Case Presentation: A 46-year-old male from Nigeria with no medical history presented to the emergency department (ED) with 5 days of dark urine, decreased oral intake, weakness, and abdominal pain. On exam, the patient was tachycardic, jaundiced, and had normal oxygen saturation. Labs revealed a leukocytosis, acute kidney injury (AKI), and a precipitous drop in hemoglobin (Hgb) from a baseline of 15 to 6.8 g/dL. Further evaluation revealed a negative Coombs test (DAT), elevated lactate dehydrogenase, decreased haptoglobin, elevated total bilirubin (predominantly indirect), elevated reticulocyte count, normal B12 and folate, and negative SARS-CoV-2 PCR. Peripheral blood smear demonstrated hypochromia and polychromasia; indirect staining for Heinz bodies was positive. Urinalysis showed blood, few RBCs, granular casts and renal tubular epithelial cell casts. Of note, the patient had presented to the ED one-month prior with dyspnea, fatigue, and anosmia, found to have mildly elevated blood pressure, blood glucose, and D-dimer; CT chest obtained was concerning for a COVID-19 infection. He was discharged home from the ED in stable condition with a presumed diagnosis of COVID-19 and given strict ED return precautions. After this initial ED visit, our patient began taking a multivitamin and berberine supplements to boost his immune system and prevent type 2 diabetes mellitus and hypertension. Thus, it was suspected that the patient developed hemolytic anemia (HA) precipitated by berberine in the setting of glucose-6-phosphate-dehydrogenase (G6PD) deficiency. He was transfused with 2 units of packed red blood cells, and his Hgb corrected appropriately and remained stable at 8-9 g/dL. Hematology recommended discontinuing berberine. The patient’s renal function improved with IV fluids and discontinuation of berberine. The patient was educated on G6PD triggers to avoid and discharged with follow up in hematology, renal and primary care clinics.

Discussion: Adverse side effects of herbal and dietary supplements contribute to approximately 23,000 ED visits and over 2,000 hospitalizations every year (1). Berberine is an isoquinoline alkaloid used in traditional Chinese and Ayurvedic medicine posited to have various metabolic benefits including lowering blood pressure and blood sugar (2,3). While some studies suggest that recommended doses of berberine are non-toxic (4), few case reports of berberine-associated HA in patients with G6PD deficiency exist (5). G6PD deficiency, the most common human enzyme defect known, commonly presents with symptoms of fatigue, jaundice, dark urine, and abdominal pain after a precipitating event (infection or medication ingestion.) While COVID-19 has been reported to cause autoimmune HA (6), this is unlikely given the patient’s negative DAT, the delay between infection and onset of HA, and the prompt, sustained resolution of HA once berberine was discontinued. The patient’s AKI was felt to be due to HA-related pigment nephropathy with sustained normalization once the offending drug was discontinued and hemolysis resolved. This case highlights the importance of thoroughly obtaining a medication history that includes use of herbal supplements.

Conclusions: Though rare, berberine ingestion is a noteworthy cause of HA in patients with G6PD deficiency. When patients present with acute HA, clinicians must have a high index of suspicion for history of complementary and alternative medicine use and potentially underlying G6PD deficiency.