Drug-Induced Liver Injury

GENERAL PRINCIPLES

• The National Institutes of Health maintains a searchable database of over 1000 drugs, herbal medications, and dietary supplements that have been associated with drug-induced liver injury (DILI) at http://livertox.nih.gov/.

• There are three major classifications of DILI that occur as a result of both intrinsic and idiosyncratic hepatotoxicity: hepatocellular, cholestatic, or mixed.

• DILI is responsible for approximately 50% of all cases of ALF in the US, with acetaminophen being the most common causative agent. Acute DILI (lt;3 months) progresses to chronic injury in 5%-10% of cases.⁶

DIAGNOSIS

Clinical Presentation

• The acute presentation can be clinically silent. Symptoms are nonspecific and include nausea/vomiting, malaise, fati gue, jaundice, pruritus, alcoholic stools, and abdominal pain. In the acute setting, the majority of patients will recover after cessation of the offending drug. Rare cases may progress to ALF.

• Fever and rash may also be seen in association with hypersensitivity reactions.

Diagnostic Criteria

• Clinical suspicion

• Temporal relation of liver injury to drug usage

• Resolution of liver injury after the suspected agent has been discontinued (except in cases of chronic DILI)

Diagnostic Testing

BIOCHEMICAL ABNORMALITIES

• Hepatocellular injury: AST and ALT elevation more than two times the ULN and disproportionately elevated when compared to ALP.

• Cholestatic injury: ALP and conjugated bilirubin elevation more than two times the ULN and disproportionately elevated when compared with AST and ALT.

• Mixed injury: Increases in all of the aforementioned biochemical abnormalities to more than two times the ULN.

• R ratio: ALT/ULN divided by ALP/ULN

î R gt;5 suggests hepatocellular injury

î R lt;2 suggests cholestatic injury

î R gt;2 and lt;5 suggests mixed injury

DIAGNOSTIC PROCEDURES

Liver biopsy may be indicated if the diagnosis is unclear.

TREATMENT

• Treatment includes cessation of offending drug and institution of supportive measures.

• An attempt to remove the agent from the GI tract should be made in most cases of acute toxic ingestion using lavage or cathartics (see Chapter 28, Toxicology).

î Few specific therapies are beneficial. Two exceptions include N-acetylcysteine (NAC) for acetaminophen toxicity and L-carnitine for valproic acid overdose.

î The effectiveness of NAC in nonacetaminophen DILI has not been well studied.

• Management of acetaminophen overdose is a medical emergency (see Chapter 28, Toxicology).

Surgical Management

Liver transplantation may be an option for patients with drug-induced ALF.

OUTCOME AND PROGNOSIS

Prognosis of DILI is often unique to the offending medication. Jaundice can take weeks to months to resolve.