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Copper Deficiency: Mimic of Myelodysplasia.

Can you tell a fake from the original? A fake Rolex from a true Rolex? Traditionally, within whatever method or profession, it takes a trained and skilled eye to distinguish a real or pseudo-occurrence. The same applies to myelodysplasia in which there are a lot of misleading characteristics that may pinpoint to a dysplastic syndrome, but in fact is not a true myelodysplastic syndrome. These conditions that are sometimes misleading can also cause difficulty in diagnosis; therefore, it is imperative that any competent laboratory scientist in microscopic analysis should be able to distinguish these occurrences to provide a timely diagnosis.

There are a variety of conditions that result in morphologically mimicking myelodysplasia. Myelodysplastic morphology of blood cells can be encountered not only in myelodysplastic syndromes but also can be seen in non-clonal disorders, cause of which can be pointed to viral, bacterial, parasitic infections, autoimmune disorders, juvenile rheumatoid arthritis, immune thrombocytopenic purpura, iron deficiency anemia, megaloblastic anemia, dysgranulopietic neutropenia, congenital neutropenia, malignant lymphoma, after administration of granulocyte colony stimulating factor, chemotherapy, steroids, smoking, alcohol, posttransplantation, copper deficiency also, together with or without cytopenia. (Olcay, 2016)

Copper is an essential element for all living organisms. Its function is related to key activities that are important involving metabolic enzymes such as superoxide dismutase and cytochrome oxidase and also important in the proteins essential for iron homoestasis such as ceruloplasmin. The recommended daily requirements for copper is low; therefore, copper is not commonly encountered. However, we should be aware that copper deficiency can cause hematological abnormalities and sometimes it may masquerade as a myelodysplastic syndrome (MDS).

According to D'Angelo, (2) copper deficiency is mainly associated with conditions such as gastric and bariatric surgery; dietary conditions like parenteral hyperalimentation; loss of proteins with enreropathies; hypoproteinemic status such as celiac disease; complications due to therapy with high doses of zinc and penicillamine; and chronic use of proton pump inhibitors. Copper deficiency can also be linked with hyperzinchemia; in some cases, this condition could be a consequence of possible use of zinc based denture adhesive creams.

The most common hematological abnormalities in copper deficiency are anemia and neutropenia. The pathogenesis of anemia in copper deficiency is complex and multifactorial. Copper and iron interact through the ceruloplasmin, a copper-dependent oxidase, which assists in iron transport in the plasma in association with transferrin by oxidation of Fe2+ into Fe3+ . The hephaestin, a transmembrane copper-containing ferroxidase, having 50% homology to ceruloplasmin, works as a facilitator for iron export from enterocytes into blood circulation.

Incorporated into ceruloplasmin, the copper is essential to mobilize the iron from the liver and transport to the bone marrow where it is utilized for erythropoiesis. In case of copper defiency, iron accumulates in the liver and iron availability is decreased in circulation and bone marrow; consequently, copper deficiency causes an ineffective erythropoiesis. (Halfdanarson et al, 2008)

Patients who present signs of copper deficiency manifest a profound insufficiency of hematopoiesis that is linked with anemia, leukopenia and less commonly, thrombocytopenia. In anemia caused by copper deficiency, the erythrocyte mean corpuscular volume (MCV) may be normal, low or increased, resulting in normocytic, microcytic or macrocytic anemia. Behind the most common anemia caused by iron deficiency or vitamin B12 and/or folate deficiencies, it is possible that, in some cases, complex multifactorial conditions including copper deficiency can be hidden. These conditions may show complex erythrocyte morphological features. (D'angelo, 2016)

The mechanism by which neutropenia develops in copper deficiency is seen as idiopathic but most likely caused by decreased survival of neutrophils in circulation by the action of hematopoietic progenitor cells through inhibition. Low serum copper levels directly support the diagnosis of copper deficiency. Although ceruloplasmin binds majority of copper in circulation and also for its transport, its plasma levels cannot be exclusive for copper deficiency, because it is also a reactive protein of acute phase.

Copper deficiency, in addition to causing cytopenia, can also generate dysplastic hematopoietic features, and sometimes it mimics MDS. It is important to note that in suspicions of dysplasia, the cytogenetic profile of patients who manifest dysplastic morphologic features will have no karyotypic abnormalities. In the bone marrow, however, erythrocyte and granulocytic precursor cells can manifest vacuolization in their cytoplasm. It is also of note that intracytoplasmic iron granules can be seen as another distinct morphologic appearance of copper deficiency.

