Jun 11, 2009 - fully for the treatment of acute lymphoblastic leukemia and mantle cell lym- .... for acute biphenotypic leukemias (ABL) are yet to be determined.
Correspondence Myelodysplasia and copper deficiency induced by denture paste
ANJALI SIBLEY ANNE-MARIE MADDOX
A 50-year-old lady with history of persistent neutropenia, worsening ataxia, and lower extremity weakness presented to our clinic. At the time of initial evaluation at an outside facility 3 years before, she had reported fatigue, weight loss, and lower extremity weakness. Her laboratory test results included white blood cell count (WBC) 1.6 K/ll (absolute neutrophil count (ANC) 350), Hg 8.1 g/dl, platelets 501 K/ll, and B12 219 (reference range 211–911 pg/ml). Initial bone marrow showed granulocytopenia, anemia, trilineage dyshematopoiesis, 4% blasts, and normal karyotype. She had been diagnosed with myelodysplasia (refractory cytopenia with multilineage dysplasia). She was treated for 3 years with intermittent granulocyte colony stimulating factor (G-CSF), an erythropoietin-stimulating agent, and red cell transfusions. She was also treated for cyanocobalamin deficiency, with little improvement of neurological symptoms. The neutropenia remained constant and the anemia stabilized. At the time of our evaluation, her laboratory test results were WBC 2.59 K/ll (ANC 381), Hg 13.2 g/dl, platelets 228 K/ll, B12 1,196 pg/ml (reference range 211–291 pg/ml), zinc 181 lg/dl (reference range 60–120 lg/dl), ferritin 107 lg/l (reference range 10–291 lg/l), iron 48 lmol/l (reference range 37–170 lg/l), and copper 7 lg/dl (reference range 80–155 lg/dl). Subsequent bone marrow aspirate and biopsy showed a normocellular marrow with trilineage maturation, mild dyspoesis in the erythroid and megakaryocytic lineages, and normal karyotype. Her copper deficiency was presumed secondary to hyperzincemia, a result of chronic usage of a commercially available denture paste. Denture paste contains a calcium/zinc copolymer and can lead to excess systemic absorption of zinc. Low-zinc pastes are available; systemic absorption from these is unclear. We advised that she use denture adhesive strips and prescribed oral copper sulfate 2 mg daily. After 4 weeks of oral copper replacement and abstaining from using denture paste, our patient’s serum copper increased to 57 lg/dl and her zinc level fell to 115 lg/dl. Her WBC count increased to 8,000 K/ll with resolution of neutropenia. Her ataxia improved slightly. Copper deficiency leading to dysfunction in cellular lineages and neuropathy has recently been reported in the literature. Fong describes five cases of neutropenia and/or anemia in the setting of copper deficiency [1]. Halfdarason presents forty cases of anemia and/or neutropenia, 75% of whom reported neurological dysfunction [2]. Huff describes the cases of eight women with moderate to severe copper deficiency and their associated comorbidities, including anemia, neutropenia, and/or neuropathy. Huff also describes common bone marrow findings in copper deficiency [3]. All series describe improvement in hematological indices with treatment of copper deficiency. It is believed that copper deficiency leads to impaired granulocyte maturation through an undefined mechanism; these changes along with the presence of ringed sideroblasts can lead to diagnostic confusion. A suggested mechanism of copper deficiency secondary to hyperzincemia lies in the binding of these metals to metallothionein. Elevated zinc leads to elevated levels of metallothionein, a protein that favors binding to copper. Metallothionein binds to copper and is then excreted in the gastrointestinal tract. Other causes of deficiency include malabsorptive conditions, gastric surgery, excess zinc absorption, and tube feedings [4–7]. Patients with copper deficiency can exhibit various types of neurological dysfunction including peripheral neuropathy, optic neuritis, and other symptoms of subacute combined degeneration. As shown by Kumar et al., treated patients sometimes (but not always) experience improvement in symptoms [8]. This patient illustrates how copper deficiency can mimic symptoms and signs of myelodysplasia. We recommend that copper levels should be determined in patients presenting with signs of myelodysplasia if use of denture paste is reported, before pursuing an aggressive treatment regimen that may be ultimately unnecessary.
