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Many drugs (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (ALT, AST, alkaline phosphatase). However, clinically significant liver injury (eg, with jaundice, abdominal pain, or pruritus) or impaired liver function—ie, resulting in deficient protein synthesis (eg, with prolonged PT, or hypoalbuminemia)—is rare.

The term drug-induced liver injury (DILI) may be used to mean clinically significant liver injury or all (including asymptomatic) liver injury. DILI includes injury caused by medicinal herbs, plants, and nutritional supplements as well as drugs.

Pathophysiology

The pathophysiology of DILI varies depending on the drug (or other hepatotoxin) and, in many cases, is not entirely understood. Drug-induced injury mechanisms include covalent binding of the drug to cellular proteins resulting in immune injury, inhibition of cell metabolic pathways, blockage of cellular transport pumps, induction of apoptosis, and interference with mitochondrial function.

In general, the following are thought to increase risk of DILI:

• Age ≥ 18 yr
• Obesity
• Pregnancy
• Concomitant alcohol consumption
• Genetic polymorphisms (increasingly recognized)

Patterns of liver injury: DILI can be predictable (when injury usually occurs shortly after exposure and is dose-related) or unpredictable (when injury develops after a period of latency and has no relation to dose). Predictable DILI (commonly, acetaminophen Some Trade Names
GENAPAP
TYLENOL
VALORIN
Click for Drug Monograph
-induced) is a common cause of acute jaundice and acute liver failure in the US. Unpredictable DILI is a rare cause of severe liver disease. Subclinical DILI may be underreported.

Biochemically, 3 types of liver injury are generally noted:

• Hepatocellular: Hepatocellular hepatotoxicity generally manifests as malaise and right upper quadrant abdominal pain, associated with marked elevation in aminotransferase levels (ALT, AST, or both), which may be followed by hyperbilirubinemia in severe cases. Hyperbilirubinemia in this setting is known as hepatocellular jaundice and, according to Hy's law, is associated with mortality rates as high as 50%. If hepatocellular liver injury is accompanied by jaundice, impaired hepatic synthesis, and encephalopathy, chance of spontaneous recovery is low, and liver transplantation should be considered. This type of injury can result from drugs such as acetaminophen Some Trade Names
  GENAPAP
  TYLENOL
  VALORIN
  Click for Drug Monograph
  and isoniazid Some Trade Names
  INH
  NYDRAZID
  Click for Drug Monograph
  .
• Cholestatic: Cholestatic hepatotoxicity is characterized by development of pruritus and jaundice accompanied by marked elevation of serum alkaline phosphatase levels. Usually, this type of injury is less serious than severe hepatocellular syndromes, but recovery may be protracted. Substances known to lead to this type of injury include amoxicillin Some Trade Names
  AMOXIL
  TRIMOX
  Click for Drug Monograph
  /clavulanic acid and chlorpromazine Some Trade Names
  THORAZINE
  Click for Drug Monograph
  . Rarely, cholestatic hepatotoxicity leads to chronic liver disease and vanishing bile duct syndrome (progressive destruction of intrahepatic bile ducts).
• Mixed: In these clinical syndromes, neither aminotransferase nor alkaline phosphatase elevations are clearly predominant. Symptoms may also be mixed. Drugs such as phenytoin Some Trade Names
  DILANTIN
  Click for Drug Monograph
  can cause this type of injury.

