Severe liver injury due to a homemade flower pollen preparation in a patient with high CYP3A enzyme activity: a case report

Herbal remedies (HR) are used worldwide with a prevalence of use in the USA of 18 % [1]. They were shown to be the cause of 16 % of drug-induced liver injury (DILI) cases [2]. DILI was lethal in 10 % of patients and 17 % developed chronic liver injury. Both patient and drug characteristics can increase the risk of DILI. We report here the case of a severe liver injury after treatment by a HR in a patient characterized as a rapid CYP3A metabolizer. A 43-year-old woman presented 10 days after the onset of fatigue, nausea, vomiting, and jaundice. She denied consuming any alcohol or illicit drugs. She had no palmar erythema, spider nevi, or ascites that would have been suggestive of chronic liver disease and no fever. She had taken a total of five tablets of 500 mg of paracetamol during the 3 days before for headaches but no other medication. On admission, laboratory values were as follows: normal blood count, INR 1.18, AST 1971 IU/l (normal range 11–42), ALT 2940 IU/l (9–42), normal alkaline phosphatase, γ-glutamyltransferase 98 IU/l (9–35), serum bilirubin 71 μmol/l (7–25). She tested negative for hepatitis A to E as well as CMVand Epstein-Barr viruses. She had no hypergammaglobulinemia, and smooth muscle antibodies were undetectable. At abdominal ultrasonography, the liver was normal in size without biliary tract obstruction. Serum bilirubin continued to rise to 138 μmol/l (Fig. 1). A liver biopsy was performed on day 5 after admission. Histological examination revealed extensive hepatocellular necrosis predominantly lobular, with portal inflammation composed of mononuclear cells and numerous polynuclear eosinophils, focal portal vein endothelitis, and signs of cholestasis. When questioned again, the patient reported having taken one tablespoon of flower pollen daily for seasonal fatigue over a period of 3 to 4 weeks prior to the development of symptoms. Her husband collected the pollen in his fields and made the preparation, which he had previously taken without any problem. The patient received IV N-acetylcysteine and vitamin K. She left the hospital after 10 days. Liver enzymes returned to normal after 2 months. The flower pollen was analyzed. It contained a high concentration of echimidine (104.0 ± 20.8 μg/kg), a pyrrolizidine alkaloid (PA) with known hepatotoxicity. Hepatotoxicity is due to the formation of a reactive metabolite via CYP2B6 and CYP3A4 [3]. Phenotyping of CYP3Awas performed using a specific probe approach with the administration of 0.1 mg of midazolam (MDZ) and evaluation of the metabolic ration between OHmidazolam (OH-MDZ) and MDZ in the plasma [4]. The patient had a high CYP3A enzyme activity (OH-MDZ/MDZ 12.2, normal range 0.48±0.16), which may have led to increased formation of the hepatotoxic metabolite. This case of severe herbal induced liver injury underlines that herbal remedies can be harmful in susceptible individuals. High CYP3A activity was a likely risk factor in our patient, although other mechanisms may have been involved, such as a variation in CYP2B6 activity or in other detoxifying metabolic pathways. CYP3A4 expression in the liver varies widely between individuals (>100-fold). While CYP3A phenotypes are highly variable, they show a unimodal distribution [5]. * Victoria Rollason victoria.rollason@hcuge.ch