Copper Deficiency and Myelodysplasia

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Copper Deficiency and Myelodysplasia

• Hematology Grand Rounds
• Tom Fong
• January 19, 2007
• Washington University School of Medicine

2
Patient Presentation

• 51 yo female with no significant medical history
  other than prior remote hysterectomy and CCK
  presents with progressive fatigue and numbness of
  her hands and feet. She is on no medications and
  has no occupational exposures.
• Physical exam is basically unremarkable,
  including no adenopathy and no splenomegaly.
• Initial labs - WBC 1.4 and Hgb 6.8.
• Platelets 147k. MCV 93.

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Patient Presentation

• Additional labs Retic 1.1
• Vitamin B12 and RBC folate normal.
• Bone marrow Mild hypercellularity,
• mild erythroid and myeloid dysplasia,
• vacuoles present in erythroid precursors

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Patient Presentation

• Further labs
• Copper (serum) lt 10 mcg/dL
• Ceruloplasmin lt 1.8 mg/dL
• Zinc (serum) 257 mcg/dL (nl 60-130)
• Further history
• No clear sources of excess zinc no nutritional
  supplements or unusual dietary patterns

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Patient Presentation

• Clinical course
• Patient was given IV copper supplementation
• (copper sulfate 1 mg IV q week).
• Her anemia, leukopenia, and mild sensory
  neuropathy resolved within 3 months.

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Copper Metabolism

• Copper is primarily absorbed in the stomach and
  proximal small intestine
• It is bound to albumin in the portal blood stream
• In the liver, it is bound to ceruloplasmin
• Then released into the blood stream bound to
  ceruloplasmin, taken up by various organs
  including brain, bone marrow, muscle, etc.
• Primarily excreted via bile in GI tract
• Small amount is filtered and excreted in kidneys
• Recommended daily intake in adults 1.5 3 mg

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Copper Metabolism
El Youssef, 2003
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Risk Factors for Copper Deficiency

• Gastrectomy
• Intestinal surgery
• Chronic gut malabsorption
• Long term TPN (historical)
• Zinc toxicity

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Zinc/Copper Interaction

• Both zinc and copper are primarily absorbed in
  the small intestine
• Excess zinc upregulates the synthesis of
  metallothionein
• Metallothionein binds preferentially to copper
  over zinc copper displaces zinc
• Copper bound to metallothionein is sequestered in
  intestinal enterocytes
• Enterocytes are sloughed, leading to GI loss of
  copper and deficient state

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Copper Deficiency and Hematopoiesis

• Copper deficiency thought to cause dysregulation
  in iron transportation and metabolism
• This may account for ring sideroblasts and
  changes in iron stores seen in bone marrow of
  copper deficient patients

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Copper Deficiency and Hematopoiesis

• Postulated mechanisms for anemia
• Cytochrome C oxidase (copper-dependent enzyme) is
  necessary for intracellular iron metabolism, iron
  transport and utilization, so copper deficiency
  may affect incorporation of iron into heme
  molecule
• Superoxide dismutase is a copper-dependent enzyme
  in erythrocytes, so RBC membrane defects may be
  accelerated due to diminished capacity to dispose
  of superoxide
• Ceruloplasmin oxidizes ferrous iron into the
  ferric form needed in the iron transportation by
  transferrin

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Copper Deficiency and Hematopoiesis
Linder et al, 1996
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Copper Deficiency and Hematopoiesis

• Bone Marrow findings
• Dysplasia (may appear to be MDS)
• Vacuoles in RBC and myeloid precursors
• Ring sideroblasts
• Increased or decreased iron stores

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Bone Marrow in Copper Deficiency

• Summerfield et al, 1992

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Bone Marrow in Copper Deficiency
Miyoshi et al, 2004
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Bone Marrow in Copper Deficiency

• Kumar et al, 2005

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Copper Deficiency Clinical Aspects

• Causes anemia and leukopenia BM dysplasia
• Thrombocytopenia is not observed
• Risk factors may be present
• Prior stomach or small intestine surgery
• Chronic malabsorptive state
• Long term TPN
• Unusual dietary habits
• Excess zinc intake (including medication)
• Neuro Gait ataxia, sensory neuropathy, weakness
• Dorsal column dysfunction and lower extremity
  spastic
• weakness similar to that observed in vitamin B12
  deficiency
• (subacute combined degeneration)

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Case Reports

• Dunlap et al, 1974 (Annals of Internal Medicine)
• Earliest clinical report of anemia and
  neutropenia caused by copper deficiency
• Two patients with prior extensive bowel surgery
  who were receiving long term TPN
• Bone marrow showed dysplasia, vacuoles in
  erythroid and myeloid elements, sideroblasts
• Cytopenias and bone marrow abnormalities
  corrected with copper supplementation

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Case Reports

• Summerfield et al, 1992
• 30 yo paraplegic male on oral zinc for decubitus
  ulcers
• Found to have anemia and leukopenia
• Hypocellular marrow, slight vacuolization of
  erythroid and myeloid precursors
• Elevated zinc level, low serum copper level
• Resolution of cytopenias and bone marrow
  abnormalities with discontinuing zinc and IV
  copper supplementation

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Case Reports

• Broun et al, 1990
• Copper deficiency and anemia in two patients with
  zinc toxicity
• Zinc supplements in one pt, coin ingestion in
  other pt
• Anemia corrected with removal of excess zinc
  alone

