Drug-induced liver disease

I. Problem/Condition.

Drug-induced liver disease is defined as liver injury related to a specific drug. It can manifest as an asymptomatic elevation in liver chemistries or symptomatically with liver dysfunction. In rare cases, patients may progress to fulminant hepatic failure. It can be either acute or chronic and can vary in its time to resolution. Drug-induced liver disease has been reported to occur in 1 in 10,000 to 1 in 100,000 patients for any given drug, yet its true incidence is likely much higher.

Hepatotoxicity is one of the most common drug-related side effects, particularly in the inpatient setting. Drugs can cause hepatic injury in a variety of ways including:

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  • Direct hepatocyte injury

  • Generation of free radicals

  • Interruption of metabolic pathways and mitochondrial injury

  • Disruption of cell membranes and immunologic sensitization

  • Altered bile transport

Reactions may be due to direct hepatotoxic effects or idiosyncratic reactions and can occur at initial administration of a medication or after months of exposure. Additionally, some drugs are involved in hypersensitivity reactions that worsen with repeated drug exposures. Hypersensitivity reactions are often associated with arthralgias, fever, rash, and eosinophilia. Agents can be systemic poisons or be converted by the liver into hepatotoxins. Patient glutathione stores may also play a role in the degree of liver injury, particularly in acetaminophen toxicity, with reduced glutathione stores increasing the risk for liver injury.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Drug-induced liver disease by definition requires the exclusion of infectious, ischemic, metabolic, and autoimmune causes of liver injury.

Although medications can cause hepatic inflammation in multiple ways, most drugs are associated with a particular pattern of injury. These patterns are often divided into hepatocellular, cholestatic, and mixed patterns of injury.

Drugs can cause injury by direct hepatotoxicity, hypersensitivity, or idiosyncratic reactions. Direct hepatotoxicity is most often seen acutely following exposure to the drug and injury follows a dose response. Hypersensitivity reactions are often associated with systemic signs and symptoms such as rash, arthralgias, fever, and eosinophilia, and tend to be increasingly severe with repeated exposure to the offending agent. Idiosyncratic reactions can occur at any time following exposure and often do not follow a dose response.

A number of drugs are associated with asymptomatic elevations in liver chemistries upon initial drug exposure, which return to normal with continuation of the drug by a form of “adaptation.” This is seen frequently with isoniazid (INH), statins, valproate, and phenytoin. However, since these drugs can also cause clinically significant hepatoxicity, patients should be monitored closely.

Drugs most often associated with hepatocellular pattern of injury are listed below:

  • Non-steroidal anti-inflammatory drugs [NSAIDs] (ibuprofen, diclofenac, sulindac): increased risk in patients with the metabolic syndrome

  • Acetominophen: via direct toxic effect

  • Anti-tuberculosis drugs (INH, rifampin, pyrazinamide): risks are increased in patients with exposure to alcohol; INH causes injury by both direct toxic and idiosyncratic mechanisms; signs of hypersensitivity are uncommon

  • Azoles (ketoconazole, fluconazole, itraconazole)

  • Antiretroviral therapy [ART] (zidovudine, didanosine, idinavir, ritonavir)—mitochondrial toxins

  • Amiodarone: toxic and idiosyncratic; note, due to the long half life of amiodarone, liver injury is often slow to resolve even with withdrawal of the drug

  • Valproic acid: toxic and idiosyncratic

  • Trimethoprim-sulfamethoxazole: idiosyncratic

  • Statins: idiosyncratic

  • Minocycline

  • Antihypertensives (angiotensin-converting enzyme inhibitor [ACEI], angiotensin receptor blocker [ARB], methyldopa, calcium channel blocker [CCB])

  • Methotrexate

Drugs typically associated with cholestatic liver chemistries:

  • NSAIDs (naproxen)

  • Antibiotics (erythromycin, amoxicillin-clavulanic acid, nitrofurantoin): idiosyncratic

  • Oral contraceptive pills

  • Anabolic steroids

  • ARB (irbesartan)

  • Methimazole

Drugs typically associated with a mixed hepatocellular and cholestatic pattern of injury:

  • Phenytoin: idiosyncratic

  • Statins: idiosyncratic, immune-mediated

  • Sulfonamides

Chronic liver disease

Although chronic liver disease patients have less hepatic reserve, they are not at increased for hepatotoxicity from all medications. Exceptions to this include aspirin, methotrexate, isoniazid, and antiretroviral therapy.

