Discussion
Copper is a trace element serving as a cofactor for enzymes involved in
respiratory oxidation, iron transport and metabolism and
neurotransmitter synthesis, also known as
cuproenzymes.1-2 Copper homeostasis regulates
absorption and distribution, with mechanisms to limit free radical
production and copper overload.1-2 Dietary copper
content drives intestinal absorption, which occurs primarily through the
proximal small intestine, to a lesser degree the
stomach.1 The recommended dietary allowance for copper
increases from infancy through adolescence and adulthood, up to 1000
µg/day in the United States and Canada.1
Up to 70% of dietary copper is absorbed enterally; deficiency may occur
secondary to states of malabsorption (e.g., celiac disease and small
bowel Crohn’s disease) as well as chronic inflammatory conditions.
Acquired deficiency may be a complication following surgical resection,
seen in short gut syndrome, gastrectomy and gastric bypass surgery.3 Additionally, prolonged parenteral nutrition without
copper supplementation and excessive zinc intake lead to deficiency.
Zinc and copper are described to have an antagonistic relationship, with
excessive zinc intake interfering with copper absorption due to
zinc-induced synthesis of a copper-binding ligand leading to
sequestration within intestinal cells preventing entry into
circulation.2
In a retrospective study of forty patients with copper deficiency and
hematologic abnormalities, thirty-nine had isolated anemia or anemia
with other cytopenias.4 Copper deficiency anemia can
range from microcytic to macrocytic, with severity correlating to extent
of deficiency.3 The pathophysiology of anemia is
theorized to derive from copper’s role in proteins involved in iron
homeostasis and transport. Reduced transport of iron across intestinal
cells leads to impaired conversion of iron by ceruloplasmin and
hephaestin (a copper-dependent ferroxidase), needed for loading onto
transferrin and incorporation into protoporyphrin.3With incomplete hemoglobin synthesis ring sideroblasts form and red cell
membrane defects occur from decreased activity of copper superoxide
dismutase against free radicals, leading to a shortened red cell
lifespan.3
Leukopenia of copper deficiency primarily consists of neutropenia.
Proposed hypotheses include impaired maturation and increased
destruction of precursors within the marrow, in addition to limited
neutrophil migration from marrow and increased clearance from
circulation.3,5 Thrombocytopenia is a less frequent
consequence and rarely copper deficiency presents as isolated
thrombocytopenia. In the previously described cohort, thrombocytopenia
was only noted in combination with anemia in two of forty
patients.4 In copper deficiency, the bone marrow is
typically hypercellular and with characteristic findings of cytoplasmic
vacuolization of both erythroid and myeloid precursor
cells.3 Iron stores are also increased with a
prominence of ring sideroblasts.3 The constellation of
all these findings is often misdiagnosed or mistaken for myelodysplastic
syndrome (MDS) and with reports of copper deficiency identified upon
referral for hematopoietic stem cell transplant.3Timely diagnosis allows for appropriate intervention; of the previously
described patients with available response to therapy follow up, 16 of
28 (57%) had complete normalization of cytopenias, nine with partial
response and three with no response.4 This response
underlies the importance of early consideration of copper deficiency in
a differential for cytopenias.
Neurologic changes can frequently accompany hematologic findings and
encompass a spectrum of disorders. This includes isolated peripheral
neuropathy or polyneuropathy, motor neuron disease, myopathy, cerebral
demyelination, cognitive dysfunction, optic neuropathy and myelopathy.
In copper deficiency myelopathy, common presenting symptoms are gait
difficulties secondary to sensory ataxia and dorsal column dysfunction
with associated extremity paresthesias.5 In a review
of 55 cases of patients with copper deficiency and neurologic symptoms,
copper supplementation led to improvement in about half of patients with
reported outcomes and stabilization of symptoms in the
remainder.5