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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0256.
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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1493-1495
BRIEF REPORT
Copper deficiency masquerading as myelodysplastic
syndrome
Xylina T. Gregg,
Vishnu Reddy, and
Josef T. Prchal
From Baylor College of Medicine, Houston, TX; and the
Department of Pathology, University of Alabama at Birmingham.
 |
Abstract |
We describe a woman with severe neutropenia and dependency on red
blood cell transfusions who had previously undergone Billroth II
surgery and whose bone marrow (BM) showed morphologic characteristics typical of myelodysplastic syndrome (MDS) with ringed sideroblasts. She
had transient reversal of anemia and severe neutropenia after therapy
with erythropoietin and granulocyte colony-stimulating factor.
Because of relapse while receiving growth factors, the patient was
referred for allogeneic BM transplantation. A pretransplantation nutritional evaluation revealed severe copper deficiency, and her
hematologic abnormalities resolved fully with copper therapy. This case
shows that copper deficiency should be an integral part of the
differential diagnosis of sideroblastic MDS, even in patients not
requiring parenteral nutrition.
(Blood. 2002;100:1493-1495)
© 2002 by The American Society of Hematology.
| |
Study design |
A 44-year-old woman with macrocytic anemia
and leukopenia had undergone a gastric resection with Billroth I
anastomosis for peptic ulcer disease 9 years earlier. Four years after
the operation, recurrent gastric ulceration and gastric outlet
obstruction developed and the Billroth I anastomosis was converted to a
Billroth II. Dumping symptoms with chronic diarrhea developed, but the
patient's weight remained stable. The patient described a history of
chronic anemia treated with oral and parenteral iron, B12, and folate, without response. One year before referral to us, the patient's hematocrit was 0.23 and her white blood cell (WBC) count was
2.3 × 109/L. She required red blood cell (RBC)
transfusions approximately every 2 months.
On presentation, the patient had the following laboratory results: WBC
count, 1.5 × 109/L, with 0.19 neutrophils; hemoglobin
(Hb) level, 64 g/L; mean corpuscular volume, (MCV) 102 fL; and platelet
count, 192 × 109/L. Occasional oval macrocytes were
observed on blood films. The patient was thin and appeared chronically
ill, but a physical examination revealed otherwise unremarkable
results. There was no splenomegaly. Serum levels of B12, RBC folate,
and ferritin were elevated; the albumin level was 34 g/L (normal,
39-48 g/L). A bone marrow (BM) assessment showed dyserythropoiesis,
dysmyelopoiesis, ringed sideroblasts (RSs), and prominent hemosiderin
in plasma cells (Figure 1 and Table
1). The results of cytogenetic
studies were normal.
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| Figure 1.
BM aspirate.
(A) Initial BM smear showing vacuoles in the erythroid
precursors, dyspoietic changes, several RSs (inset), and iron
granules in plasma cell cytoplasm (arrowhead) (original magnifications,
× 890). (B) BM aspirate smears (initial BM aspirate) showing several
plasma cells containing blue-black particulate material in the
cytoplasm that stained positive with Prussian blue reaction
(hemosiderin deposits) (original magnification, × 970).
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Because of the BM morphologic findings, the patient was presumed to
have myelodysplastic syndrome (MDS), French-American-British subtype
refractory anemia with RSs (RARS). There was no response to pyridoxine
therapy. The patient was then given granulocyte colony-stimulating
factor (G-CSF; 75 µg/day) and erythropoietin (EPO; 5000 U/day).
Peripheral blood counts became normal (Table 1) 3 weeks after therapy
began, and no further RBC transfusions were given.
The Hb response was not sustained, however, and 3 months after
initiation of therapy, the patient again required frequent RBC
transfusions. On the other hand, even though the G-CSF dose was tapered
to every other day, WBC counts remained in the normal range (Table 1).
Another BM examination showed hypercellular BM with the same
morphologic abnormalities shown in Figure 1 and listed on Table 1.
During this interval, the patient's diarrhea resolved spontaneously.
An esophagogastroduodenoscopy with small-bowel biopsy was performed,
and the results were normal. The patient was also found to have a
severe progressive peripheral neuropathy and an optic neuritis.
