induced liver toxicity （dilt）药物引起的肝毒性（dilt）课件

1 Drug Induced Liver Toxicity (DILT) By: Mahmoud Mahmoud, MD, PhD 2 Illustration of the proposed mechanism of DILI, which involves drug metabolism, hepatocyte damage, activation of innate immune cells, and production of tissue- damaging and tissue-protective mediators. CYP indicates cytochrome P450; IFN, interferon; IL, interleukin; NK, natural killer cell; NKT, natural killer T cell; TNF, tumor necrosis factor. 3 nLiver injury occurs with many drugs through a variety of mechanisms . nThe annual incidence is generally felt to be between one in 10,000 to 100,000; 4 It is responsible for nIt accounts for up to 10 percent of all adverse drug reactions. nIt is seen in up to 30 percent of patients who present with acute hepatitis and represents up to 10 percent of consultations by hepatologists, and about 1 percent of all general medical admissions. nIt is the cause of acute jaundice in up to 50 percent of patients. nIt is the most common cause of acute liver failure in the United States, and is the most frequently cited reason for withdrawal of medications from the marketplace. 5 Classifications of drug-induced liver injury Type of classificationExamples Clinical laboratory Hepatocellular Cholestatic Mixed hepatocellular/cholestatic Mechanism of hepatotoxicity Direct hepatotoxicity Idiosyncratic Immune-mediated Metabolic Histologic findings Cellular necrosis or apoptosis Cholestasis Steatosis Fibrosis Phospholipidosis Granulomatous Sinuoidal obstruction syndrome 6 SPECTRUM OF DRUG- INDUCED LIVER INJURY nClassification is based upon: The clinical presentation and laboratory features, the mechanism of toxicity, and/or the histological findings. nAcute presentations range from asymptomatic mild biochemical abnormalities to an acute illness with jaundice that resembles viral hepatitis to acute liver failure. Acute Presentation: njaundice (serum bilirubin 3 times the upper limit of normal) + aminotransferase elevations is associated with a worse prognosis than isolated aminotransferase abnormalities. nsome drugs are associated with chronic histologic inflammatory changes and a clinical syndrome resembling autoimmune hepatitis while others cause endothelial damage or thrombosis leading to vascular complications such as veno-occlusive disease or Budd-Chiari syndrome. nWithdrawal of the offending drug usually leads to reversal of the injury. However, some types of toxicity can be associated with a progressive course, possibly leading to fibrosis or cirrhosis, despite discontinuation of the drug. 7 Subclinical nMany drugs can induce asymptomatic elevations in liver enzymes without producing overt clinical disease. n Drug-induced liver injury (DILI) is generally considered subclinical or insignificant if the serum alanine aminotransferase (ALT) is 2 to 5 ALT: alanine aminotransferase; ALP: alkaline phosphatase; ULN: upper limit normal; R: ALT/ULN divided by ALP/ULN. 37 Acute injury Hepatocellular Acarbose Acetaminophen Allopurinol Aspirin Buproprion Bromfenac Diclofenac Fluoxetine Halothane Isoniazid Ketoconazole Lisinopril Losartan Ethanol Methyl-dopa Nefazodone Nevirapine Paroxetine Phenytoin Risperidone Sertraline Statins Tetracycline Trazodone Thiazolidinediones Trovafloxacin Valproate Pyrazinamide Riphampin Cholestasis ACE inhibitors Amoxicillin/Clavulanate Anabolic Steroids Azathioprine Chlorpromazine Clopidogrel Cytarabine Erythromycins Estrogens Ethanol Irbesartan Phenothiazines Sulindac Terbinafine Tricyclics Mixed Amitryptilline Azathioprine Captopril Carbamazepine Clindamycin Cyproheptadine Enalapril Flutamide Ibuprofen Nitrofurantoin Phenobarbital Phenothiazines Phenytoin Sulfonamides Trazodone Sulfonamides Verapamil 38 Treatment for drug-induced hepatitis: nThe goal of treatment for drug-induced hepatitis is to : n1- discontinue taking the causative agent n2- monitor the liver closely while it recovers. n3- Some drugs may cause a slight increase in liver enzymes without symptoms. It may not be necessary to discontinue using these medications. n4- N-acetylcysteine for acetaminophen toxicity n5- L-carnitine for cases of valproic acide overdose n6- Corticosteroids are of unproven benefit for most