As part of erythroblastic dysplasia, in copper deficiency, ringed sideroblasts can also be detected, and in this case, copper supplement can correct the anemia contrary to cases of clonal refractory ane mia with ringed sideroblasts (Figure 1). In addition to erythroblasts and myeloid precursors dysplasia, hematogone hyperplasia can be detected by flow cytometry in copper deficiency. Clinicians should be made aware that before making a diagnosis of MDS, it is important to consider that copper deficiency should be ruled out.

Zinc-induced copper deficiency that may manifest hematological abnormalities can be linked to some denture adhesives because excess zinc is ingested and taken up by enterocytes lining the intestine. Zinc is bound to metallothionines with the cell and their expression will also up-regulate their expression. Copper displaces zinc from the methallothionienes from the enterocytes so zinc is then free to be absorbed into the blood stream but copper is lost as cells in the intestinal tract desquamate; therefore, the ensuing result is copper deficiency. This condition may result in anemia and manifest dysplastic changes.

It is well known that copper deficiency can induce hematological abnormalities. In copper deficiency, commonly observed abnormalities in bone marrow include vacuolization in a single or multiple cell lines including myeloid precursors. Another manifestation is iron-containing plasma cells, a decrease in granulocyte precursors and ring sideroblasts. Sometimes these features may lead to misdiagnosis as MDS. In patients with cytopenia and/or low-grade MDS, copper dosage can be appropriate. However, it should be emphasized that copper deficiency is treatable by copper therapy.

References

(1.) Collins JF, Prohaska JR, Knutson MD. Medtabolic crossroads of iron and copper. Nutr Rev. 2010;68:133-147.

(2.) D'angelo, G. (2016). Copper deficiency mimicking myelodysplastic syndrome. Blood Research, 51(4), 217. doi:10.5045/ br.2016.51.4.217

(3.) Doherty, K., Connor, M., & Cruickshank, R. (2011). Zinc-containing denture adhesive: A potential source of excess zinc resulting in copper deficiency myelopathy. Bdj, 210(11), 523525. doi:10.1038/sj.bdj.2011.428

(4.) Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ. Hematological manifestations of copper deficiency: a retrospective review. Eur J Haematol. 2008;80:523-531

(5.) Olcay, L., & Yetgin, S. (2016). Disorders Mimicking Myelodysplastic Syndrome and Difficulties in its Diagnosis. Myelodysplastic Syndromes. doi:10.5772/64422

Carlo Ledesma, MS, MT(AMT), SH(ASCP)QLS, MT(ASCPi), Program Director, Medical Laboratory Technology and Phlebotomy, Rose State College, Midwest City, OK

Caption: Figure 1: The iron and copper transport pathways and their interactions. Into the enterocytes, dietary iron and copper are absorbed by DMT1 and CTR1, repectively, after reduction. Iron and copper are exported from enterocyte by ferroportin and ATP7A, respectively. Copper deficiency decreases the quantity of HP which is required for efficient enterocyte iron efflux and loading onto TF. CP carries 70-95% of the total copper in plasma. Hepatocytes can take up Fe-TF by TFR. Copper taken up by hepatocyte CTR1 is delivered to ATP7B and CP CP facilitates iron loading onto TF by oxidation (Fe2+ Fe3+). Hepatocytes control iron metabolism by producing the hepcidin which inhibits iron export. Fe-TF is transported to the marrow and utilized for the erythropoietic activity. Iron taken up by erythrocyte, the major iron consumer, is transferred to the mitochondria together with copper, and used for heme systhesis. Copper deficiency can impair the uptake of iron by mitochondria and cause decrease of heme synthesis. Macrophage phagocytoses senescent RBC and the irons are utilized or stored in ferritin. (D'angelo, 2016)

Caption: Intracytoplasmic iron granules in plasma cell: a diagnostic clue for copper deficiency. Source: ISLH

Caption: Vacuolization manifesting displasia in three cell lines. Note granularity and mononuclearity of megakaryocytic (B), binuclearity of erythroid precursors (C) and pseudo Pelger-Huet (D). Source: Haematologica 2007; 92:1429-1430
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Title Annotation:Article 451 1 Clock Hour
Author:Ledesma, Carlo
Publication:Journal of Continuing Education Topics & Issues
Article Type:Disease/Disorder overview
Date:Apr 1, 2018
Words:1331
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