Copper Deficiency Anemia and Neutropenia Due to Ketogenic Diet

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).

Copper is an essential trace element that plays a crucial role in the normal functioning of the hematologic system.^2,5,6,12,13 Copper is absorbed in the stomach and proximal duodenum, but absorption can be impaired after gastrointestinal surgery¹² and in malabsorption syndromes, such as celiac disease and short bowel syndrome.^14,15 Copper deficiency can also occur in prolonged TPN in the absence of copper supplementation,¹⁵ protein-losing enteropathies, and zinc toxicity because zinc competes with copper for absorption in the gastrointestinal tract.¹ 

The mechanism of copper deficiency neutropenia and anemia is not well understood.^1,16 However, the hematologic manifestations are well described, including microcytic, normocytic, and macrocytic anemia; severe absolute neutropenia; and, rarely, thrombocytopenia.¹⁷ Given the low incidence of copper deficiency and usual adequate intake in children from developed countries, copper deficiency as the cause of anemia and neutropenia is often overlooked.^5,13,14,18 Although we have focused on the hematologic abnormalities of copper deficiency, neurologic manifestations have also been described. Copper deficiency neuromyopathy, including lower-limb paresthesias and gait disorders with sensory ataxia or spasticity (if present), may help identify this uncommon cause of hematologic abnormalities.⁶ Other symptoms of copper deficiency may include fragile, abnormally formed hair; depigmentation of the skin; edema; hepatosplenomegaly; and osteoporosis.

Once a patient is diagnosed with copper deficiency, management includes copper supplementation with copper salts, which can be given orally or intravenously. Although there is no standard supplementation regimen, current practices are to supplement with a recommended daily amount of 40 to 50 μg/kg of elemental copper.^6,11,12 The hematologic abnormalities resolve within 4 to 12 weeks of therapy.^6,19,20 

Most reported cases of copper deficiency–associated neutropenia and anemia in the pediatric population have been caused by inadequate supplementation while receiving TPN, malabsorption, or (in rare cases) zinc toxicity.¹⁸ However, in up to 30% of cases in adults, there is no identified cause of copper deficiency.² Previously, Caraballo et al²¹ reported 1 case of low-serum copper without hematologic manifestations in a cohort of 216 children prescribed a ketogenic diet, suggesting that copper deficiency is relatively rare in this patient population. Recently, in a case report, Rashidian et al²² described a similar case of severe neutropenia and anemia because of copper deficiency in a patient prescribed a ketogenic diet. However, in that case, the patient did receive adequate copper intake from her diet and required supratherapeutic supplementation of copper for the resolution of hematologic manifestations, suggesting that copper metabolism may have been atypical in this patient.²² Our case illustrates a novel etiology with the development of copper deficiency–associated neutropenia and anemia being caused by dietary restrictions in transitioning from a formula-based to a pureed food–based ketogenic diet.

Ketogenic diets are highly restrictive, which put patients at risk for nutritional deficiencies. Comprehensive nutritional evaluation and follow-up are important in these patients, including regular evaluation for vitamin and mineral deficiencies.³ Multivitamins with minerals should be recommended for all patients who are on ketogenic diets.

In evaluating neutropenia and anemia of unknown etiology, we highlight the need to elucidate a thorough dietary history and consider copper deficiency in not only patients with risks of malabsorption but also in those with restrictive diets.

ANC

absolute neutrophil count

Hb

hemoglobin

MCV

mean corpuscular volume

PCR

polymerase chain reaction

TPN

total parenteral nutrition

WBC

white blood cell