The following common medications infrequently cause hepatotoxicity, but have an appreciable incidence given their common use:

  • Acetominophen

  • Non-steroidal anti-inflammatory drugs

  • Antibiotics (azithromycin, trimethoprim-sulfamethoxazole, amoxicillin)

  • Estrogens/oral contraceptive pills (OCPs)

  • Levothyroxine

  • Statins

  • Angiotensin-converting enzyme inhibitors

  • Angiotensin receptor blockers

  • Calcium channel blockers

  • Antiretroviral therapy

B. Describe a diagnostic approach/method to the patient with this problem

This is a step-by-step diagnostic approach.

  • Rule out infectious (i.e., viral hepatitis, cholangitis, sepsis, hepatic abscess), ischemic (i.e., shock, thromboembolic disease), metabolic (i.e., iron, copper overload, fatty liver/steatohepatitis), and autoimmune causes (i.e., autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) of liver injury.

  • Determine whether liver chemistries are consistent with primarily hepatocellular injury versus cholestatic injury versus mixed. Hepatocellular injury is suggested by elevations in alanine transaminase (ALT) and aspartate transaminase (AST) out of proportion to alkaline phosphatase and cholestatic injury is suggested by elevations in alkaline phosphatase out of proportion to ALT and AST. Mixed injury has proportional elevations of both alkaline phosphatase and ALT/AST.

  • Take an alcohol intake history.

  • Check urine and full serum toxicology.

  • Check for specific drug levels to see if patient has ingested the drug. Note: most hepatotoxic drugs do not have to be at toxic levels to cause liver damage.

  • Obtain a detailed medical history (any previous exposures, new medications, chronic medications, signs of hypersensitivity).

  • Review medications known to cause idiosyncratic reactions at any time.

  • Review medications that have been stopped and started as these can cause hypersensitivity reactions which worsen with repeated exposure.

  • Assess for signs of liver failure (jaundice, ascites, coagulopathy, encephalopathy).

1. Historical information important in the diagnosis of this problem.

Important historical information includes:

  • Medication exposures

  • Previous medications that have caused a reaction

  • New medications that could alter clearance of other toxic medications (i.e. drugs that could alter CYP450 such as rifampin, renal clearance such as trimethoprim-sulfamethoxazole or ACEIs)

  • Alcohol consumption (depletes glutathione and actives CYP system thereby threshold for acetominophen toxicity)

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Assess for signs of hepatic failure including jaundice, asterixis, altered sensorium/attention, and ascites.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

  • Serum and urine drug levels/toxicology

  • Albumin levels (may alter free levels of drugs that are predominanty protein bound, i.e. phenytoin)

  • Recent weight changes or malnutrition—reduced glutathione stores can predispose to accumulation of toxic metabolites, this is particularly important in acetaminophen toxicity

  • Rule out other liver disease including labs for viral, metabolic, and autoimmune liver disease including viral hepatitis panels, iron studies, autoimmune serologies, and serum immunoglobulins

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

There are no tests to confirm that drug-induced liver injury is due to a particular drug. The best way to diagnose a drug-induced liver injury is to withdraw the offending agent and monitor for clinical improvement, noting that some forms of hepatic damage from drug exposure may not normalize until weeks after the drug has been stopped.

Liver biopsy can also sometimes be helpful in discerning which drug is the cause of liver injury.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Ordering drug levels is not typically helpful in making the diagnosis of a drug-induced liver injury since most drugs that cause liver injury do so at therapeutic drug levels.

III. Management while the Diagnostic Process is Proceeding

A. Management of drug-induced liver disease

Monitor for signs of fulminant hepatic failure including encephalopathy and coagulopathy.

Acetominophen toxicity should be treated with N-acetylcysteine. N-acetylcysteine may reduce the risk of liver failure secondary to non-acetominophen drug-induced liver injury as well. Valproate toxicity should be treated with intravenous carnitine.

Treatment for acetaminophen and valproate toxicity should be started empirically in any patient where there is suspicion.

Since hypersensitivity reactions may be related to immunologic phenomena, patients in whom hypersensitivity reactions develop as part of their hepatotoxicity may be at increased risk of even more severe reactions upon repeat exposure to the same agent as a result of sensitization.

Search livertox.nih.gov for information on whether an agent has been reported to cause liver injury.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Idiosyncratic reactions causing drug-related hepatotoxicity are relatively common and can occur at any time during the course of a patient’s treatment. Chronic exposure to medications known for idiosyncratic reactions do not rule out a drug as the cause of hepatotoxicity.

IV. What's the Evidence?

Stine, JG, Chalasani, N. “Chronic liver injury induced by drugs: a systematic review”. Liver Int. vol. 35. 2015. pp. 2343-53.

Leise, MD, Poterucha, JJ, Talwalkar, JA. “Drug-induced liver injury”. Mayo Clin Proc. vol. 89. 2014. pp. 95-106.

Lee, WM, Hynan, LS, Rossaro, L. “Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure”. Gastroenterology. vol. 137. 2009. pp. 856-864.