The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury
Background & Aims Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset p...
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| Veröffentlicht in: | Liver international 2019-02, Vol.39 (2), p.401-410 |
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| creator | Gonzalez‐Jimenez, Andres McEuen, Kristin Chen, Minjun Suzuki, Ayako Robles‐Diaz, Mercedes Medina‐Caliz, Inmaculada Bessone, Fernando Hernandez, Nelia Arrese, Marco Parana, Raymundo Lucena, M. Isabel Stephens, Camilla Andrade, Raúl J. |
| description | Background & Aims
Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry.
Methods
Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two‐tier regression‐based model was used to assess host/drug interactions affecting the probability of delayed onset.
Results
Antibacterial and anti‐inflammatory drugs accounted for the delayed onset cases. Drug property of |
| doi_str_mv | 10.1111/liv.13952 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2172062591</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2172062591</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4192-e94dfe34634e7fcb1ffef2747567b94cad380f8da489d2a410b4ed12a70fb93f3</originalsourceid><addsrcrecordid>eNp1kL1OwzAYRS0EoqUw8ALIEhND2vgnTTwixE-lSiyFNXLizzRVEgc7AWXjEXhGngS3Kd3w4ivr-PjzReiShFPi16wsPqaEiYgeoTHhcRIwysjxIVM2QmfObcKQCBGRUzRiPkU0SsaoWq0BF7UuO6hzwEZjZbs33FjTgG0LcFjWCq-Na7GWeWusw6bGCkrZg_LRQbu95PqqaU3lvGon-Pn6LmrV5Z7xw4H155vO9ufoRMvSwcV-n6CXh_vV3VOwfH5c3N0ug5wTQQMQXGlgfM44xDrPiNagaczjaB5ngudSsSTUiZI8EYpKTsKMgyJUxqHOBNNsgq4Hr__HeweuTTems7V_MqUkpuGcRoJ46magcmucs6DTxhaVtH1KwnRbbOpnT3fFevZqb-yyCtSB_GvSA7MB-CxK6P83pcvF66D8BaKJhNw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2172062591</pqid></control><display><type>article</type><title>The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury</title><source>MEDLINE</source><source>Wiley Online Library All Journals</source><creator>Gonzalez‐Jimenez, Andres ; McEuen, Kristin ; Chen, Minjun ; Suzuki, Ayako ; Robles‐Diaz, Mercedes ; Medina‐Caliz, Inmaculada ; Bessone, Fernando ; Hernandez, Nelia ; Arrese, Marco ; Parana, Raymundo ; Lucena, M. Isabel ; Stephens, Camilla ; Andrade, Raúl J.</creator><creatorcontrib>Gonzalez‐Jimenez, Andres ; McEuen, Kristin ; Chen, Minjun ; Suzuki, Ayako ; Robles‐Diaz, Mercedes ; Medina‐Caliz, Inmaculada ; Bessone, Fernando ; Hernandez, Nelia ; Arrese, Marco ; Parana, Raymundo ; Lucena, M. Isabel ; Stephens, Camilla ; Andrade, Raúl J.</creatorcontrib><description>Background & Aims
Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry.
Methods
Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two‐tier regression‐based model was used to assess host/drug interactions affecting the probability of delayed onset.
Results
Antibacterial and anti‐inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4‐32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3‐6.1, P = 0.0063) and the absence of pre‐existing conditions in a patient (OR: 2.55, 95% CI: 1.3‐4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre‐existing cardiac diseases.
