title: Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations.
abstract: Drug-induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury.
  
  
  CONCLUSIONS
  We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome.
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: Naga P
authors.initials: NP
authors.lastname: Chalasani
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fontana
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.forename: Paul H
authors.initials: PH
authors.lastname: Hayashi
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Davern
authors.forename: Victor
authors.initials: V
authors.lastname: Navarro
authors.forename: Rajender
authors.initials: R
authors.lastname: Reddy
authors.forename: Jayant A
authors.initials: JA
authors.lastname: Talwalkar
authors.forename: Andrew
authors.initials: A
authors.lastname: Stolz
authors.forename: Jiezhun
authors.initials: J
authors.lastname: Gu
authors.forename: Huiman
authors.initials: H
authors.lastname: Barnhart
authors.forename: Jay H
authors.initials: JH
authors.lastname: Hoofnagle
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002648:Child; D002779:Cholestasis / Q000473:pathology*; D002908:Chronic Disease; D005260:Female; D006505:Hepatitis / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010641:Phenotype; D011446:Prospective Studies; D055815:Young Adult
references.citation: Liver Int. 2006 Dec;26(10):1225-33
references.pmid: 17105588
references.citation: Hepatology. 2011 Sep 2;54(3):931-9
references.pmid: 21674554
references.citation: J Hepatol. 1995 Jun;22(6):696-9
references.pmid: 7560864
references.citation: Gastroenterology. 2008 Dec;135(6):1924-34, 1934.e1-4
references.pmid: 18955056
references.citation: Clin Liver Dis. 2007 Aug;11(3):477-505, v
references.pmid: 17723916
references.citation: J Clin Pathol. 2009 Jun;62(6):481-92
references.pmid: 19474352
references.citation: Hepatology. 2010 Aug;52(2):730-42
references.pmid: 20564754
references.citation: Hepatology. 2010 Jun;51(6):2117-26
references.pmid: 20512999
references.citation: Toxicol Pathol. 2005;33(1):155-64
references.pmid: 15805067
references.citation: Semin Liver Dis. 2009 Nov;29(4):364-72
references.pmid: 19826970
references.citation: J Clin Epidemiol. 1993 Nov;46(11):1323-30
references.pmid: 8229110
references.citation: Scand J Gastroenterol. 1979;14(4):497-502
references.pmid: 482863
references.citation: J Hepatol. 1986;3(2):228-32
references.pmid: 3794303
references.citation: Drug Saf. 2009;32(1):55-68
references.pmid: 19132805
references.citation: Handb Exp Pharmacol. 2010;(196):311-65
references.pmid: 20020267
references.citation: Aliment Pharmacol Ther. 2007 Jun 15;25(12):1411-21
references.pmid: 17539980
references.citation: Am J Med. 1980 Nov;69(5):733-8
references.pmid: 7435512
references.citation: Ann Intern Med. 2002 Dec 17;137(12):947-54
references.pmid: 12484709