Clopidogrel-induced liver failure

The thienopyridine derivative clopidogrel (CPG) inhibits ADP-induced platelet activation. It is rapidly hydrolysed in the liver via cytochrome P450 enzymes, by an irreversible and NADPHdependent mechanism. Clopidogrel therapy is indicated in the prevention of thrombotic events in patients with acute coronary syndromes, ischemic stroke and peripheral arterial disease or after percutaneous stent placement. Currently, it is widely used with a low occurrence of adverse side-effects. Hepatotoxicity is extremely rare. There are 10 cases of pure liver injury reported in the literature, with liver failure in only one, and in two, liver injury was part of a systemic inflammatory response syndrome. We report here the second case of clopidogre-associated hepatitis with acute liver failure. An 80-year-old woman with history of hypertension, type 2 diabetes, heart failure and dyslipidaemia was on glibenclamide, furosemide, isossorbide dinitrate, acetylsalicylic acid and simvastatin for several years with no evidence of adverse effects. More recently clopidogrel was introduced following angioplasty and stent placement for treatment of acute myocardial infarction. The patient was not taking any overthe-counter, herbal or alternative medicines. Thirty days after starting clopidogrel she was admitted to the hospital with a one-week history of dyspnoea, orthopnoea, lower limb oedema, nausea and vomiting. Physical exam revealed inspiratory rales and ankle oedema. Laboratory evaluation yielded the following abnormal values: AST 110 U/L (normal range [NR] 0–31 U/L); ALT 190 U/L (NR 0–31 U/L); total serum bilirubin 1.7 mg/dL (NR 0.1–1.1 mg/dL); direct serum bilirubin 0.7 mg/ dL (NR 0–0.3 mg/dL), γ-glutamyltransferase 166U/L (NR 5–36 U/L); lactate dehydrogenase 707 U/L (NR 240–480 U/L). Serum albumin levels and coagulation profile were normal. Therapy for congestive heart failure was optimized with resolution of the oedema and pulmonary stasis. Despite the improvement of heart failure, there was worsening of liver biochemical tests with AST 388 U/L; ALT 540 U/L; total serum bilirubin 3.5 mg/dL; γ-glutamyltransferase 209 U/L; alkaline phosphatase 139 U/L (NR 35–100 U/L) and lactate dehydrogenase 1412 U/L and development of liver failure as shown by increased prothrombin time (INR 1.6) and low levels of factor V (4%, NR >5%). Clopidogrel was then stopped. Serology for acute viral hepatitis was negative and there was no history of alcohol intake. Blood and urine cultures were also negative. Autoimmune hepatitis was excluded based on negative antinuclear, antineutrophil cytoplasmic, anti-mitochondria and anti-smooth muscle antibodies. The abdominal ultrasound and endoscopic retrograde cholangiopancreaticography showed no abnormalities. Drug-induced liver disease with an hepatocellular pattern was therefore diagnosed and clopidogrel was considered the most probable causative drug given the close temporal relationship between therapy initiation and liver injury, exclusion of alternative causes and liver function/biochemical DECLARATIONS