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