Epidemiology

• Drug-Induced Hepatic Injury is the Most Frequently Stated Reason for Drug Withdrawal from the Marketplace: likely related to small size of most drug trials (and low-frequency of hepatic adverse events)

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Clinical Patterns of Toxicity

Asymptomatic Elevation of Hepatic Transaminases (Isolated “Transaminitis”)

• General Comments: defined as asymptomatic elevation of transaminases which do not progress despite continued use of the medication
• Gemcitabine (Gemzar) (see Gemcitabine): transaminitis occurs in 67-68% of cases
• HMG-CoA Reductase Inhibitors (Statins) (see HMG-CoA Reductase Inhibitors, [[HMG-CoA Reductase Inhibitors]]): elevated transaminases occur in <5% of cases
• Isoniazid (INH) (see Isoniazid)
• α-Methyldopa (see α-Methyldopa)
• Phenytoin (see Phenytoin)
• Quinidine (see Quinidine)
• Salicylates (see Salicylates)
• Sulfonamides (see Sulfonamides)
• Sulfonylureas (see Sulfonylureas)
  • First Generation Sulfonylureas
    • Acetohexamide
    • Carbutamide
    • Chlorpropamide
    • Tolbutamide
  • Second Generation Sulfonylureas
    • Glibornuride
    • Gliclazide
    • Glimepiride (Amaryl) (see Glimepiride)
    • Glipizide (Glucotrol) (see Glipizide)
    • Gliquidone
    • Glisoxepide
    • Glyburide (Diabeta, Micronase, Glynase, Glibenclamide) (see Glyburide)
    • Glyclopyramide
• Tacrine (Cognex) (see Tacrine): elevated transaminases occur in up to 50% of cases

Elevation of Hepatic Transaminases with Acute Hepatocellular Injury

• General Comments: defined as hepatocellular if the ALT level is >2x the upper limit of the reference range (with associated normal-minimally elevated alkaline phosphatase)
  • AST>ALT Elevation (Especially >2x Greater): suggests ethanol abuse as the etiology
  • AST: suggests viral hepatitis as the etiology
  • In viral and drug-induced hepatitis, transaminases gradually increase, peaking at the low thousands in 7-14 days
• Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]])
• Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]]): transaminases may rise above 10k IU/L in the setting of acetaminophen overdose
• Erythromycin (see Erythromycin, [[Erythromycin]])
• Ethanol (see Ethanol, [[Ethanol]]): AST > ALT elevation (especially over 2x greater) is consistent with a history of ethanol abuse
• Fluconazole (Flucon) (see Fluconazole, [[Fluconazole]])
• Griseofulvin (see Griseofulvin, [[Griseofulvin]])
• Isoniazid (INH) (see Isoniazid, [[Isoniazid]])
• Niacin (Nicotinic Acid, Vitamin B3) (see Niacin, [[Niacin]])
• Nonsteroidal Anti-Inflammatory Drug (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]])
  • Diclofenac (Aclonac, Cataflam, Voltaren): also appears to induce a unique ANA-positive, autoimmune hepatitis-like syndrome [MEDLINE]
• Sulfonamides (see Sulfonamides, [[Sulfonamides]])

Cholestasis

• General Comments: defined as elevated alkaline phosphatase (with or without hepatocyte injury)
  • Pure Cholestasis (Bland/Canalicular/Non-Inflammatory Cholestasis): characeterized by prominent hepatocellular/canalicular cholestasis with very little hepatocellular injury or inflammation
    • These drugs interfere with hepatocyte secretion of bile components (and other pigments) via the bile salt excretory protein (BSEP)
  • Cholestatic Hepatitis (Hepatocanalicular/Cholangiolitic/Inflammatory Cholestasis): characterized by portal inflammation, prominent cholestasis, hepatocellular injury (usually localized to the zones of cholestasis), and occasionally bile duct proliferation
• Anabolic Steroids: usually pure cholestasis
• Angiotensin-Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors, [[Angiotensin Converting Enzyme Inhibitors]])
  • Captopril (Capoten) (see Captopril, [[Captopril]])
• Chlorpromazine (Largactil, Thorazine) (see Chlorpromazine, [[Chlorpromazine]])
• Cimetidine (Tagamet) (see Cimetidine, [[Cimetidine]])
• Fluoroquinolones
  • Ciprofloxacin (Cipro) (see Ciprofloxacin, [[Ciprofloxacin]])
  • Ofloxacin (xxxxx) (see Ofloxacin, [[Ofloxacin]])
• Macrolides
  • Azithromycin (Zithromax) (see Azithromycin, [[Azithromycin]])
  • Erythromycin (see Erythromycin, [[Erythromycin]])
• Nonsteroidal Anti-Inflammatory Drugs (NSAID’s) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]])
  • Naproxen (Naprosyn) (see Naproxen, [[Naproxen]])
  • Sulindac (see Sulindac, [[Sulindac]]): causes extrahepatic cholestasis due to biliary sludging/calculi
• Octreotide (see Octreotide, [[Octreotide]]): causes extrahepatic cholestasis due to biliary sludging/calculi
• Oral Contraceptives (OCP) (see Oral Contraceptives, [[Oral Contraceptives]]): usually pure cholestasis
• Penicillins (see Penicillins, [[Penicillins]])
  • Amoxicillin-Clavulanic Acid (Augmentin) (see Amoxicillin-Clavulanic Acid, [[Amoxicillin-Clavulanic Acid]]): may progress to bile duct loss (and rarely, cirrhosis/liver failure)
  • Dicloxacillin (see Dicloxacillin, [[Dicloxacillin]])
  • Flucloxacillin: may progress to bile duct loss (and rarely, cirrhosis/liver failure)
• Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
• Terbinafine: may progress to bile duct loss (and rarely, cirrhosis/liver failure)