Acknowledgments The authors would like to thank Dr. Paulette Mehta for her assistance in the preparation of this work.
Division of Hematology/Oncology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas Published online 11 June 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21471 Conflict of interest: Nothing to report.
References 1. Fong T, Vij R, Vijayan A, DiPersio J, Blinder M. Copper deficiency: An important consideration in the differential diagnosis of myelodysplastic syndrome. Haematologica 2007;92:1429–1430. 2. Halfdanarson TR, Hogan WJ, Phyliky RL, Kumar N, Tefferi A, Elliott M. The increasing relevance of copper deficiency in hematological practice. Blood 2005;106:1679. 3. Huff JD, Keung YK, Thakuri M, Beaty MW, Hurd DD, Owen J, Molna´r I. Copper deficiency causes reversible myelodysplasia. Am J Hematol 2007;82: 625–630. 4. Summerfield AL, Steinberg FU, Gonzalez JG. Morphologic findings in bone marrow precursor cells in zinc-induced copper deficiency anemia. Am J Clin Pathol 1992;97:665–668. 5. Dunlap WM, James GW III, Hume DM. Anemia and neutropenia caused by copper deficiency. Ann Intern Med 1974;80:470–476. 6. Brewer GJ. Causes and diagnosis of copper deficiency. Am J Hematol 2008;83:87–88. 7. Klevay L. Copper deficiency and diet. Am J Hematol 2007;82:684. 8. Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63: 33–39.
Postvaccination hyperhemolysis coinciding with remission of Epstein Barr virus (EBV)-associated immune thrombocytopenic purpura (ITP) To the editor: Primary Epstein-Barr virus (EBV) infection, and vaccinations to a lesser degree, may associate with immune cytopenias, particularly in the seronegative vulnerable years of childhood [1]. To date, reports of vaccination-associated hemolysis have been limited to fourteen children [2–4]. We present an adult case of hyperhemolysis, the onset of which followed vaccinations against encapsulated organisms, and which was also coordinated with the response of EBV-associated immune thrombocytopenic purpura (ITP). This 22-year-old male, with a remote history of liver transplantation for congenital biliary atresia, presented with a platelet count of 0 3 109/L and biochemical markers for hepatitis. His only medication had been tacrolimus. There was no lymphadenopathy and only mild splenomegaly. High-dose steroids and intravenous immunoglobulin 2 g/kg were administered. Bone marrow revealed megakaryocytic thrombocytopenia, and testing for HIV 1 and 2, hepatitis B and C, and cytomegalovirus were negative. With day 5 EBV loads of 9,348 DNA copies/mL, EBV-related hepatitis and ITP was diagnosed and a 10 week course of ganciclovir begun. Severe thrombocytopenia persisted, and in preparation for splenectomy, he was vaccinated on day 12 with 23-valent pneumococcal polysaccharide (Pnemovax1 23, Merck Frosst Canada, Kirkland, QC, Canada), quadrivalent meningococcal polysaccharide (Menomune1A/C/Y/W-135, Sanofi-Pasteur, Swiftwater, PA), and Haemophilus influenza type B capsular polysaccharide (ActHIB1, Sanofi-Pasteur SA, Lyon, France). One week later, glucocorticoids were stopped because of worsening hepatitis and viremia, at which time the direct antiglobulin test (DAT) and indirect antiglobulin test (IAT) were negative, and hemoglobin (Hb) 8.3 g/dL. In the next 3 days (9–11 days postvaccination), the Hb fell from 6.5 to 3.0 g/dL, and severe hemolysis became apparent with spherocytosis, indirect bilirubin 249 lmol/L [normal 11], LDH 1572 U/L [normal 190], and haptoglobin
