Clinical record

A 66-year-old man with a history of ischaemic heart disease, hypertension and hypercholesterolaemia presented to a rural centre with a 2-week history of malaise, jaundice, right upper quadrant pain and daily rigors. Liver function tests revealed a raised bilirubin level (100 μmol/L; reference range [RR], 1–20 μmol/L) and abnormal levels of liver enzymes (alkaline phosphatase, 357 U/L [RR, 40–135 U/L]; γ-glutamyltransferase [GGT], 687 U/L [RR, 15–73 U/L]; alanine aminotransferase, 344 U/L [RR, 21–72 U/L]; aspartate aminotransferase, 216 U/L [RR, 17–59 U/L]). Results of serology tests for hepatitis B and C were negative. Full blood examination revealed a normal level of total white blood cells and mild thrombocytopenia (platelet count, 124 × 109/L [RR, 150–400 × 109/L]). Results of a computed tomography scan of the abdomen and pelvis were unremarkable. A presumptive diagnosis of acute cholangitis was made, and intravenous ceftriaxone (1 g daily) and metronidazole (500 mg every 8 h) therapy was initiated.

The patient had undergone a percutaneous coronary intervention with bare-metal stent placement about 2 months earlier, and had been prescribed clopidogrel (an antiplatelet agent; 75 mg daily) at this time. His other regular medications included aspirin, irbesartan–hydrochlorothiazide, simvastatin and omeprazole.

Clopidogrel was ceased on the day of admission to the rural centre because of concern about increased bleeding risk if potential urgent endoscopic or surgical intervention was required. After 24 hours, the patient’s condition had improved markedly, and he was discharged 7 days after admission. Clopidogrel was restarted on the day of discharge from the rural centre. His symptoms returned within 24 hours of discharge, upon which he presented to our tertiary institution.

The patient was tachycardic (pulse rate, 114 beats/min), hypotensive (blood pressure, 90/60 mmHg), febrile (temperature, 39.6°C) and jaundiced. The remainder of his physical examination was unremarkable. Results of liver function tests at this time were markedly abnormal (Figure, A). His serum creatinine level was elevated (167 μmol/L; RR, 60–120 μmol/L). His international normalised ratio was 1.3 (RR, 0.8–1.2), with an activated partial thromboplastin time of 35 s (RR, 26–40 s). Abdominal ultrasound and magnetic resonance cholangiopancreatography showed no evidence of gallstones, biliary tree dilatation or choledocholithiasis. He was prescribed intravenous ceftriaxone (1 g daily), ampicillin (1 g every 6 h) and metronidazole (500 mg every 8 h). Clopidogrel was ceased on the day of admission, pending surgical review.

His symptoms abated and liver function improved over the next 3 days. Clopidogrel was recommenced on Day 4 of admission. On Day 5 he had a fever of 40°C with rigors, and his liver function deteriorated significantly (Figure, A). Clopidogrel was withheld again in anticipation of surgery, and his antibiotic therapy was changed to intravenous ticarcillin–clavulanate (3 g/0.1 g every 6 h). His condition gradually improved over the next 5 days. Clopidogrel was restarted on Day 10. His condition deteriorated again within 24 hours, with a fever to 39.0°C and rise in GGT to 2205 U/L. His antibiotic therapy was changed to intravenous meropenem (500 mg every 8 h) and endoscopic retrograde cholangiopancreatography (ERCP) was scheduled, prior to which clopidogrel was ceased on Day 11. He suffered ongoing rigors between Days 10 and 17. On Day 17, ERCP revealed a normal intrahepatic and extrahepatic biliary tree. His symptoms and liver function abnormalities persisted; on Day 25, a transjugular liver biopsy revealed scattered poorly formed granulomas within the portal tracts and the hepatic lobules (Figure, B). The granulomas did not involve the interlobular bile ducts. Neutrophils were seen in the bile ductule epithelium, in keeping with acute cholangiolitis (Figure, C).

The liver histopathology was initially thought to be consistent with primary biliary cirrhosis, a diagnosis that did not correlate with the clinical presentation. A review of the patient’s medication chart revealed that he had received clopidogrel intermittently since Day 10, despite the treating medical team’s request that it be ceased. Given this new information, the liver histopathology was reviewed and clopidogrel-induced granulomatous hepatitis was diagnosed. Clopidogrel was ceased permanently and he was discharged. At follow-up about 2 months later, his liver function had completely normalised and his symptoms had not recurred.

Liver function test results throughout the patient’s tertiary hospital admission (arrows indicate prescribed and documented clopidogrel administration).

Section of transjugular liver biopsy specimen (Picro-Mallory trichrome stain, magnification x 100) showing granuloma formation (arrow).

Section of transjugular liver biopsy specimen (haematoxylin–eosin stain, magnification x 400) showing neutrophils (arrow) surrounding small bile ducts in the portal tract.