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 functioning of the hematologic system. Often misdiagnosed as myelodysplastic disease, copper deficiency is an uncommon cause of hematologic abnormalities in children. Most often, copper deficiency is associated with total parenteral nutrition (TPN) without copper supplementation, protein-losing enteropathies, gastrointestinal surgeries, malabsorption syndromes, and zinc toxicity.1 However, in a recent review, 30% of patients who presented with hematologic abnormalities because of copper deficiency had no identified cause.2 Additionally, the median time to diagnosis of copper deficiency was 1 year.2 This illustrates the difficulty in diagnosing copper deficiency, although it is a known cause of hematologic abnormalities.

Ketogenic diets are an effective treatment for drug-resistant epilepsy in children. However, the mechanisms of action in controlling seizures are not well understood.3 All ketogenic diets are essentially high-fat, low-carbohydrate diets that induce the production of ketone bodies through fatty acid catabolism.4 An all-liquid ketogenic formula is available; however, transition to solid foods is possible as long as patients can adhere to a restricted diet of ∼90% of calories from fat and only 10% from carbohydrates and proteins.3 

In this report, we describe a 2-year-old girl who presented with neutropenia and anemia, which were found to be caused by copper deficiency because of dietary restrictions related to her 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: levetiractem7,9 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).

TABLE 1

Laboratory Values

AdmissionInitiated Copper Supplement
February 22, 2016March 3, 2016October 3, 2016November 3, 2016April 4, 2016
WBC, K/μL 2.83 3.17 7.05 8.74 
Hb, g/dL 7.6 7.1 7.7 10.6 
MCV, fL 107 113.4 111.7 112.1 98.3 
Platelet, K/μL 349 213 228 350 401 
ANC, K/μL — 255 250 1520 
B12, pg/mL 3912 Normal range: 254–1060 — — 
Folate, ng/mL 32 Normal range: 8.1–30.4 — — 
Copper, μg/dL — <10 Normal range: 12–67 μg/dL 76 
AdmissionInitiated Copper Supplement
February 22, 2016March 3, 2016October 3, 2016November 3, 2016April 4, 2016
WBC, K/μL 2.83 3.17 7.05 8.74 
Hb, g/dL 7.6 7.1 7.7 10.6 
MCV, fL 107 113.4 111.7 112.1 98.3 
Platelet, K/μL 349 213 228 350 401 
ANC, K/μL — 255 250 1520 
B12, pg/mL 3912 Normal range: 254–1060 — — 
Folate, ng/mL 32 Normal range: 8.1–30.4 — — 
Copper, μg/dL — <10 Normal range: 12–67 μg/dL 76 

—, not applicable.

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

FUNDING: No external funding.

