Drug-induced liver injury: Diagnosing (and treating) it early
Drug-induced liver injury can have an insidious—and unpredictable—course. Left unchecked, it can progress to liver failure. This article and algorithm can facilitate prompt diagnosis and treatment.
A stepwise approach to evaluation
DILI is a diagnosis of exclusion.16 Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).16 First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.
Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).17 A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.17
Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.16
Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.16 In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.
Once DILI is confirmed, identify offending agent, grade severity
Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”16)
DILI severity can be graded as mild (1+) to fatal (5+).19 Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).19 Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.
American College of Gastroenterology guidelines recommend liver biopsy if autoimmune hepatitis is suspected, liver enzymes remain elevated for more than 6 months, or liver enzymes continue to rise even after stopping the suspected offending drug.16
Biopsy should also be considered if a patient’s alanine aminotransferase level fails to fall by at least half 60 days after stopping the suspected medication (in a patient with a hepatocellular pattern) or if a patient’s peak alkaline phosphatase level doesn’t fall by at least half at 180 days after stopping the suspected medication (in a patient with a cholestatic pattern).
CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.
For many patients, stopping the offending drug will be sufficient
The first step in managing DILI is to stop the medication suspected of causing the liver injury.20 Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).18 Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.
