CopperAlan Chin, MD Deficiency Anemia and

Neutropenia Due to Ketogenicabstract Diet Copper deficiency is an uncommon cause of hematologic abnormalities in children that is often overlooked or misdiagnosed. Although cases have been – reported because of malabsorption syndromes or after gastrointestinal surgeries, we report a case of copper deficiency associated anemia – and neutropenia in a child because of dietary restrictions, specifically, ’ transitioning from a formula-based ketogenic diet to a pureed food based ketogenic diet. On copper supplementation, the patient s anemia and neutropenia resolved. To our knowledge, this report is the first revealing copper deficiency anemia and neutropenia developing because of a ketogenic diet.

Copper is an essential element in the however, transition to solid foods ∼ functioning of the hematologic system. is possible as long as patients can Often misdiagnosed as myelodysplastic adhere to a restricted diet of 90% of disease, copper deficiency is an calories from fat and only 10%3 from uncommon cause of hematologic carbohydrates and proteins. abnormalities in children. Most often, In this report, we describe a 2-year-old copper deficiency is associated with girl who presented with neutropenia total parenteral nutrition (TPN) and anemia, which were found to be University of California, Los Angeles Mattel Children’s without copper supplementation, caused by copper deficiency because Hospital, Los Angeles, California protein-losing enteropathies, of dietary restrictions related to her DOI: https://​doi.​org/​10.​1542/​peds.​2017-​3286 gastrointestinal surgeries, ketogenic diet. Accepted for publication Dec 18, 2017 malabsorption1 syndromes, and zinc CASE REPORT toxicity. However, in a recent review, Address correspondence to Alan Chin, MD, 30% of patients who presented with Department of Pediatrics, UCLA Mattel Children’s hematologic abnormalities because Hospital, 757 Westwood Plaza, 3018, Los Angeles, CA A 2-year-old girl with a past medical 90095-1752. E-mail: [email protected] of copper2 deficiency had no identified history of microcephaly, lissencephaly, cause. Additionally, the median time PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, cerebellar hypoplasia, agenesis of the 1098-4275). to diagnosis2 of copper deficiency was corpus collosum, and seizure disorder 1 year. This illustrates the difficulty in Copyright © 2018 by the American Academy of presented to our medical center Pediatrics diagnosing copper deficiency, although ° in March 2016 with lethargy and FINANCIAL DISCLOSURE: The author has indicated it is a known cause of hematologic hypothermia to 91 F. Blood cell µ he has no financial relationships relevant to this abnormalities. counts revealed leukopenia, with a article to disclose. Ketogenic diets are an effective white blood cell (WBC) count of 2830/ L; µ FUNDING: No external funding. treatment for drug-resistant epilepsy neutropenia, with an absolute POTENTIAL CONFLICT OF INTEREST: The author has in children. However, the mechanisms neutrophil count (ANC) of 255/ L; indicated he has no potential conflicts of interest of action in controlling3 seizures are and a macrocytic anemia, with a to disclose. not well understood. All ketogenic hemoglobin (Hb) of 9 g/dL and mean diets are essentially high-fat, low- corpuscular volume (MCV) of 113.4 fL. To cite: Chin A. Copper Deficiency Anemia and carbohydrate diets that induce the Her platelet count, chemistry profile, Neutropenia Due to Ketogenic Diet. Pediatrics. 2018;141(5):e20173286 production of ketone 4bodies through and urinalysis results were all normal. fatty acid catabolism. An all-liquid Of note, 6 months before, the patient ketogenic formula is available; had completely normal blood counts. Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018:e20173286 CASE REPORT ’ TABLE 1 Laboratory Values Admission Initiated Copper In evaluating the patient s new- Supplement onset neutropenia and anemia, we – February 22, March 3, October 3, 2016 November 3, 2016 April 4, 2016 performed an extensive workup. 2016 2016 Viral- or other infection induced WBC, K/μL 5 2.83 3.17 7.05 8.74 bone marrow suppression was Hb, g/dL 7.6 9 7.1 7.7 10.6 considered; however, blood culture, MCV, fL 107 113.4 111.7 112.1 98.3 urine culture, respiratory virus Platelet, K/μL 349 213 228 350 401 polymerase chain reaction (PCR) ANC, K/μL — 255 0 250 1520 panel, cytomegalovirus PCR, Ebstein- B12, pg/mL 3912 Normal range: 254–1060 — — Folate, ng/mL 32 Normal range: 8.1–30.4 — — Barr virus PCR, and parvovirus B19 Copper, μg/dL — <10 Normal range: 12–67 μg/dL 76 PCR drawn at the time of admission —, not applicable. yielded negative results. Folate and vitamin B12 deficiencies were considered, but levels obtained μ 2 weeks before presentation normal blood cell counts while on Her serum copper level was 76 g/dL were normal. Hypothyroidism these medications, suggesting that (Table 1). was ruled out because thyroid- these would not be the cause of her DISCUSSION stimulating hormone and free acute hematologic abnormalities. thyroxine levels were normal. In specifically evaluating anemia, the The patient was also noted to be on Copper is an essential trace element direct antibody testing result was an oral ketogenic diet as part of her that plays a crucial role in the normal negative and haptoglobin and lactate seizure management, without the functioning of the hematologic dehydrogenase results were normal, need for supplemental gastric or 2,5,​ 6,​ 12,​ 13​ system. ‍ ‍ ‍ Copper is absorbed in making hemolysis unlikely, and