{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:58:07Z","timestamp":1790927887150,"version":"4.1.0"},"reference-count":14,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>Elevated aminotransferases with concomitant jaundice in drug\u2010induced liver injury (DILI) are associated with adverse\u00a0outcomes, but the prognostic significance of very high aminotransferases without jaundice is unclear. We\u00a0examined selected outcomes of patients with DILI and markedly elevated aminotransferases but normal or near\u2010normal total bilirubin (TBL). We analyzed the data from the prospective Drug\u2010Induced Liver Injury Network (DILIN) and the Spanish DILI registries. Patients were categorized based on peak alanine or aspartate aminotransferase (ALT\/AST) levels\u2014very high (500\u20131,000\u2009U\/L) or towering (&gt;1,000\u2009U\/L)\u2014and concomitant normal (\u22641.0\u2009mg\/dL) or near\u2010normal (1.1\u20132.5\u2009mg\/dL) TBL levels. Primary outcome was subsequent development of nR\u2010based Hy's Law (nR\u00a0\u22655 with TBL &gt;2.5\u2009mg\/dL). A total of 964 patients were analyzed (692 DILIN; 272 Spanish DILI). In both cohorts, very high aminotransferases with normal TBL were rarely followed by nR\u2010based Hy's Law. In DILIN, only 1.3% of patients with very high ALT and normal TBL developed nR\u2010based Hy's Law, whereas risk increased markedly with minimally elevated TBL (odds ratio (OR) 7.8). Towering aminotransferases conferred increased risk regardless of TBL,\u00a0with the highest risk observed when accompanied by minimally elevated TBL (OR 23.6). Similar inflection points were observed in the Spanish DILI Registry, in patients with very high aminotransferases and minimally elevated TBL or towering aminotransferases with or without elevated TBL. In conclusion, patients with DILI and very high aminotransferases may tolerate liver injury well when bilirubin is normal, but even minimal bilirubin elevation or towering aminotransferases signal increased risk for poor outcomes.<\/jats:p>","DOI":"10.1002\/cpt.70397","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T06:33:45Z","timestamp":1785047625000},"page":"1041-1048","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond Hy's Law: Importance of Markedly Elevated Aminotransferases without Hyperbilirubinemia"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-3178","authenticated-orcid":false,"given":"Naga","family":"Chalasani","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-0604","authenticated-orcid":false,"given":"Ismael","family":"Alvarez\u2010Alvarez","sequence":"additional","affiliation":[{"name":"Servicios de Aparato Digestivo y Farmacolog\u00eda Cl\u00ednica, Hospital Universitario Virgen de la Victoria, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA) \u2013 Plataforma BIONAND, Universidad de M\u00e1laga  M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-1020","authenticated-orcid":false,"given":"Paul H.","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Food and Drug Administration  Silver Spring Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0637-1577","authenticated-orcid":false,"given":"Raj","family":"Vuppalanchi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Ghabril","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5848-0493","authenticated-orcid":false,"given":"Ronald","family":"Kamusiime","sequence":"additional","affiliation":[{"name":"Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0988-3439","authenticated-orcid":false,"given":"Huiman","family":"Barnhart","sequence":"additional","affiliation":[{"name":"Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3030-3972","authenticated-orcid":false,"given":"Hao","family":"Niu","sequence":"additional","affiliation":[{"name":"Servicios de Aparato Digestivo y Farmacolog\u00eda Cl\u00ednica, Hospital Universitario Virgen de la Victoria, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA) \u2013 Plataforma BIONAND, Universidad de M\u00e1laga  M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9586-4896","authenticated-orcid":false,"given":"M. Isabel","family":"Lucena","sequence":"additional","affiliation":[{"name":"Servicios de Aparato Digestivo y Farmacolog\u00eda Cl\u00ednica, Hospital Universitario Virgen de la Victoria, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA) \u2013 Plataforma BIONAND, Universidad de M\u00e1laga  M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1565-0757","authenticated-orcid":false,"given":"Raul J.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Servicios de Aparato Digestivo y Farmacolog\u00eda Cl\u00ednica, Hospital Universitario Virgen de la Victoria, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA) \u2013 Plataforma BIONAND, Universidad de M\u00e1laga  M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Drug Induced Liver Injury Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0105-0"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001281"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29283"},{"key":"e_1_2_9_4_1","volume-title":"Guidance for Industry: Drug\u2010Induced Liver Injury\u2014Premarketing Clinical Evaluation","author":"U.S. Food and Drug Administration","year":"2009"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-014-0182-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.02.012"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20081"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.03.050"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000003145"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gastro.2005.05.006"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200932010-00005"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.09.011"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.03.006"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.01.029"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70397","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70397","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70397","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:50:49Z","timestamp":1790927449000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,25]]},"references-count":14,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/cpt.70397"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70397","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,25]]},"assertion":[{"value":"2026-02-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}