Diagnostic evaluation of suspected Drug-Induced Liver Injury Ynto de Boer, MD Department of Gastroenterology and Hepatology
Disclosure No disclosures
Drug-induced liver injury?
Outline What is DILI? What, other than the drug, causes DILI? How to diagnose DILI? Resources
Drug-induced liver injury Hepatotoxicity: Hepatocytes ALT/AST elevation Cholangiocytes Alk Phos elevation Direct toxicity, dose dependent (eg. Paracetamol; ~50% of DILI) Idiosyncratic injury
Drug-induced liver injury Ciprofloxacin - Acute hepatitic injury Isoniazid - chronic hepatitic injury Anabolic steroid - Acute cholestatic injury Amox-clav - Chronic cholestatic injury Duloxetine - Cholestatic hepatitis injury Kleiner et al. Hepatology 2014
Mechanisms Cell death: apoptosis and necrosis Reactive metabolite formation/bioactivation Drug transporter mediated drug-induced hepatotoxicity Immune-mediated response Mitochondrial dysfunction Activation of stress signaling pathways Shesu et al. Clin Liv Dis 2017
Mechanisms Shesu et al. Clin Liv Dis 2017
Genetics - Flucloxacillin HLA-B*57:01 Daly et al. Nat Genet 2009
Genetics overall 864 cases of DILI without amox/clav and fluclox Nicolleti et al. Gastroenerology 2016
Genetics Association Effect Size of rs72631567, A*33:01, and rs28521457 Across Different Liver Injury Patterns Cohort Associated variant OR 95% CI P value AF cases AF controls Entire DILI cohort rs72631567 2.0 1.6 2.5 9.7 10 9 0.05 0.03 A*33:01 2.6 1.8 3.7 7.0 10 8 0.02 0.01 rs28521457 1.5 1.3 1.9 7.0 10 8 0.06 0.04 Cholestatic and mixed DILI cohort rs72631567 2.4 1.7 3.4 9.5 10 7 0.06 0.03 A*33:01 5.0 3.3 7.9 4.2 10 13 0.04 0.01 rs28521457 1.0 0.7 1.5.9 0.04 0.04 Hepatocellular DILI cohort rs72631567 1.6 1.2 2.3 2.5 10 3 0.04 0.03 A*33:01 1.5 0.8 2.6.19 0.01 0.011 rs28521457 2.1 1.6 2.7 4.8 10 9 0.08 0.040 Nicolleti et al. Gastroenerology 2016
Epidemiology Ahmad et al. Clin Liv Dis 2017
Idiosyncratic DILI National studies of drug-induced liver injury incidence Country Iceland France Korea United Kingdom Spain Sweden Years of study 2010 2011 1997 2000 2005 2007 1994 1999 2004 2009 1995 2005 Study type Prospective Prospective Prospective Retrospective Retrospective Retrospective Number of DILI cases 96 34 371 128 57 77 Crude DILI incidence rate/100,000 per year 19.1 13.9 12 2.4 3.01 2.3 Ahmad et al. Clin Liv Dis 2017
Idiosyncratic DILI Drug-induced liver injury registries across the world Country United States Spain Korea Years of study 2004 2013 1994 2004 2005 2007 Study type Prospective Prospective Prospective Number of DILI cases 899 461 371 Antimicrobials (% of total) 45.3% 32% HDS (% of total) 16.1% 73% Ahmad et al. Clin Liv Dis 2017
Idiosyncratic DILI Prospective US DILIN study in 899 patients 2004 2014: Chalasani et al. Gastroenterology 2015
Idiosyncratic DILI Prospective US DILIN study in 899 patients 2004 2014: Therapeutic classes n Individual agents n 1 Antimicrobials 408 1 Amoxicillin-clavulanate 91 2 Herbal and dietary supplements 145 2 Isoniazid 48 3 Cardiovascular agents 88 3 Nitrofurantoin 42 4 Central nervous system agents 82 4 Sulfamethoxazole/trimethoprim 31 5 Anti-neoplastic agents 49 5 Minocycline 28 6 Analgesics 33 6 Cefazolin 20 7 Immunomodulatory 27 7 Azithromycin 18 8 Endocrine 20 8 Ciprofloxacin 16 9 Rheumatologic 13 9 Levofloxacin 13 10 Gastrointestinal 12 10 Diclofenac 12 Chalasani et al. Gastroenterology 2015
Clinical presentation Mild transaminase elevation Acute liver failure Bilirubinemia Up to 51% of transplantation for acute liver failure is due to DILI Ostapowicz et al. Ann Intern Med 2002
Augmentin Mild transaminase elevation Acute liver failure Bilirubinemia 64 year old man Up to 51% of transplantation for acute liver failure is due to DILI livertox.nih.gov
