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 with 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, acetaminophenSome 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 (see Table 1: Drugs and the Liver: Potentially Hepatotoxic Drugs):

Table 1
PrintOpen table
Potentially Hepatotoxic Drugs Finding Drug Hepatocellular: Elevated ALT AcarboseSome Trade Names PRECOSE Click for Drug Monograph AcetaminophenSome Trade Names GENAPAP TYLENOL VALORIN Click for Drug Monograph AllopurinolSome Trade Names ZYLOPRIM Click for Drug Monograph AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph BaclofenSome Trade Names LIORESAL Click for Drug Monograph BupropionSome Trade Names WELLBUTRIN ZYBAN Click for Drug Monograph FluoxetineSome Trade Names PROZAC SARAFEM Click for Drug Monograph Germander HAART drugs IsoniazidSome Trade Names INH NYDRAZID Click for Drug Monograph Kava KetoconazoleSome Trade Names NIZORAL Click for Drug Monograph LisinoprilSome Trade Names PRINIVIL ZESTRIL Click for Drug Monograph LosartanSome Trade Names COZAAR Click for Drug Monograph MethotrexateSome Trade Names RHEUMATREX Click for Drug Monograph NSAIDs OmeprazoleSome Trade Names PRILOSEC Click for Drug Monograph ParoxetineSome Trade Names PAXIL Click for Drug Monograph PyrazinamideSome Trade Names No US trade name Click for Drug Monograph RifampinSome Trade Names RIFADIN RIMACTANE Click for Drug Monograph RisperidoneSome Trade Names RISPERDAL Click for Drug Monograph SertralineSome Trade Names ZOLOFT Click for Drug Monograph Statins Tetracyclines TrazodoneSome Trade Names DESYREL Click for Drug Monograph Trovafloxacin ValproateSome Trade Names DEPAKENE Click for Drug Monograph Cholestatic: Elevated alkaline phosphatase and total bilirubin Amoxicillin/clavulanateSome Trade Names AUGMENTIN Anabolic steroids ChlorpromazineSome Trade Names THORAZINE Click for Drug Monograph ClopidogrelSome Trade Names PLAVIX Click for Drug Monograph Oral contraceptives Erythromycins EstrogensSome Trade Names PREMARIN Click for Drug Monograph IrbesartanSome Trade Names AVAPRO Click for Drug Monograph MirtazapineSome Trade Names REMERON Click for Drug Monograph Phenothiazines TerbinafineSome Trade Names LAMISIL AT LAMISIL Click for Drug Monograph Tricyclic antidepressants Mixed: Elevated alkaline phosphatase and ALT AmitriptylineSome Trade Names ELAVIL ENDEP Click for Drug Monograph AzathioprineSome Trade Names IMURAN Click for Drug Monograph CaptoprilSome Trade Names CAPOTEN Click for Drug Monograph CarbamazepineSome Trade Names TEGRETOL Click for Drug Monograph ClindamycinSome Trade Names CLEOCIN Click for Drug Monograph CyproheptadineSome Trade Names PERIACTIN Click for Drug Monograph EnalaprilSome Trade Names VASOTEC Click for Drug Monograph NitrofurantoinSome Trade Names FURADANTIN MACROBID MACRODANTIN Click for Drug Monograph PhenobarbitalSome Trade Names LUMINAL Click for Drug Monograph PhenytoinSome Trade Names DILANTIN Click for Drug Monograph Sulfonamides TrazodoneSome Trade Names DESYREL Click for Drug Monograph Trimethoprim/sulfamethoxazoleSome Trade Names BACTRIM SEPTRA Click for Drug Monograph VerapamilSome Trade Names CALAN ISOPTIN Click for Drug Monograph HAART = highly active antiretroviral therapy.

• 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 acetaminophenSome Trade Names
  GENAPAP
  TYLENOL
  VALORIN
  Click for Drug Monograph
  and isoniazidSome 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/clavulanateSome Trade Names
  AUGMENTIN
  
  acid and chlorpromazineSome 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 phenytoinSome Trade Names
  DILANTIN
  Click for Drug Monograph
  can cause this type of injury.

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 be avoided. Suspected cases of DILI should be reported to MedWatch (the FDA's adverse drug reaction monitoring program).

Pearls & Pitfalls Do not rechallenge with a drug suspected of causing liver injury.

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-acetylcysteineSome Trade Names
MUCOMYST
Click for Drug Monograph
for acetaminophenSome 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, now increasingly mandated by FDA, 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.

Key Points

• Drugs are much more likely to cause an asymptomatic abnormality in liver function than clinically evident liver damage or dysfunction.
• Risk factors for drug-induced liver injury (DILI) include age ≥ 18 yr, obesity, pregnancy, concomitant alcohol consumption, and certain genetic polymorphisms.
• DILI can be predictable and dose-related or unpredictable and unrelated to dose.
• DILI can be hepatocellular, cholestatic (usually less serious than hepatocellular), or mixed.
• To confirm the diagnosis, exclude other causes of liver disease, especially viral, biliary, alcoholic, autoimmune, and metabolic disorders.
• Do not rechallenge patients with drugs suspected of causing DILI.

Last full review/revision January 2013 by Steven K. Herrine, MD

Content last modified January 2013