Hematological Abnormalities in Copper Deficiency.
Authors: Karri Sirisha , Doshi Vaishali 
Published: April 2020

Abstract
Introduction: Copper deficiency can rarely present as anemia and leucopenia. Copper and iron are essential trace elements through their functions as co-factors in numerous biochemical reactions. Hephaestin is a transmembrane copper-dependent ferroxidase necessary for effective iron transport from intestinal enterocyte into the circulation. Copper is hence required for the efficient utilization of iron in the mammalian system. Copper enzymes such as superoxide dismutase and cytochrome oxidase have an essential role in red cell development and heme maturation. We present 4 patients of copper deficiency. The first patient presented with anemia and leucopenia and the bone marrow showed increased vacuolated erythroblasts with and erythroid dysplasia. This patient had a bone marrow picture resembling erythroleukemia. However, as this patient had undergone a gastric bypass, further studies in the form of vitamin B12, red cell folate and copper were performed. Patient was found to have low copper and low ceruloplasmin levels, with normal B12 and red cell folate levels. Three patients had anemia and neutropenia and showed dysplasia in erythroid lineage, ring sideroblasts, and abnormal accumulation of iron granules in plasma cells. In all four cases, repletion of copper resulted in normalization of peripheral counts and bone marrow showed normal trilineage hematopoiesis.
Discussion: Copper deficiency is known to present with microcytic anemia. However we report three cases in which patients presented as normocytic anemia and neutropenia.Bone marrow findings in addition to dysplasia, also showed abnormal iron granules in plasma cells as well as ring sideroblasts. Presence of ringed sideroblasts in myelodysplasia is associated with numerous point mutations in mitochondrial DNA. Mutations identified to date involve among others the cytochrome oxidase subunits I and II. Cytochrome c oxidase is involved in oxidizing FE++ to Fe+++ and incorporation into heme. Copper is a component of cytochrome c oxidase and superoxide dismutase and its deficiency leads to low levels of these enzymes. We propose that copper deficiency plays role in causing dysplastic changes in bone marrow and increase in ringed sideroblasts. Any patient presenting with unexplained anemia or leucopenia, with dysplasia and ringed sideroblasts should be evaluated for copper deficiency. Abnormal iron granules in plasma cells have been reported in other conditions like ethanol toxicity, however we report two patients with copper deficiency who were found to have iron granules in plasma cells. We consider copper an important component of the work-up of patients thought to have myelodysplasia especially if they have undergone a gastric bypass and have normal cytogenetics which is not suggestive of clonal hematopoiesis.
Hematological abnormalities in patients with copper deficiency patient 1 anemia neutropenia normocytic patient 2 anemia neutropenia normocytic patient 3 anemia neutropenia microcytic patient 4 anemia neutropenia normocytic bone marrow findings in patients with copper deficiency erythroids myeloid ring sideroblasts iron granules in plama cells patient 1 dysplastic hypoplasia none abnormal iron granules in plama cells patient 2 dysplastic dysplasia 15% abnormal iron granules in plasma cells patient 3 dysplastic hypoplasia none none patient 4 dysplastic dysplasia none none