] 3 => array:3 [ "identificador" => "s0010" "titulo" => "HEPATOTOTOXICITY OF THE DIFERENT CLASS OF NSAIDS" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "s0015" "titulo" => "Propionic acid derivatives" ] 1 => array:2 [ "identificador" => "s0020" "titulo" => "Acetic acid derivatives" ] 2 => array:2 [ "identificador" => "s0025" "titulo" => "Salicylates," ] 3 => array:2 [ "identificador" => "s0030" "titulo" => "Enolic acid derivatives (Oxicams)," ] 4 => array:2 [ "identificador" => "s0035" "titulo" => "Selective COX-2 inhibitors," ] 5 => array:2 [ "identificador" => "s0040" "titulo" => "Sulfonanilides," ] ] ] 4 => array:2 [ "identificador" => "s0045" "titulo" => "SYNTHESIS OF NSAID HEPTATOTOXICITY" ] 5 => array:2 [ "identificador" => "s0050" "titulo" => "NEW BIOLOGICAL MARKERS OF DRUG-INDUCED LIVER INJURY>" ] 6 => array:2 [ "identificador" => "s0055" "titulo" => "GENETIC FACTORS,,," ] 7 => array:2 [ "identificador" => "s0060" "titulo" => "CONCLUSIONS" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-01-24" "fechaAceptado" => "2018-01-24" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1109518" "palabras" => array:5 [ 0 => "Non-steroidal-anti-inflammatory drugs" 1 => "NSAID" 2 => "Hepatotoxicity" 3 => "Drug-induced hepatitis" 4 => "Pharmacogenetics" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Non-steroidal-anti-inflammatory drugs (NSAIDs) make a heterogenous pharmaco-therapeutic class of drugs among the most used drugs worldwide with various indications, modes of administration and increasing automedication. NSAIDs can cause acute liver injury with variable severity. The recent identification of genetic markers might facilitate the diagnosis and the prediction of hepatotoxicity risk.</p></span>" ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 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">NSAID \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">NSAID Class \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">Molecular structure \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">Clinical Phenotype \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">Proposed mechanism \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">Frequency<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">*</span></a> LiverTox<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">**</span></a> (8) RUCAM Evaluation<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">***</span></a> \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">Increase transaminases Symptomatic hepatitis (Transaminases > 3N) \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">Diclofenac \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">Acetic acid derivatives \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"><elsevierMultimedia ident="201905140709370461"></elsevierMultimedia> \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">Acute hepatitis Hepatocellular \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">Metabolic-Idiosyncratic Increased toxic metabolic formation Mitochondrial dysfunction \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">34.1% > 50 cases \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">15% 2-4% \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">Ibuprofen \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">Propionic acid derivatives \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"><elsevierMultimedia ident="201905140709370462"></elsevierMultimedia> \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">Acute hepatitis Hepatocellular Cholestatic Vanishing bile duct syndrome \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">Metabolic-Idiosyncratic Mitochondrial dysfunction \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">14.6% \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">Same as placebo at low dosages but > 16% for higher dosages \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">Sulindac \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">Acetic acid derivatives \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"><elsevierMultimedia ident="201905140709370463"></elsevierMultimedia> \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">Acute hepatitis Cholestatic or mixed \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">Immunoallergic-Idiosyncratic \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">12.4% > 50 cases \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">Severe rare hepatitis 0.1% of users (5/100,000) \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">Acetylsalicylic acid \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">Salicylates \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"><elsevierMultimedia ident="201905140709370464"></elsevierMultimedia> \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">Acute hepatitis Hepatocellular Reye syndrome \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">Intrinsic toxicitydose dependent Mitochondrial dysfunction \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">12% \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"> \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">Naproxen \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">Propionic acid derivatives \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"><elsevierMultimedia ident="201905140709370465"></elsevierMultimedia> \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">Acute hepatitis Hepatocellular Cholestatic \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">Metabolic and Immunoallergic Idiosyncratic \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">11.1% \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">4% of users 9-12 cases/ 100,000 \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">Piroxicam \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">Enolic acid derivatives \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"><elsevierMultimedia ident="201905140709370466"></elsevierMultimedia> \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">Acute hepatitis Cholestatic hepatocellular \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">Immunoallergic-diosyncratic Increased toxic metabolic formation \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">9.3% \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">3-18% of users 1-5/100,000 \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">Nimesulide \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">Sulfonanilides \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"><elsevierMultimedia ident="201905140709370467"></elsevierMultimedia> \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">Acute hepatitis hepatocellular Cholestatic \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">Metabolic-diosyncratic Mitochondrial dysfunction \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">5.8% > 50 cases \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">15% <1% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2030504.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Frequencies are based on the WHO Program for international Drug Monitoring, Vigibase and on drug-induced liver injury registries from Europe and the US, total cases for NSAIDs = 6023:</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "**" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">LiverTox.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "***" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">RUCAM evaluation: ibuprofen; acetylsalicylic acid; naproxen; nimesulide.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Characteristics of most common NSAIDs associated with hepatotoxicity.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p>" ] ] 1 => array:5 [ "identificador" => "201905140709370461" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 119 "Ancho" => 137 "Tamanyo" => 2607 ] ] ] 2 => array:5 [ "identificador" => "201905140709370462" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 72 "Ancho" => 140 "Tamanyo" => 1723 ] ] ] 3 => array:5 [ "identificador" => "201905140709370463" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 146 "Ancho" => 131 "Tamanyo" => 2960 ] ] ] 4 => array:5 [ "identificador" => "201905140709370464" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 76 "Ancho" => 92 "Tamanyo" => 1700 ] ] ] 5 => array:5 [ "identificador" => "201905140709370465" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 72 "Ancho" => 153 "Tamanyo" => 2003 ] ] ] 6 => array:5 [ "identificador" => "201905140709370466" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 97 "Ancho" => 133 "Tamanyo" => 3041 ] ] ] 7 => array:5 [ "identificador" => "201905140709370467" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 124 "Ancho" => 136 "Tamanyo" => 2773 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nonsteroidal antiinflammatory drugs and leukotriene receptor antagonists" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Lewis J.H." 1 => "Stine J.G." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "KaplowitzN., DeLeveD.L." "titulo" => "Drug-induced liver disease" "paginaInicial" => "369" "paginaFinal" => "401" "edicion" => "3" "serieFecha" => "2013" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prescription and non-prescription analgesic use among the US adult population: results from the third National Health and Nutrition Examination Survey (NHANES III)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Paulose-Ram R." 1 => "Hirsch R." 2 => "Dillon C." 3 => "Losonczy K." 4 => "Cooper M." 5 => "Ostchega Y." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pds.755" "Revista" => array:6 [ "tituloSerie" => "Pharmacoepidemiol Drug Saf" "fecha" => "2003" "volumen" => "12" "paginaInicial" => "315" "paginaFinal" => "326" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12812012" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatotoxicity by Drugs: The Most Common Implicated Agents" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Björnsson E.S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/ijms17020224" "Revista" => array:6 [ "tituloSerie" => "Int J Mol Sci" "fecha" => "2016" "volumen" => "17" "paginaInicial" => "224" "paginaFinal" => "231" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26861310" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Andrade R.J." 1 => "Lucena M.I." 2 => "Fernández M.C." 3 => "Pelaez G." 4 => "Pachkoria K." 5 => "García-Ruiz E." 6 => "Garcia-Munoz B." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.gastro.2005.05.006" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2005" "volumen" => "129" "paginaInicial" => "512" "paginaFinal" => "521" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16083708" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Gulmez S.E." 1 => "Larrey D." 2 => "Pageaux G-P" 3 => "Lignot S." 4 => "Lassalle R." 5 => "Jové J." 6 => "Gatta A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40264-012-0013-7" "Revista" => array:6 [ "tituloSerie" => "Drug Saf" "fecha" => "2013" "volumen" => "36" "paginaInicial" => "135" "paginaFinal" => "144" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23325533" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver injury from nonsteroidal anti-inflammatory drugs in the United States" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Schmeltzer P.A." 1 => "Kosinski A.S." 2 => "Kleiner D.E." 3 => "Hoofnagle J.H." 4 => "Stolz A." 5 => "Fontana R.J." 6 => "Russo M.W." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Liver Int Off J Int Assoc Study Liver" "fecha" => "2016" "volumen" => "36" "paginaInicial" => "603" "paginaFinal" => "609" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nonsteroidal anti-inflammatory drug-induced hepatoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Unzueta A." 1 => "Vargas H.E." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cld.2013.07.009" "Revista" => array:6 [ "tituloSerie" => "Clin Liver Dis" "fecha" => "2013" "volumen" => "17" "paginaInicial" => "643" "paginaFinal" => "656" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24099022" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "LiverTox: http://livertox.nlm.nih.gov." ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-Induced hepatotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Larrey D." 1 => "Ursic-Bedoya J." 2 => "Meunier L." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "SchiffE.R." "titulo" => "Schiff ’s diseases of the liver" "paginaInicial" => "740" "paginaFinal" => "773" "edicion" => "12" "serieFecha" => "2018" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Aithal G.P." 1 => "Ramsay L." 2 => "Daly A.K." 3 => "Sonchit N." 4 => "Leathart J.BS." 5 => "Alexander G." 6 => "Kenna J.G." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.20205" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2004" "volumen" => "39" "paginaInicial" => "1430" "paginaFinal" => "1440" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15122773" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe acute liver injury associated with lumiracoxib" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Pillans P.I." 1 => "Ghiculescu R.A." 2 => "Lampe G." 3 => "Wilson R." 4 => "Wong R." 5 => "Macdonald G.A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1440-1746.2011.07036.x" "Revista" => array:6 [ "tituloSerie" => "J Gastroenterol Hepatol" "fecha" => "2012" "volumen" => "27" "paginaInicial" => "1102" "paginaFinal" => "1105" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22142375" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug induced liver injury: Accuracy of diagnosis in published reports" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Teschke R." 1 => "Frenzel C." 2 => "Wolff A." 3 => "Eickhoff A." 4 => "Schulze J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Hepatol" "fecha" => "2014" "volumen" => "13" "paginaInicial" => "248" "paginaFinal" => "255" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24552867" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RUCAM in drug and herb-induced liver: the update" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Danan G." 1 => "Teschke R." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/ijms17010014" "Revista" => array:5 [ "tituloSerie" => "Int J Mol Sci" "fecha" => "2015" "volumen" => "17" "paginaInicial" => "E14" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26712744" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Case definition and phenotype standardization in drug-induced liver injury" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Aithal G.P." 1 => "Watkins P.B." 2 => "Andrade R.J." 3 => "Larrey D." 4 => "Molokhia M." 5 => "Takikawa H." 6 => "Hunt C.M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/clpt.2011.58" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacol Ther" "fecha" => "2011" "volumen" => "89" "paginaInicial" => "806" "paginaFinal" => "815" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21544079" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug induced liver injury: Do we still need a routine liver biopsy for diagnosis today" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Teschke R." 1 => "Frenzel C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Ann