Conclusions
This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.</description><identifier>ISSN: 1478-3223</identifier><identifier>EISSN: 1478-3231</identifier><identifier>DOI: 10.1111/liv.13952</identifier><identifier>PMID: 30195258</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Adult ; Aged ; Chemical and Drug Induced Liver Injury - etiology ; Confidence intervals ; Coronary artery disease ; Data Mining ; Diagnostic systems ; Drug Interactions ; Drugs ; Electronegativity ; Female ; Heart diseases ; hepatotoxicity ; Humans ; Inflammation ; interactions ; Internationality ; Liability ; Liver ; Male ; Metabolism ; Middle Aged ; Mitochondria ; Multivariate Analysis ; Patients ; Phenotype ; Phenotypes ; Properties (attributes) ; Registries ; Regression analysis ; Regression models ; Risk Factors ; Severity of Illness Index ; Signs and symptoms ; Statistical analysis</subject><ispartof>Liver international, 2019-02, Vol.39 (2), p.401-410</ispartof><rights>2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><rights>2019 John Wiley & Sons A/S</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4192-e94dfe34634e7fcb1ffef2747567b94cad380f8da489d2a410b4ed12a70fb93f3</citedby><cites>FETCH-LOGICAL-c4192-e94dfe34634e7fcb1ffef2747567b94cad380f8da489d2a410b4ed12a70fb93f3</cites><orcidid>0000-0003-1824-1067 ; 0000-0002-6453-2351 ; 0000-0001-9586-4896 ; 0000-0002-0499-4191</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fliv.13952$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fliv.13952$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27923,27924,45573,45574</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30195258$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gonzalez‐Jimenez, Andres</creatorcontrib><creatorcontrib>McEuen, Kristin</creatorcontrib><creatorcontrib>Chen, Minjun</creatorcontrib><creatorcontrib>Suzuki, Ayako</creatorcontrib><creatorcontrib>Robles‐Diaz, Mercedes</creatorcontrib><creatorcontrib>Medina‐Caliz, Inmaculada</creatorcontrib><creatorcontrib>Bessone, Fernando</creatorcontrib><creatorcontrib>Hernandez, Nelia</creatorcontrib><creatorcontrib>Arrese, Marco</creatorcontrib><creatorcontrib>Parana, Raymundo</creatorcontrib><creatorcontrib>Lucena, M. Isabel</creatorcontrib><creatorcontrib>Stephens, Camilla</creatorcontrib><creatorcontrib>Andrade, Raúl J.</creatorcontrib><title>The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury</title><title>Liver international</title><addtitle>Liver Int</addtitle><description>Background & Aims
Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry.
Methods
Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two‐tier regression‐based model was used to assess host/drug interactions affecting the probability of delayed onset.
Results
Antibacterial and anti‐inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4‐32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3‐6.1, P = 0.0063) and the absence of pre‐existing conditions in a patient (OR: 2.55, 95% CI: 1.3‐4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre‐existing cardiac diseases.
Conclusions
This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.</description><subject>Adult</subject><subject>Aged</subject><subject>Chemical and Drug Induced Liver Injury - etiology</subject><subject>Confidence intervals</subject><subject>Coronary artery disease</subject><subject>Data Mining</subject><subject>Diagnostic systems</subject><subject>Drug Interactions</subject><subject>Drugs</subject><subject>Electronegativity</subject><subject>Female</subject><subject>Heart diseases</subject><subject>hepatotoxicity</subject><subject>Humans</subject><subject>Inflammation</subject><subject>interactions</subject><subject>Internationality</subject><subject>Liability</subject><subject>Liver</subject><subject>Male</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Mitochondria</subject><subject>Multivariate Analysis</subject><subject>Patients</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Properties (attributes)</subject><subject>Registries</subject><subject>Regression analysis</subject><subject>Regression models</subject><subject>Risk Factors</subject><subject>Severity of Illness Index</subject><subject>Signs and symptoms</subject><subject>Statistical analysis</subject><issn>1478-3223</issn><issn>1478-3231</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kL1OwzAYRS0EoqUw8ALIEhND2vgnTTwixE-lSiyFNXLizzRVEgc7AWXjEXhGngS3Kd3w4ivr-PjzReiShFPi16wsPqaEiYgeoTHhcRIwysjxIVM2QmfObcKQCBGRUzRiPkU0SsaoWq0BF7UuO6hzwEZjZbs33FjTgG0LcFjWCq-Na7GWeWusw6bGCkrZg_LRQbu95PqqaU3lvGon-Pn6LmrV5Z7xw4H155vO9ufoRMvSwcV-n6CXh_vV3VOwfH5c3N0ug5wTQQMQXGlgfM44xDrPiNagaczjaB5ngudSsSTUiZI8EYpKTsKMgyJUxqHOBNNsgq4Hr__HeweuTTems7V_MqUkpuGcRoJ46magcmucs6DTxhaVtH1KwnRbbOpnT3fFevZqb-yyCtSB_GvSA7MB-CxK6P83pcvF66D8BaKJhNw</recordid><startdate>201902</startdate><enddate>201902</enddate><creator>Gonzalez‐Jimenez, Andres</creator><creator>McEuen, Kristin</creator><creator>Chen, Minjun</creator><creator>Suzuki, Ayako</creator><creator>Robles‐Diaz, Mercedes</creator><creator>Medina‐Caliz, Inmaculada</creator><creator>Bessone, Fernando</creator><creator>Hernandez, Nelia</creator><creator>Arrese, Marco</creator><creator>Parana, Raymundo</creator><creator>Lucena, M. Isabel</creator><creator>Stephens, Camilla</creator><creator>Andrade, Raúl J.