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Case Reports

• Gregg et al, 2002 (Blood)
• 44 yo woman with prior gastric resection for PUD
• Billroth anastamosis, chronic diarrhea symptoms
• Anemia, leukopenia, bone marrow c/w MDS - RARS
• Referred for BMT, found to have severe Cu
  deficiency
• Cytopenias, marrow abnormalities corrected with Cu

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Case Reports

• Halfdanarson et al, ASH 2005 Abstract 1680

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Case Reports

• Huff et al, ASH 2005 Abstract 1681

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Therapy Copper Repletion

• Administration of IV or PO copper has led to
  rapid resolution of hematologic abnormalities in
  all reported cases.
• Bone marrow abnormalities are also shown to be
  reversible.
• Reports show variable correction of neurologic
  abnormalities.

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Bone Marrow in Copper Deficiency

• Hayton et al, 1995

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Copper Deficiency Incidence?

• Actual incidence is unknown
• Bariatric surgery becoming more common
• Seven patients with anemia and copper deficiency
  dx within 16 months at Wake Forest (Huff et al,
  2005)
• Three patients with copper deficiency presenting
  as MDS dx within 12 months here at Siteman Cancer
  Center
• Likely more common than diagnosed

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Copper Deficiency DDx of MDS

• Given correction of hematologic findings with
  supplementation, copper deficiency should be
  considered in pts dx with MDS
• Consider checking copper levels esp. if
• Younger age than usual (i.e. non-elderly)
• Risk factors GI surgery, chronic diarrhea or
  malabsorption, zinc/supplement use, etc.
• Typical BM features (vacuoles, sideroblasts)
• Low risk MDS (low blast count, nl cytogenetics)
• Neurologic sx (ataxia, sensory neuropathy)

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Copper deficiency It can make all the difference
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References

• Broun, E.R., Greist, A., Tricot, G., Hoffman,
  R. (1990) Excessive Zinc Ingestion A Reversible
  Cause of Sideroblastic Anemia and Bone Marrow
  Depression. The Journal of the American Medical
  Association, 264, 1441-1443.
• Dunlap, W.M., James, G.W. III, Hume, D.M.
  (1974) Anemia and Neutropenia Caused by Copper
  Deficiency. Annals of Internal Medicine, 80,
  470-476.
• El Yousself (2003) Wilson Disease. Mayo Clinic
  Proceedings, 78, 1126-1136.
• Fiske, D.N., McCoy, H.E. III, Kitchens, C.S.
  (1994) Zinc-Induced Sideroblastic Anemia Report
  of a Case, Review of the Literature, and
  Description of the Hematologic Syndrome.
  American Journal of Hematology, 46, 147-150.
• Gregg, X., Reddy, V., Prchal, J. (2002) Copper
  Deficiency Masquerading as Myelodysplastic
  Syndrome. Blood, 100, 493-1495.
• Halfdanarson, T.R., Hogan, W.J., Phyliky, R.L.,
  Kumar, N., Tefferi, A., Elliott, M., Li, C.Y.
  (2005) The Increasing Relevance of Copper
  Deficiency in Hematological Practice. Blood, ASH
  2005 Abstract 1679.
• Hayton, B.A., Broome, H.E., Lilenbaum, R.C.
  (1995) Copper Deficiency-Induced Anemia and
  Neutropenia Secondary to Intestinal
  Malabsorption. American Journal of Hematology,
  48, 45-47.
• Huff, J.D., Keung, Y.K., Thakuri, M.C., Beaty,
  M.W., Owen, J., Molnar, I. (2005) Copper
  Deficiency Anemia Is Not Uncommon in a Hematology
  Practice. Blood, ASH 2005 Abstract 1681.

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References

• Kumar, N., Elliott, M.A., Hoyer, J.D., Harper,
  C.M. Jr., Ahlskog, J.E. Phyliky, R. L. (2005)
  Myelodysplasia, Myeloneuropathy, and Copper
  Deficiency. Mayo Clinic Proceedings, 80, 943-6.
• Lee, G.R. Herbert, V. (1999) Nutritional
  Factors in the Production and Function of
  Erythrocytes. In Lee, G.R., editor. Wintrobes
  Clinical Hematology, 10th ed., 254-6
• Linder, M.C. Hazegh-Azam, M. (1996) Copper
  Biochemistry and Molecular Biology. American
  Journal of Clinical Nutrition, 63, 797S-811S.
• List, A.F. Dill, D.C. (1999) The
  Myelodysplastic Syndromes. In Lee, G.R., editor.
  Wintrobess Clinical Hematology, 10th ed.,
  2320-1.
• Miyoshi, I., Saito, T., Iwahara, Y. (2004)
  Copper Deficiency Anaemia. British Journal of
  Haematology, 125, 106.
• Olivares, M. Uauy, R. (1996) Copper as an
  Essential Nutrient. American Journal of Clinical
  Nutrition, 63, 791S-6S.
• Summerfield, A.L., Steinberg, F.U., Gonzalez,
  J.G. (1992) Morphologic Findings in Bone Marrow
  Precursor Cells in Zinc-Induced Copper Deficiency
  Anemia. American Journal of Clinical Pathology,
  97, 665-668.