Table 1
Potentially Hepatoxic Drugs Laboratory Findings Drug Hepatocellular Elevated ALT Acarbose Some Trade Names PRECOSE Click for Drug Monograph Acetaminophen Some Trade Names GENAPAP TYLENOL VALORIN Click for Drug Monograph Allopurinol Some Trade Names ZYLOPRIM Click for Drug Monograph Amiodarone Some Trade Names CORDARONE Click for Drug Monograph Baclofen Some Trade Names LIORESAL Click for Drug Monograph Bupropion Some Trade Names WELLBUTRIN ZYBAN Click for Drug Monograph Fluoxetine Some Trade Names PROZAC SARAFEM Click for Drug Monograph Germander HAART drugs Isoniazid Some Trade Names INH NYDRAZID Click for Drug Monograph Kava kava Ketoconazole Some Trade Names NIZORAL Click for Drug Monograph Lisinopril Some Trade Names PRINIVIL ZESTRIL Click for Drug Monograph Losartan Some Trade Names COZAAR Click for Drug Monograph Methotrexate Some Trade Names RHEUMATREX Click for Drug Monograph NSAIDs Omeprazole Some Trade Names PRILOSEC Click for Drug Monograph Paroxetine Some Trade Names PAXIL Click for Drug Monograph Pyrazinamide Some Trade Names No US trade name Click for Drug Monograph Rifampin Some Trade Names RIFADIN RIMACTANE Click for Drug Monograph Risperidone Some Trade Names RISPERDAL Click for Drug Monograph Sertraline Some Trade Names ZOLOFT Click for Drug Monograph Statins Tetracyclines Trazodone Some Trade Names DESYREL Click for Drug Monograph Trovafloxacin Valproate Some Trade Names DEPAKENE Click for Drug Monograph Cholestatic Elevated alkaline phosphatase and total bilirubin Amoxicillin/clavulanate Some Trade Names AUGMENTIN Click for Drug Monograph Anabolic steroids Chlorpromazine Some Trade Names THORAZINE Click for Drug Monograph Clopidogrel Some Trade Names PLAVIX Click for Drug Monograph Oral contraceptives Erythromycins Estrogens Some Trade Names PREMARIN Click for Drug Monograph Irbesartan Some Trade Names AVAPRO Click for Drug Monograph Mirtazapine Some Trade Names REMERON Click for Drug Monograph Phenothiazines Terbinafine Some Trade Names LAMISIL AT LAMISIL Click for Drug Monograph Tricyclic antidepressants Mixed Elevated alkaline phosphatase and ALT Amitriptyline Some Trade Names ELAVIL ENDEP Click for Drug Monograph Azathioprine Some Trade Names IMURAN Click for Drug Monograph Captopril Some Trade Names CAPOTEN Click for Drug Monograph Carbamazepine Some Trade Names TEGRETOL Click for Drug Monograph Clindamycin Some Trade Names CLEOCIN Click for Drug Monograph Cyproheptadine Some Trade Names PERIACTIN Click for Drug Monograph Enalapril Some Trade Names VASOTEC Click for Drug Monograph Nitrofurantoin Some Trade Names FURADANTIN MACROBID MACRODANTIN Click for Drug Monograph Phenobarbital Some Trade Names LUMINAL Click for Drug Monograph Phenytoin Some Trade Names DILANTIN Click for Drug Monograph Sulfonamides Trazodone Some Trade Names DESYREL Click for Drug Monograph Trimethoprim/sulfamethoxazole Some Trade Names BACTRIM SEPTRA Click for Drug Monograph Verapamil Some Trade Names CALAN ISOPTIN Click for Drug Monograph HAART = highly active antiretroviral therapy.

Diagnosis

• Identification of characteristic patterns of laboratory abnormalities
• Exclusion of other causes

Presentation varies widely, ranging from absent or nonspecific symptoms (eg, malaise, nausea, anorexia) to jaundice, impaired hepatic synthesis, and encephalopathy. Early recognition of DILI improves prognosis.

Identification of a potential hepatotoxin and a pattern of liver test abnormalities that is characteristic of the substance (its signature) make the diagnosis likely.

Because there is no confirmatory diagnostic test, other causes of liver disease, especially viral, biliary, alcoholic, autoimmune, and metabolic causes, need to be excluded. Drug rechallenge, although it can strengthen evidence for the diagnosis, should usually be avoided. Suspected cases of DILI should be reported to MedWatch (the FDA's adverse drug reaction monitoring program).

Treatment

• Early drug withdrawal

Management emphasizes drug withdrawal, which, if done early, usually results in recovery. In severe cases, consultation with a specialist is indicated, especially if patients have hepatocellular jaundice and impaired liver function, because liver transplantation may be required. Antidotes for DILI are available for only a few hepatotoxins; such antidotes include N- acetylcysteine Some Trade Names
MUCOMYST
Click for Drug Monograph
for acetaminophen Some Trade Names
GENAPAP
TYLENOL
VALORIN
Click for Drug Monograph
toxicity and silymarin or penicillin for Amanita phalloides toxicity.

Prevention

Efforts to avoid DILI begin during the drug development process, although apparent safety in small preclinical trials does not ensure eventual safety of the drug after it is in widespread use. Postmarketing surveillance, although often voluntary in the US, can call attention to potentially hepatotoxic drugs. Routine monitoring of liver enzymes has not been shown to decrease the incidence of hepatotoxicity. Use of pharmacogenomics may allow tailoring of drug use and avoidance of potential toxicities in susceptible patients.

Last full review/revision May 2009 by Steven K. Herrine, MD; Victor J. Navarro, MD

Content last modified May 2009