Hepatology
In clinical practice these scales are not consistently used for the diagnosis of DILI. In order to obtain better data concerning drug hepatotoxicity and to provide access to a case registry, the National Institutes of Health (US) has sponsored an on-going research consortium titled the Drug-Induced Liver Injury Network (DILIN).42–44
Management of DILI
The management of DILI is based upon proper diagnosis, recognition of the offending agent, and its withdrawal. The decision to discontinue the medication is based on the values of liver enzymes. Drug administration should be stopped whenever ALT > 8 x upper limit of normal (ULN), ALT > 5 x ULN for three weeks, ALT > 3 x ULN + bilirubin > 2 x ULN, prothrombin time/international normalized ratio (PT-INR) > 1.5 x ULN or in the presence of symptoms suggesting liver injury.36
Even after
stopping the drug, the outcome may vary from complete resolution to acute liver failure and death. With the exception of N-acetylcysteine employed in acetaminophen intoxication, no other specific antidotes are currently employed.
Severe cases that progress to acute liver failure may require liver transplantation. Several different scoring systems have been proposed to determine candidates for this procedure. The King’s College Criteria for acute liver failure divides patients in two classes, depending on the etiology (see Table 2), and is useful to predict which patients will survive and which patients will require liver transplantation.45
More recently, computed tomography (CT)-obtained hepatic volumetric analysis has been suggested as a novel parameter in predicting prognosis in DILI patients.47
The model for end-stage liver disease (MELD) criteria, which uses bilirubin, creatinine, and INR can also be used to assess the risk of developing fulminant hepatic failure following acetaminophen intoxication.46
Additional factors associated with a
poor prognosis are concurrent hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV infection.
Specific Examples of DILI
Nearly every class of medication can illicit liver injury; listed below are some examples, but the list is not meant to be conclusive. Consultation with a pharmaceutical reference such as Micromedix is recommended if DILI is suspected.
Generated NAPQI is rapidly bound by glutathione (GST), which prevents the toxic effects. Hepatotoxicity occurs when GST is depleted or when NAPQI generation exceeds GST binding capacity. It is important to recognize that both GST depletion and increased generation of NAPQI occur in alcoholics, and these patients can develop severe liver injury even with low (2–4g/day) doses of acetaminophen.48
Acetaminophen is the classic example of acute, dose-related DILI, and is responsible for the largest number of cases. Acetaminophen is either glucuronylated or sulfa-conjugated to compounds that are excreted in urine. A fraction of the drug is metabolized by CYP2E1, CYP1A2 and CYP3A4 to a toxic intermediate metabolite (N-acetyl-p-benzo-quinone imine, NAPQI) that can interact with intracellular proteins and induce hepatocyte death.9
Symptoms in
the first 24 hours post ingestion typically consist of nausea, vomiting and malaise (phase 1). These symptoms usually abate for 24 hours (phase 2). Then, hepatocellular destruction occurs between 72 and 96 hours post
76
ingestion and is associated with abdominal pain and jaundice, accompanied by nausea and vomiting. Coagulopathy, hepatic encephalopathy and renal failure characterize severe cases, potentially resulting in death. Rising serum levels of AST and ALT reflect hepatocyte destruction. Centrilobular necrosis in zone 3 is classically observed on liver biopsy. Clinical suspicion and a good history provide the diagnosis, which is confirmed by serum acetaminophen levels. The acetaminophen concentration (plotted on the Rumack–Matthew nomogram) and the King’s College Criteria are used to predict prognosis.49
Initial therapeutic
measures include gastric emptying by lavage or ipecac syrup and activated charcoal administration within four hours of ingestion. N-acetyl- cysteine is the specific antidote and can be administered orally or intravenously. Patients that recover from acetaminophen toxicity have no long-term hepatic sequelae. Severe acetaminophen intoxication cases may progress to acute liver failure, and need for liver transplantation is predicted by the King’s College Criteria.
Anesthetics
Halothane-induced DILI usually occurs after multiple exposures and is thought to be driven by immunologic mechanisms.50,51
The conversion of
halothane to trifluoroacetylchloride by the cytochrome p450 (especially by CYP2E1) results in the formation of trifluoroacetylated proteins that serve as neoantigens and drive the production of autoantibodies (anti- CYP2E1) that mediate hepatic destruction.52–54
Clinical history may reveal
fever and jaundice after previous administration(s). Hepatocyte destruction is reflected by elevated serum transaminases, while eosinophilia suggests the immune reaction. Biopsy findings may range from leukocyte infiltration to massive hepatic necrosis. Most of the cases are mild, but acute liver failure may occur, potentially requiring liver transplant.51
Although case reports exist, liver toxicity from newer-generation halogenated anesthetics, such as isofluorane or sevofluorane, is uncommon.
Non-steroidal Anti-inflammatory Drugs
Due to their extensive use, non-steroidal anti-inflammatory drugs (NSAIDs) are also an important cause of hepatotoxicity.55,56
Diclofenac, the
most studied in this class, is glucuronylated and also subjected to cytochrome p450-mediated reactions that result in bioactive products.57,58 Both reactive metabolites and immune mechanisms mediate toxicity. Decreased prostaglandin synthesis due to cyclooxygenase (COX) inhibition may also enhance injury. Chronic diclofenac administration may result in elevated ALT levels in the first four–six months of therapy, but severe toxicity has also been reported.59
Besides diclofenac, bromfenac,
nimesulide and sulindac are the NSAIDs most frequently associated with hepatotoxicity.56,60
severe toxicity resulting in acute liver failure.61
Nimesulide administration has been reported to illicit Sulindac and ibuprofen are
associated with cholestatic DILI that is reversible after drug withdrawal, although fatal cases have also been reported.62,63
Antimicrobial Medications
Antituberculosis drugs are reported to be hepatotoxic in up to 35% of patients receiving these medications.66–69
Antibiotic-induced hepatotoxicity is responsible for 25–45% of DILI cases.43,64,65
The American Thoracic
Isoniazid (INH) is metabolized in the liver mainly to mono- and diacetylhydrazine and several other compounds. Genetic variations in
Society has published formal guidelines on how to monitor these patients for DILI.70
US GASTROENTEROLOGY & HEPATOLOGY REVIEW
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