Copper Deficiency Anemia and Neutropenia Due to Ketogenic Diet

Case Report

A 2-year-old girl with a past medical history of microcephaly, lissencephaly, cerebellar hypoplasia, agenesis of the corpus collosum, and seizure disorder presented to our medical center in March 2016 with lethargy and hypothermia to 91°F. Blood cell counts revealed leukopenia, with a white blood cell (WBC) count of 2830/µL; neutropenia, with an absolute neutrophil count (ANC) of 255/µL; and a macrocytic anemia, with a hemoglobin (Hb) of 9 g/dL and mean corpuscular volume (MCV) of 113.4 fL. Her platelet count, chemistry profile, and urinalysis results were all normal. Of note, 6 months before, the patient had completely normal blood counts.

In evaluating the patient’s new-onset neutropenia and anemia, we performed an extensive workup. Viral- or other infection–induced bone marrow suppression was considered; however, blood culture, urine culture, respiratory virus polymerase chain reaction (PCR) panel, cytomegalovirus PCR, Ebstein-Barr virus PCR, and parvovirus B19 PCR drawn at the time of admission yielded negative results. Folate and vitamin B12 deficiencies were considered, but levels obtained 2 weeks before presentation were normal. Hypothyroidism was ruled out because thyroid-stimulating hormone and free thyroxine levels were normal. In specifically evaluating anemia, the direct antibody testing result was negative and haptoglobin and lactate dehydrogenase results were normal, making hemolysis unlikely, and an iron panel result was normal, ruling out iron deficiency. Myelodysplastic syndromes and other hematologic malignancies were ruled out with a peripheral smear, revealing neutropenia with no blasts and an appropriate reticulocytosis and a bone marrow biopsy revealing normocellular marrow with reduced and left-shifted myelopoiesis, adequate megakaryopoiesis, moderate hematogone hyperplasia, and occasional ring sideroblasts.

After a review of the initial workup, we determined that there were 2 possible etiologies for the patient’s neutropenia and anemia: drug-induced from the patient’s antiepileptic medications or a nutritional deficiency of trace elements, specifically copper, which may present with ringed sideroblasts.^5,6 The patient was taking 2 antiepileptic medications that are known to cause neutropenia: levetiractem^7–9 and zonisamide.¹⁰ However, she had been on stable doses of these medications for >1 year before the development of neutropenia and anemia and had normal blood cell counts while on these medications, suggesting that these would not be the cause of her acute hematologic abnormalities.

The patient was also noted to be on an oral ketogenic diet as part of her seizure management, without the need for supplemental gastric or transpyloric feeds. A detailed diet history revealed that in the past 6 months, she had transitioned from a powdered ketogenic formula to pureed foods. Given the restrictions of her ketogenic diet, her pureed foods were limited to green beans, turkey, chicken, and olive oil. Although the preformulated ketogenic formula contained adequate amounts of copper, the pureed foods did not. On the basis of the pureed ketogenic diet recipes, the patient received a range of 55 to 75 μg of copper per day when the recommended daily amount is 350 μg per day for her age and weight (40 μg/kg daily).¹¹ Although the patient was taking a pediatric multivitamin suspension, the specific formulation contained no copper. Our patient’s serum copper was found to be <10 μg/dL (normal is 12–67 μg/dL). She was treated for copper deficiency with intravenous copper (2 doses of 20 μg/kg) and discharged on oral copper glycinate powder (40 μg/kg daily). At her follow-up visit 1 month later, her complete blood cell count improved, with a WBC count of 8740/µL, ANC of 1520/µL, Hb of 10.6 g/dL, and MCV of 98.3 fL. Her serum copper level was 76 μg/dL (Table 1).