Hepatic Steatosis (see Non-Alcoholic Fatty Liver Disease, [[Non-Alcoholic Fatty Liver Disease]])

• xxxxx (see xxxx, [[]])
• xxxxx (see xxxx, [[]])
• xxxxx (see xxxx, [[]])

Hepatic Fibrosis and Cirrhosis (see Hepatic Fibrosis, [[Hepatic Fibrosis]])

• Any Drug Causing Submassive Hepatocellular Injury: fibrosis, followed by nodular regeneration and cirrhosis may subsequently occur
• Enalapril (Vasotec, Enalaprilat) (see Enalapril, [[Enalapril]])
  • Epidemiology: prolonged therapy may lead to cirrhosis
• Heroin (see Heroin, [[Heroin]])
  • Physiology: increase in collagen deposition (with minimal or absent necrosis or inflammation)
• Hypervitaminosis A (see Vitamin A, [[Vitamin A]])
  • Physiology: increase in collagen deposition (with minimal or absent necrosis or inflammation)
• Isoniazid (INH) (see Isoniazid, [[Isoniazid]])
  • Clinical: prolonged therapy may lead to cirrhosis
• Methotrexate (see Methotrexate, [[Methotrexate]])
  • Physiology: increase in collagen deposition (with minimal or absent necrosis or inflammation)
  • Clinical: prolonged therapy may lead to cirrhosis
• Perhexiline (see Perhexiline, [[Perhexiline]])
  • Clinical: prolonged therapy may lead to cirrhosis
• Thorotrast (see Thorotrast, [[Thorotrast]])
  • Physiology: increase in collagen deposition (with minimal or absent necrosis or inflammation)
• Ticrynafen (see Ticrynafen, [[Ticrynafen]])
  • Clinical: prolonged therapy may lead to cirrhosis
• Valproic Acid (Depakote) (see Valproic Acid, [[Valproic Acid]])
  • Clinical: prolonged therapy may lead to cirrhosis
• Polyvinyl Chloride (see Polyvinyl Chloride, [[Polyvinyl Chloride]])
  • Physiology: increase in collagen deposition (with minimal or absent necrosis or inflammation)

Subfulminant Hepatic Failure (see Fulminant Hepatic Failure, [[Fulminant Hepatic Failure]])

• General Comments: defined as elevated aminotransferases and bilirubin with clinical picture consistent with subfulminant/fulminant hepatic failure
  • Normally, total bilirubin is <1.1 mg/dL and approximately 70% is indirect (unconjugated bilirubin)
  • Unconjugated hyperbilirubinemia (>80% indirect): suggests Gilbert Syndrome or hemolysis
  • Conjugated hyperbilirubinemia (>50% direct): suggests hepatocellular dysfunction or cholestasis
  • Total bilirubin >25-30 mg/dL: extrahepatic cholestasis is unlikely (since conjugated bilirubin is water soluble and is easily excreted by the kidneys)
• Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
• Cocaine (see Cocaine, [[Cocaine]])
• Dihydralazine (see Dihydralazine, [[Dihydralazine]])
• Ferrous Sulfate (see Ferrous Sulfate, [[Ferrous Sulfate]])
• General Anesthetics
  • Enflurane (see Enflurane, [[Enflurane]])
  • Halothane (see Halothane, [[Halothane]])
  • Methoxyflurane (see Methoxyflurane, [[Methoxyflurane]])
• Ketoconazole (see Ketoconazole, [[Ketoconazole]])
• White Phosphorus (“Yellow Phosphorus”) Intoxication (see White Phosphorus, [[White Phosphorus]])
• Tacrine (Cognex) (see Tacrine, [[Tacrine]])
• Toxic Mushrooms (see Toxic Mushrooms, [[Toxic Mushrooms]])
• Troglitazone (see Troglitazone, [[Troglitazone]])
• Trovafloxacin (see Trovafloxacin, [[Trovafloxacin]])

Fulminant Hepatic Failure (see Fulminant Hepatic Failure, [[Fulminant Hepatic Failure]])

• Ecstasy (see Ecstasy, [[Ecstasy]])
• Isoniazid (INH) (see Isoniazid, [[Isoniazid]])
• Kava Kava (see Kava Kava, [[Kava Kava]])
• Nonsteroidal Anti-Inflammatory Drugs (NSAID’s) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]])
  • Naproxen (Naprosyn) (see Naproxen, [[Naproxen]])
  • Diclofenac (xxxxxx) (see Diclofenac, [[Diclofenac]])
• Phenelzine (xxxxxx) (see Phenelzine, [[Phenelzine]])
• Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
• Propylthiouracil (PTU) (see Propylthiouracil, [[Propylthiouracil]])
• Sertraline (Zoloft) (see Sertraline, [[Sertraline]])

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References

• Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis. Dig Dis Sci. 1993;38(4):744 [MEDLINE]