RT Book, Section
A1 Lee, William M.
A1 Dienstag, Jules L.
A2 Jameson, J. Larry
A2 Fauci, Anthony S.
A2 Kasper, Dennis L.
A2 Hauser, Stephen L.
A2 Longo, Dan L.
A2 Loscalzo, Joseph
SR Print(0)
ID 1159156173
T1 Toxic and Drug-Induced Hepatitis
T2 Harrison's Principles of Internal Medicine, 20e
YR 2018
FD 2018
PB McGraw-Hill Education
PP New York, NY
SN 9781259644016
LK accesspharmacy.mhmedical.com/content.aspx?aid=1159156173
RD 2024/04/19
AB Liver  injury  is  a  possible  consequence  of  ingestion  of  any  xenobiotic,  including  industrial  toxins,  pharmacologic  agents,  and  complementary  and  alternative  medications  (CAMs).  Among  patients  with  acute  liver  failure,  drug-induced  liver  injury  (DILI)  is  the  most  common  cause,  and  evidence  for  hepatotoxicity  detected  during  clinical  trials  for  drug  development  is  the  most  common  reason  for  failure  of  compounds  to  reach  approval  status.  DILI  requires  careful  history  taking  to  identify  unrecognized  exposure  to  chemicals  used  in  work  or  at  home,  drugs  taken  by  prescription  or  bought  over  the  counter,  and  herbal  or  dietary  supplement  medicines.  Hepatotoxic  drugs  can  injure  the  hepatocyte  directly,  for  example,  via  a  free-radical  or  metabolic  intermediate  that  causes  peroxidation  of  membrane  lipids  and  that  results  in  liver  cell  injury.  Alternatively,  a  drug  or  its  metabolite  may  activate  components  of  the  innate  or  adaptive  immune  system,  stimulate  apoptotic  pathways,  or  initiate  damage  to  bile  excretory  pathways  (Fig.  333-1).  Interference  with  bile  canalicular  pumps  can  allow  endogenous  bile  acids,  which  can  injure  the  liver,  to  accumulate.  Such  secondary  injury,  in  turn,  may  lead  to  necrosis  of  hepatocytes;  injure  bile  ducts,  producing  cholestasis;  or  block  pathways  of  lipid  movement,  inhibit  protein  synthesis,  or  impair  mitochondrial  oxidation  of  fatty  acids,  resulting  in  lactic  acidosis  and  intracellular  triglyceride  accumulation  (expressed  histologically  as  microvesicular  steatosis).  In  other  instances,  drug  metabolites  sensitize  hepatocytes  to  toxic  cytokines.  The  differences  observed  between  susceptible  and  nonsusceptible  drug  recipients  may  be  attributable  to  human  leukocyte  antigens  (HLA)  haplotypes  that  determine  binding  of  drug-related  haptens  on  the  cell  surface  as  well  as  to  polymorphisms  in  elaboration  of  competing,  protective  cytokines,  as  has  been  suggested  for  acetaminophen  hepatotoxicity  (see  below).  Immune  mechanisms  may  include  cytotoxic  lymphocytes  or  antibody-mediated  cellular  cytotoxicity.  In  addition,  a  role  has  been  shown  for  activation  of  nuclear  transporters,  such  as  the  constitutive  androstane  receptor  (CAR)  or,  more  recently,  the  pregnane  X  receptor  (PXR),  in  the  induction  of  drug  hepatotoxicity.