1
Lazarchick
J
.
Update on anemia and neutropenia in copper deficiency.
Curr Opin Hematol
.
2012
;
19
(
1
):
58
60
[PubMed]
2
Halfdanarson
TR
,
Kumar
N
,
Li
CY
,
Phyliky
RL
,
Hogan
WJ
.
Hematological manifestations of copper deficiency: a retrospective review.
Eur J Haematol
.
2008
;
80
(
6
):
523
531
[PubMed]
3
Luat
AF
,
Coyle
L
,
Kamat
D
.
The ketogenic diet: a practical guide for pediatricians.
Pediatr Ann
.
2016
;
45
(
12
):
e446
e450
[PubMed]
4
Youngson
NA
,
Morris
MJ
,
Ballard
JWO
.
The mechanisms mediating the antiepileptic effects of the ketogenic diet, and potential opportunities for improvement with metabolism-altering drugs.
Seizure
.
2017
;
52
:
15
19
[PubMed]
5
Dalal
N
,
Hooberman
A
,
Mariani
R
,
Sirota
R
,
Lestingi
T
.
Copper deficiency mimicking myelodysplastic syndrome.
Clin Case Rep
.
2015
;
3
(
5
):
325
327
[PubMed]
6
Gabreyes
AA
,
Abbasi
HN
,
Forbes
KP
,
McQuaker
G
,
Duncan
A
,
Morrison
I
.
Hypocupremia associated cytopenia and myelopathy: a national retrospective review.
Eur J Haematol
.
2013
;
90
(
1
):
1
9
[PubMed]
7
Bunnell
K
,
Pucci
F
.
Levetiracetam-induced neutropenia following traumatic brain injury.
Brain Inj
.
2015
;
29
(
1
):
115
117
[PubMed]
8
Oh
SJ
,
Kwon
HI
,
Moon
SH
,
Ro
YS
,
Ko
JY
.
Toxic epidermal necrolysis with isolated neutropenia related to the use of levetiracetam.
J Dermatol
.
2016
;
43
(
8
):
969
971
[PubMed]
9
Taberner Bonastre
MT
,
Peralta Muñoz
S
,
Boza
FM
,
Gumà I Padró
J
.
Neutropenia secondary to exposure to levetiracetam.
Tumori
.
2015
;
101
(
5
):
e145
e146
[PubMed]
10
Zonegran (Zonisamide) [Prescribing Information]
.
Woodcliff Lake, NJ
:
Eisai Inc
;
2012
11
Hughes
G
,
Kelly
VJ
,
Stewart
RA
.
The copper content of infant foods.
Pediatrics
.
1960
;
25
:
477
484
[PubMed]
12
Chhetri
SK
,
Mills
RJ
,
Shaunak
S
,
Emsley
HC
.
Copper deficiency.
BMJ
.
2014
;
348
:
g3691
[PubMed]
13
Gregg
XT
,
Reddy
V
,
Prchal
JT
.
Copper deficiency masquerading as myelodysplastic syndrome.
Blood
.
2002
;
100
(
4
):
1493
1495
[PubMed]
14
Khera
D
,
Sharma
B
,
Singh
K
.
Copper deficiency as a cause of neutropenia in a case of coeliac disease.
BMJ Case Rep
.
2016
;
2016
:
bcr2016214874
15
Mullally
AM
,
Vogelsang
GB
,
Moliterno
AR
.
Wasted sheep and premature infants: the role of trace metals in hematopoiesis.
Blood Rev
.
2004
;
18
(
4
):
227
234
[PubMed]
16
Percival
SS
.
Neutropenia caused by copper deficiency: possible mechanisms of action.
Nutr Rev
.
1995
;
53
(
3
):
59
66
[PubMed]
17
Sutton
L
,
Vusirikala
M
,
Chen
W
.
Hematogone hyperplasia in copper deficiency.
Am J Clin Pathol
.
2009
;
132
(
2
):
191
199; quiz 307
[PubMed]
18
Sochet
AA
,
Jones
A
,
Riggs
CD
 Jr
,
Weibley
REA
.
A 3-year-old boy with severe anemia and neutropenia.
Pediatr Ann
.
2013
;
42
(
1
):
15
17
[PubMed]
19
Huff
JD
,
Keung
YK
,
Thakuri
M
, et al
.
Copper deficiency causes reversible myelodysplasia.
Am J Hematol
.
2007
;
82
(
7
):
625
630
[PubMed]
20
Naismith
RT
,
Shepherd
JB
,
Weihl
CC
,
Tutlam
NT
,
Cross
AH
.
Acute and bilateral blindness due to optic neuropathy associated with copper deficiency.
Arch Neurol
.
2009
;
66
(
8
):
1025
1027
[PubMed]
21
Caraballo
R
,
Vaccarezza
M
,
Cersósimo
R
, et al
.
Long-term follow-up of the ketogenic diet for refractory epilepsy: multicenter Argentinean experience in 216 pediatric patients.
Seizure
.
2011
;
20
(
8
):
640
645
22
Rashidian
H
,
Liu
YMC
,
Geraghty
MT
,
Kobayashi
J
,
Donner
EJ
,
Klaassen
RJ
.
Severe neutropenia and anemia in a child with epilepsy and copper deficiency on a ketogenic diet.
Pediatr Neurol
.
2017
;
76
:
93
94
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.