Hepa-tol" "fecha" => "2014" "volumen" => "13" "paginaInicial" => "121" "paginaFinal" => "127" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver biopsy in chronic liver diseases: is there a favorable benefit: risk balance" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Larrey D." 1 => "Meunier L." 2 => "Ursic-Bedoya J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5604/01.3001.0010.0272" "Revista" => array:6 [ "tituloSerie" => "Ann Hepatol" "fecha" => "2017" "volumen" => "16" "paginaInicial" => "487" "paginaFinal" => "489" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28612749" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug Induced Liver Injury: can biomarkers Assist RUCAM in causality Assessment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Teschcke R." 1 => "Schulze J." 2 => "Eickhoff A." 3 => "Danan G." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Int J Mol Sci" "fecha" => "2017" "volumen" => "18" "paginaInicial" => "803" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug-induced liver injury: recent advances in diagnosis and risk assessment" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Kullak-Ublick G.A." 1 => "Andrade R.J." 2 => "Merz M." 3 => "End P." 4 => "Benesic A." 5 => "Gerbes A.L." 6 => "Aithal G.P." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gutjnl-2016-313369" "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "2017" "volumen" => "66" "paginaInicial" => "1154" "paginaFinal" => "1164" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28341748" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent advances in biomarkers and therapeutic interventions for hepatic drug safety-false dawn or new horizon" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Clarke J.I." 1 => "Dear J.W." 2 => "Antoine D.J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1517/14740338.2016.1160057" "Revista" => array:6 [ "tituloSerie" => "Expert Opin Drug Saf" "fecha" => "2016" "volumen" => "15" "paginaInicial" => "625" "paginaFinal" => "634" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26923482" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and other Genes in a Genome-Wide Association Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Nicoletti P." 1 => "Aithal G.P." 2 => "Bjornsson E.S." 3 => "Andrade R.J." 4 => "Sawle A." 5 => "Arrese M." 6 => "Barnhart H.X." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2016.12.016" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2017" "volumen" => "152" "paginaInicial" => "1078" "paginaFinal" => "1089" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28043905" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301504/v1_201905140709/en/main.assets" "Apartado" => array:4 [ "identificador" => "77722" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Viewpoint" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/16652681/0000001700000002/v1_201905140709/S1665268119301504/v1_201905140709/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301504?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 0 | 7 |
| 2024 October | 139 | 16 | 155 |
| 2024 September | 159 | 18 | 177 |
| 2024 August | 86 | 4 | 90 |
| 2024 July | 76 | 5 | 81 |
| 2024 June | 51 | 3 | 54 |
| 2024 May | 32 | 3 | 35 |
| 2024 April | 58 | 8 | 66 |
| 2024 March | 53 | 7 | 60 |
| 2024 February | 43 | 2 | 45 |
| 2024 January | 55 | 21 | 76 |
| 2023 December | 52 | 10 | 62 |
| 2023 November | 43 | 10 | 53 |
| 2023 October | 43 | 8 | 51 |
| 2023 September | 22 | 4 | 26 |
| 2023 August | 29 | 6 | 35 |
| 2023 July | 18 | 2 | 20 |
| 2023 June | 23 | 2 | 25 |
| 2023 May | 56 | 6 | 62 |
| 2023 April | 53 | 0 | 53 |
| 2023 March | 43 | 3 | 46 |
| 2023 February | 24 | 3 | 27 |
| 2023 January | 18 | 6 | 24 |
| 2022 December | 25 | 2 | 27 |
| 2022 November | 27 | 9 | 36 |
| 2022 October | 16 | 8 | 24 |
| 2022 September | 19 | 7 | 26 |
| 2022 August | 39 | 11 | 50 |
| 2022 July | 20 | 11 | 31 |
| 2022 June | 17 | 4 | 21 |
| 2022 May | 16 | 9 | 25 |
| 2022 April | 11 | 14 | 25 |
| 2022 March | 34 | 18 | 52 |
| 2022 February | 19 | 6 | 25 |
| 2022 January | 44 | 11 | 55 |
| 2021 December | 22 | 12 | 34 |
| 2021 November | 34 | 9 | 43 |
| 2021 October | 37 | 14 | 51 |
| 2021 September | 37 | 21 | 58 |
| 2021 August | 62 | 7 | 69 |
| 2021 July | 58 | 12 | 70 |
| 2021 June | 27 | 15 | 42 |
| 2021 May | 40 | 14 | 54 |
| 2021 April | 63 | 21 | 84 |
| 2021 March | 50 | 9 | 59 |
| 2021 February | 38 | 8 | 46 |
| 2021 January | 41 | 11 | 52 |
| 2020 December | 11 | 7 | 18 |
| 2020 November | 12 | 6 | 18 |
| 2020 October | 8 | 13 | 21 |
| 2020 September | 9 | 12 | 21 |
| 2020 August | 14 | 4 | 18 |
| 2020 July | 6 | 11 | 17 |
| 2020 June | 10 | 1 | 11 |
| 2020 May | 10 | 9 | 19 |
| 2020 April | 5 | 4 | 9 |
| 2020 March | 7 | 9 | 16 |
| 2020 February | 6 | 11 | 17 |
| 2020 January | 4 | 8 | 12 |
| 2019 December | 5 | 7 | 12 |
| 2019 November | 3 | 6 | 9 |
| 2019 October | 12 | 3 | 15 |
| 2019 September | 10 | 7 | 17 |
| 2019 August | 7 | 3 | 10 |
| 2019 July | 4 | 11 | 15 |
| 2019 June | 15 | 6 | 21 |
| 2019 May | 15 | 8 | 23 |
Show all
