A case of hepatitis attributable to repeated exposure to methoxyflurane during its use for procedural analgesia

A 33-year-old woman was admitted to our service for investigation and management of acute hepatitis. She reported symptoms of nausea, fatigue, pruritus and right upper abdominal discomfort. The symptoms had first occurred 3 weeks earlier, resolving over 5 days, then recurred 2-3 days before presentation. The symptoms were temporally related to varicose vein sclerosing procedures, of which she had had three in total. The first procedure occurred 4 weeks before admission, with no subsequent side effects. It was after the second procedure, 1 week later, that symptoms first developed. The final procedure occurred a week before admission. During each procedure, the patient was given methoxyflurane as an inhaled analgesic administered from a 3 mL disposable cartridge. Other medications administered during the procedures were the sclerosing agent sodium tetradecyl sulfate and fexofenadine. There was no history of exposure to alcohol or to other prescription or over-the-counter medications. The patient had no risk factors for viral hepatitis, and there was no history of hepatitis or liver disease in her family. Clinical examination revealed jaundice and mild tender hepatomegaly only. Initial investigations showed hepatic enzymosis, with an elevated alanine transaminase level (2710 U/L [reference range, < 34 U/L]) and hyperbilirubinaemia (bilirubin 921 μmol/L [reference range, < 20 μmol/L]). Markers of liver synthetic function (albumin and prothrombin time) were within normal limits, as were full blood counts, electrolyte levels and renal function. Abdominal ultrasound demonstrated a normal-sized spleen and mild hepatomegaly, with an increased liver echotexture. Doppler sonography of the portal vein was normal. Serological tests for hepatitis A, B and C, Epstein-Barr virus, cytomegalovirus and HIV were negative. Iron and copper studies and levels of α-1-antitrypsin, antinuclear antibodies, antimitochondrial antibodies, anti-liver/kidney microsomal antibodies, anti-smooth-muscle antibodies and antinuclear cytoplasmic antibodies were all normal. Paracetamol was undetectable. Bilirubin levels continued to rise over the following 8 days (peaking at 202 μmol/L), although liver synthetic function remained normal throughout this time. A liver biopsy revealed evidence of resolving acute hepatitis with confluent perivenular hepatocyte dropout and bridging necrosis. There was no evidence of cholestasis or underlying fibrosis. The pathological diagnosis was of an idiosyncratic drug reaction, with the implicated drug being methoxyflurane. The patient's condition continued to improve, with resolution of symptoms over 4 weeks and associated normalisation of liver enzyme and bilirubin levels. She has since remained well, and has been advised to avoid future exposure to methoxyflurane. ♦