an transpyloric feeds. A detailed diet the stomach and proximal duodenum, iron panel result was normal, ruling history revealed that in the past 6 but absorption can be impaired out iron deficiency. Myelodysplastic months, she had transitioned from 12 after gastrointestinal surgery and syndromes and other hematologic a powdered ketogenic formula to in malabsorption syndromes, such malignancies were ruled out with pureed foods. Given the restrictions as celiac disease and short bowel a peripheral smear, revealing of her ketogenic diet, her pureed 14,15​ syndrome. ‍ Copper deficiency can neutropenia with no blasts and an foods were limited to green also occur in prolonged TPN in the appropriate reticulocytosis and beans, turkey, chicken, and olive 15 absence of copper supplementation,​ a bone marrow biopsy revealing oil. Although the preformulated protein-losing enteropathies, and normocellular marrow with reduced ketogenic formula contained zinc toxicity because zinc competes and left-shifted myelopoiesis, adequate amounts of copper, the with copper for absorption in the adequate megakaryopoiesis, pureed foods did not. On the basis 1 gastrointestinal tract. moderate hematogone hyperplasia, of the pureed ketogenic diet recipes, μ and occasional ring sideroblasts. the patient received a range of 55 The mechanism of copper deficiency μ to 75 g of copper per day when the neutropenia and 1,anemia16​ is not After a review of the initial recommended daily amount is 350 g well understood. ‍ However, the μ workup, we determined that per day for her age and weight hematologic manifestations are well ’ 11 there were 2 possible etiologies (40 g/kg daily). Although the patient described, including microcytic, for the patient s neutropenia and was taking a pediatric multivitamin normocytic, and macrocytic anemia; ’ ’ anemia: drug-induced from the suspension, the specific formulation severe absolute neutropenia;17 and, patient s antiepileptic medications contained no copper. Our patient s rarely, thrombocytopenia. Given the μ – μ or a nutritional deficiency of trace serum copper was found to be low incidence of copper deficiency elements, specifically copper, <10 g/dL (normal is 12 67 g/dL). and usual adequate intake in children which may present with ringed She was treated for copper deficiency from developed countries, copper 5,6​ μ sideroblasts. ‍ The patient was with intravenous copper (2 doses deficiency as the cause of anemia and μ 5,13,​ ​ taking 2 antiepileptic– medications of 20 g/kg) and discharged on oral 14,neutropenia18​ is often overlooked. that are known7 9 to cause neutropenia:10 copper glycinate powder (40 g/kg ‍ ‍ Although we have focused on the levetiractem ‍ and zonisamide. daily). At her follow-up visit hematologic abnormalities of copper However, she had been on stable 1 month later, her complete blood deficiency, neurologic manifestations µ µ doses of these medications for >1 cell count improved, with a WBC have also been described. Copper year before the development of count of 8740/ L, ANC of 1520/ L, deficiency neuromyopathy, including neutropenia and anemia and had Hb of 10.6 g/dL, and MCV of 98.3 fL. lower-limb paresthesias and gait Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 CHIN 5. Dalal N, Hooberman A, Mariani R, Sirota R, Lestingi T. Copper deficiency disorders with sensory ataxia or being caused by dietary restrictions – mimicking myelodysplastic syndrome. spasticity (if present), may help in transitioning from a formula-based Clin Case Rep. 2015;3(5):325–327 identify this uncommon cause6 of to a pureed food based ketogenic 6. Gabreyes AA, Abbasi HN, Forbes KP, hematologic abnormalities. Other diet. McQuaker G, Duncan A, Morrison symptoms of copper deficiency may Ketogenic diets are highly I. Hypocupremia associated include fragile, abnormally formed restrictive, which put patients at cytopenia and myelopathy: a national hair; depigmentation of the skin; risk for nutritional deficiencies. retrospective review. Eur J Haematol. 2013;90(1):1 9 edema; hepatosplenomegaly; and Comprehensive nutritional – osteoporosis. evaluation and follow-up are 7. Bunnell K, Pucci F. Levetiracetam- Once a patient is diagnosed with important in these patients, induced neutropenia following traumatic brain injury. Brain Inj. copper deficiency, management including regular evaluation for 3 2015;29(1):115 117 includes copper supplementation vitamin and mineral deficiencies. – with copper salts, which can be given Multivitamins with minerals should 8. Oh SJ, Kwon HI, Moon SH, Ro YS, Ko orally or intravenously. Although be recommended for all patients who JY. Toxic epidermal necrolysis with there is no standard supplementation are on ketogenic diets. isolated neutropenia related to the use of levetiracetam. J Dermatol. regimen, current practices are to In evaluating neutropenia and μ 2016;43(8):969–971 supplement with a recommended anemia of unknown etiology, we 9. Taberner Bonastre MT, Peralta daily amount of 40 to6, 11,​5012​ g/kg highlight the need to elucidate of elemental copper. ‍ ‍ The a thorough dietary history and Muñoz S, Boza FM, Gumà I Padró J. Neutropenia secondary to hematologic abnormalities resolve6,19,​ 20​ consider copper deficiency in exposure to levetiracetam. Tumori. within 4 to 12 weeks of therapy. ‍ not only patients with risks of – 2015;101(5):e145–e146 Most reported cases of copper malabsorption but also in those with restrictive diets. 10. Zonegran (Zonisamide) [Prescribing deficiency associated neutropenia Information]. 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