Minocycline Mild transaminase elevation Acute liver failure Bilirubinemia 64 year old man 55 year old woman Up to 51% of transplantation for acute liver failure is due to DILI livertox.nih.gov
Unexplained liver test abnormalities Ascertain the type of injury Exclusion of other etiologies: obstruction, (acute) viral hepatitis, (non-)alcoholic hepatitis, shock liver, autoimmune liver disease History of exposure to drugs, herbals and dietary supplements? Look for typical/distinguishing features: immunoallergic or autoimmune features
Hepatocellular vs cholestatic: the R-ratio Normalised ALT/ALP ratio: (ALT/ULN) (Alk Phos/ULN) >5: hepatocellular 2 5: mixed hepatic injury <2: cholestatic
Characteristics for causality assessment Time to onset/latency Course Risk factors Concomitant drugs Nondrug causes of liver injury Previous information on the hepatotoxicity of the drug Response to rechallenge Danan et al. Clin Epidemiol 1993
Risk factors Age: exposure, multiple drugs Gender: metabolism, exposure Alcohol Other liver disease Ethnicity/Genetics: Asian ethnicity HLA genotypes Danan et al. Clin Epidemiol 1993
Phenotypes Autoimmune (ANA, SMA, IgG): nitrofurantoin, minocycline, hydralazine, methyldopa Immunoallergic (rash, fever, eosinophilia): aromatic anticonvulsants, allopurinol, sulfonamides and fluoroquinolones Drug specific phenomena: icterus in anabolic steroids
Diagnostic scores: RUCAM Roussel-Uclaf Causality Assessment Method: The individual points range from -3 to +3 The total possible score ranges from -9 to +14. 0 or less excluded 1 to 2 unlikely 3 to 5 possible 6 to 8 probable >8, highly probable Danan et al. Clin Epidemiol 1993
Diagnostic scores: RUCAM Danan et al. Clin Epidemiol 1993
Liver biopsy Can be helpful, but is usually not necessary Exclusion of other etiologies Distinctive patterns can be recognised Kleiner et al. Hepatology 2014
Liver biopsy DILI and AIH Histologic features AIH DILI Severe portal inflammation ( grade 2) * Prominent intra-acinar lymphocytes *h Prominent intra-acinar eosinophils * Cholestasis canalicular *h, *c Prominent portal plasma cells * Rosette formation * Any levels of fibrosis ( grade 1) * Prominent port neutrophils *c Hepatocellular cholestasis *c Severer focal necrosis ( grade 4) * Suzuki et al. Hepatology 2011
Autoimmune features in DILI adslkf nitrofurantoin, minocycline, methyldopa and hydralazine De Boer et al. Clin Gastroenterol Hepatol 2017
Hy s Law Hyman Zimmerman: drug-induced hepatocellar jaundice is a serious lesion, with mortality from 10 to 50% Bob Temple: Hepatocellular-type injury (ALT > 3 upper limit of normal: ULN) Bilirubin >2x ULN, no evidence of obstruction (> Alk Phos) or Gilbert s syndrome Exclude other causes Temple Pharmacoepidemiol Drug Saf 2006
Outcome US DILIN outcome data Characteristics Antimicrobials Cardiovascular CNS agents Antineoplastics Analgesics (n = 408) (n = 88) (n = 82) (n = 49) (n = 33) Fatal, (%) 6.9 5.7 6 10 3 Death, at any time (%) 5.1 5.7 6.1 29 3 Liver transplantation (%) 3.9 2.3 3.7 0 0 Chalasani et al. Gastroenterology 2015
Outcome Iceland Björnsson et al. Gastroenterology 2013
Herbal and dietary supplements The incidence of HDS-ILI is rising Ask, and ask again De Boer et al. Clin Liv Dis 2017
Herbal and dietary supplements De Boer et al. Clin Liv Dis 2017
Livertox adslkf livertox.nih.gov
Conclusion DILI can mimic any other liver disease and diagnosis is based on careful history and pattern of injury Liver biopsy may be helpful but generally not necessary HDS product are often not perceived as drugs or potentially dangerous: Ask and ask again A helpful resource: livertox.nih.gov
Thank you for your attention!