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0003-1824-1067</orcidid><orcidid>https://orcid.org/0000-0002-6453-2351</orcidid><orcidid>https://orcid.org/0000-0001-9586-4896</orcidid><orcidid>https://orcid.org/0000-0002-0499-4191</orcidid></search><sort><creationdate>201902</creationdate><title>The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury</title><author>Gonzalez‐Jimenez, Andres ; McEuen, Kristin ; Chen, Minjun ; Suzuki, Ayako ; Robles‐Diaz, Mercedes ; Medina‐Caliz, Inmaculada ; Bessone, Fernando ; Hernandez, Nelia ; Arrese, Marco ; Parana, Raymundo ; Lucena, M. Isabel ; Stephens, Camilla ; Andrade, Raúl J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4192-e94dfe34634e7fcb1ffef2747567b94cad380f8da489d2a410b4ed12a70fb93f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Chemical and Drug Induced Liver Injury - etiology</topic><topic>Confidence intervals</topic><topic>Coronary artery disease</topic><topic>Data Mining</topic><topic>Diagnostic systems</topic><topic>Drug Interactions</topic><topic>Drugs</topic><topic>Electronegativity</topic><topic>Female</topic><topic>Heart diseases</topic><topic>hepatotoxicity</topic><topic>Humans</topic><topic>Inflammation</topic><topic>interactions</topic><topic>Internationality</topic><topic>Liability</topic><topic>Liver</topic><topic>Male</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Mitochondria</topic><topic>Multivariate Analysis</topic><topic>Patients</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Properties (attributes)</topic><topic>Registries</topic><topic>Regression analysis</topic><topic>Regression models</topic><topic>Risk Factors</topic><topic>Severity of Illness Index</topic><topic>Signs and symptoms</topic><topic>Statistical analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gonzalez‐Jimenez, Andres</creatorcontrib><creatorcontrib>McEuen, Kristin</creatorcontrib><creatorcontrib>Chen, Minjun</creatorcontrib><creatorcontrib>Suzuki, Ayako</creatorcontrib><creatorcontrib>Robles‐Diaz, Mercedes</creatorcontrib><creatorcontrib>Medina‐Caliz, Inmaculada</creatorcontrib><creatorcontrib>Bessone, Fernando</creatorcontrib><creatorcontrib>Hernandez, Nelia</creatorcontrib><creatorcontrib>Arrese, Marco</creatorcontrib><creatorcontrib>Parana, Raymundo</creatorcontrib><creatorcontrib>Lucena, M. Isabel</creatorcontrib><creatorcontrib>Stephens, Camilla</creatorcontrib><creatorcontrib>Andrade, Raúl J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Liver international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gonzalez‐Jimenez, Andres</au><au>McEuen, Kristin</au><au>Chen, Minjun</au><au>Suzuki, Ayako</au><au>Robles‐Diaz, Mercedes</au><au>Medina‐Caliz, Inmaculada</au><au>Bessone, Fernando</au><au>Hernandez, Nelia</au><au>Arrese, Marco</au><au>Parana, Raymundo</au><au>Lucena, M. Isabel</au><au>Stephens, Camilla</au><au>Andrade, Raúl J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury</atitle><jtitle>Liver international</jtitle><addtitle>Liver Int</addtitle><date>2019-02</date><risdate>2019</risdate><volume>39</volume><issue>2</issue><spage>401</spage><epage>410</epage><pages>401-410</pages><issn>1478-3223</issn><eissn>1478-3231</eissn><abstract>Background & Aims
Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry.
Methods
Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two‐tier regression‐based model was used to assess host/drug interactions affecting the probability of delayed onset.
Results
Antibacterial and anti‐inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4‐32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3‐6.1, P = 0.0063) and the absence of pre‐existing conditions in a patient (OR: 2.55, 95% CI: 1.3‐4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre‐existing cardiac diseases.
Conclusions
This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30195258</pmid><doi>10.1111/liv.13952</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-1824-1067</orcidid><orcidid>https://orcid.org/0000-0002-6453-2351</orcidid><orcidid>https://orcid.org/0000-0001-9586-4896</orcidid><orcidid>https://orcid.org/0000-0002-0499-4191</orcidid></addata></record> |
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| subjects | Adult Aged Chemical and Drug Induced Liver Injury - etiology Confidence intervals Coronary artery disease Data Mining Diagnostic systems Drug Interactions Drugs Electronegativity Female Heart diseases hepatotoxicity Humans Inflammation interactions Internationality Liability Liver Male Metabolism Middle Aged Mitochondria Multivariate Analysis Patients Phenotype Phenotypes Properties (attributes) Registries Regression analysis Regression models Risk Factors Severity of Illness Index Signs and symptoms Statistical analysis |
| title | The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury |
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