Hematopathological Findings in Patients with Copper Deficiency and Hematologic Manifestations.
Authors: Halfdanarson Thorvardur R. , Li Chin-Yang , Phyliky Robert L. , Kumar Neeraj , Hogan William J. 
Published: April 2020

Abstract
Background: Copper deficiency is increasingly being diagnosed in adults with malabsorption syndromes, especially following GI surgery such as gastric and bowel resections and bariatric surgery. The most common hematologic manifestations are refractory anemia and neutropenia and patients have been misdiagnosed as having myelodysplasia. Certain findings on bone marrow examination are felt to be characteristic for copper deficiency such as maturation arrest in the myeloid lineage, vacuolization of the erythroid and myeloid precursors and ringed sideroblasts.
Methods: We reviewed all cases of copper deficiency diagnosed at the Mayo Clinic from 1974 – 2005. We also reviewed all cases of low serum copper (&lt; 0.75 μg/ml) identified in our heavy metals laboratory.
Results: 123 patients with hypocupremia were identified. 77 patients were excluded as the hypocupremia was either transient or due to other factors such as Wilson’s disease. Twenty-five patients had hematologic manifestations, including anemia and leukopenia (13), isolated anemia (6), pancytopenia (5), and isolated neutropenia (1). Eighteen patients had a bone marrow biopsy. We were able to retrieve and review bone marrow slides in 11 cases. The bone marrow examination findings are shown in the table. The marrow cellularity was decreased in four cases. All cases had granulocytic hypoplasia but preserved megakaryopoiesis. Nine cases had relative erythroid hyperplasia. All but one bone marrow had cytoplasmic vacuoles in pronormoblasts and myelocytes. Increased iron within macrophages was seen in 9 cases and increased iron in plasma cells was noted in 8 cases. This was especially prominent in the cases with low peripheral white blood count. Ringed sideroblasts were seen in 4 cases and were more commonly seen in anemic patients. The initial bone marrow examination commonly suggested toxic effect (drugs or alcohol), myelodysplasia or were non-diagnostic.
Conclusion: We have described the bone marrow findings in 11 copper deficient patients with abnormal blood counts. None of these patients was suspected of copper deficiency based on the initial marrow examination. The initial impression was commonly toxic effect due to the presence of cytoplasmic vacuolization. Patients with ringed sideroblasts were suspected of having MDS. Copper deficiency should be considered in patients with cytopenias and the described bone marrow findings, especially if there is evidence of malabsorption or a history of GI surgery such as gastric resection or bariatric surgery.
Bone marrow findings Patient Cellularity Ery/gran/meg Vacuoles Iron (mø/PC) RS Hgb/Plt WBC/ANC nl: normal, 0: absent, Ery/gran/meg: erythro-/granulo-/megakaryopoiesis, Iron (mø/PC): Iron in macrophages and plasma cells, RS: Ringed sideroblasts 1 ↓ ↑/↓/nl Yes ↑/↑ No 11.3/203 3.2/1.1 2 Nl ↑/↓/nl Yes 0/0 No 11.4/192 5.6/4.0 3 Nl ↑/↓/nl No ↑/0 No 10.6/95 3.0/2.2 4 ↓ ↑/↓/nl Yes ↑/↑ No 13.6/128 4.2/0.92 5 Nl ↑/↓/nl Yes ↑/↑ 10% 9.8/215 1.4/0.6 6 ↓ ↑/↓/nl Yes ↑/↑ No 7.9/292 1.8/0.18 7 Nl ↑/↓/nl Yes ↑/↑ No 10.6/280 2.7/1.4 8 Nl nl/↓/nl Yes ↑/↑ 20% 8.1/330 1.5/0.24 9 Nl ↑/↓/nl Yes ↑/↑ &lt;1% 9.4/252 1.3/0.25 10 ↓ Nl/↓/nl Yes 0/0 No 10.5/167 2.4/1.67 11 Nl ↑/↓/nl Yes ↑/↑ yes 12.5/224 4.2/3.9