Clopidogrel-Induced Severe Hepatitis: A Case Report and Literature Review

Clopidogrel is a commonly prescribed antiplatelet agent that carries a rare risk of hepatotoxicity. We describe a case of severe clopidogrel-induced hepatitis with liver biopsy assessment. Prompt recognition and withdrawal of the offending agent are imperative to prevent progression and potentially fatal liver injury.


Case Description
A 34-year-old male with a history of coronary artery disease and remote coronary artery stent was placed on aspirin plus clopidogrel. His baseline liver biochemistries were normal. He had been on clopidogrel for 2 months 12 years ago without adverse effects but discontinued the medication on his own at that time due to nonadherence. Four and a half months after restarting clopidogrel, he presented with jaundice and fatigue. He denied fever, rash, arthralgias, or abdominal pain. His only other medications were aspirin and metoprolol, which he had been on for many years with normal liver biochemistries.
The patient was not on a statin. He denied recent alcohol or herbal medications. Physical examination was significant only for icterus. There was no hepatosplenomegaly, clubbing, rash, asterixis, or other stigmata of chronic liver disease.
Imaging studies were negative, and bile ducts were not dilated, including by ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography. No gallstones were present on any imaging modality. Liver biopsy revealed severe acute hepatitis with mixed inflammatory portal tract infiltrates including plasma cells, neutrophils and eosinophils, bile ductular reaction, patchy hepatocyte ballooning degeneration, and extensive periportal hepatocyte dropout, without fibrosis ( Figure 1).
The patient was diagnosed with clopidogrel-induced severe hepatitis. Despite discontinuing clopidogrel, AST increased to 2,107 U/L, ALT to 1,567 U/L, and bilirubin to 37 mg/dL (predominately direct bilirubin). INR had increased to 2.1 despite empiric administration of vitamin K. A brief course of prednisone and ursodiol was initiated, with subsequent normalization of liver biochemistries.
Our patients liver biopsy revealed severe hepatocellular injury. This adds to the histological findings in clopidogrelinduced hepatitis, as liver biopsy was only performed in 3 of the previously reported cases [1,2,11]. Clopidogrel-induced liver injury can be cholestatic, hepatocellular [11], or mixed hepatocellular plus cholestatic [1,2].
The exact mechanism of clopidogrel-induced hepatitis is unclear. The delayed onset of 4.5 months in our case suggests a toxic-metabolic etiology, whereas the inflammatory infiltrate and response to corticosteroids raise the possibility of a superimposed immune mediated mechanism of injury. Clopidogrel is a prodrug which is metabolized to inactive clopidogrel carboxylate (90%) and an active metabolite containing a mercapto group (10%) by cytochrome P450 3A4 and 2C19. In vitro studies suggest that the active metabolite is responsible for the hepatotoxicity and that high cytochrome 3A4 activities coupled with cellular glutathione depletion are potential risk factors [19]. Interestingly, an earlier antiplatelet agent, ticlopidine, has also been reported to cause druginduced cholestatic hepatitis [20,21].
Clopidogrel-induced hepatitis is a rare but potentially serious adverse effect. A high degree of clinical suspicion is required in patients presenting with abnormal liver biochemistries within a few months after starting clopidogrel. Prompt recognition and discontinuation of the offending agent are necessary, as progressive liver injury and even death can occur.