The patient was referred for evaluation for BM transplantation to treat
MDS. As part of the pretransplantation evaluation, a nutrition
consultation was obtained, and the patient's copper level was found to
be undetectable (< 1.57 µmol/L [< 10 µ/dL]; normal, 11-24.3 µmol/L [70-155 µ/dL]). She was treated with intravenous copper
chloride (2.5 mg daily for 14 doses; total dose, 35 mg) and EPO and
G-CSF were discontinued. The patient's Hb concentration became normal
within 6 weeks. She was given oral copper supplementation (3 mg copper
sulfate 3 times daily). Three months after initiation of copper
therapy, the patient's copper level was normal (14.4 µmol/L [92
µ/dL]), as were her ceruloplasmin, complete blood count, and MCV
values. BM aspiration and biopsy showed reversal of previous abnormalities (Table 1). Hemosiderin was observed only in macrophages, and plasma cells did not contain histologically identifiable iron. The
patient's general well-being improved, but the peripheral and optic
neuropathies persisted and her weight remained stable.
| |
Results and discussion |
Deficiency of copper has been reported to result in anemia,
neutropenia,1 and less commonly,
thrombocytopenia.2 BM morphologic findings vary, but
vacuolated erythroid precursors are often found. Other abnormalities
include megaloblastic changes and RSs. Although textbooks describe
anemia of copper deficiency as microcytic,3 a review of
the literature revealed that macrocytic, microcytic, and normocytic
anemia occur.1,4-6 Our patient had macrocytic anemia, with
occasional oval macrocytes, a finding further supporting the suspected
diagnosis of MDS. The importance of the plasma cell iron in the patient
was unclear; however, it was likely due to copper deficiency, since it
resolved after copper therapy.
Most cases of copper deficiency in adults occur in patients receiving
total parenteral hyperalimentation,3 although there have
been cases resulting from enteral feeding that did not include copper.7 To our knowledge, there have been only 2 previous reports4,5 of copper deficiency due to intestinal
malabsorption after partial gastrectomy in patients who, like our
patient, were not receiving parenteral or enteral nutrition.
One of these patients5 also had neurologic abnormalities.
The mechanism by which copper deficiency induces anemia and other
cytopenias is unknown. Copper is an essential cofactor for various
redox enzymes, and decreased activity of copper-dependent enzymes, such
as ceruloplasmin ferroxidase and cytochrome oxidase, has been
hypothesized to be a potential cause. Mitochondria isolated from
copper-deficient animals were deficient in cytochrome oxidase activity
and failed to synthesize heme from ferric iron and protoporphyrin at
the normal rate, perhaps leading to mitochondrial iron accumulation, that is, RSs.8 The association of copper and iron
metabolism is of increasing interest. The molecular basis for the
anemia due to a defect in intestinal iron transport in sex-linked
anemic (sla) mice was identified as a multicopper ferroxidase,
hephaestin.9 The Wilson disease protein product
was localized to mitochondria,10 the copper-containing
mitochondrial transporter frataxin was identified in
yeast,11 and its human analogue was identified
subsequently.12 Interestingly, acquired somatic mutations
of mitochondrial cytochrome c oxidase (a copper-containing enzyme) were
found in 2 patients with acquired sideroblastic anemia (MDS); one of
them had macrocytic anemia and the other had microcytic
anemia.6 An acquired somatic mutation is not a
satisfactory explanation for our patient's condition, given that her
hematologic abnormalities reversed rapidly with copper repletion. The
molecular defect in sideroblastic anemia of copper deficiency remains
to be elucidated.
The cause of neutropenia in copper deficiency remains obscure, but such
neutropenia is observed consistently.8 Similarly, we do
not know whether the severe peripheral and optic neuropathies in our
patient, which did not respond to copper replacement, were related to
the copper deficiency. However, copper deficiency associated with myelopathy in a patient who also had microcytic anemia and neutropenia (no mention of RSs) was reported previously,5
and myelopathy has also been observed in copper-deficient
sheep.13
Our patient's condition responded to hematopoietic growth factors with
normalization of Hb levels and neutrophil counts, although the Hb
response was transient. To our knowledge, this response has not
previously been reported. However, this observation shows that
therapeutic responses to these cytokines may occur regardless of the
causative event.
Copper deficiency is not often considered as a cause of cytopenias in
adults. Most current hematology textbooks do not list copper deficiency
in the differential diagnosis of RARS, indicating a limited awareness
of this correctable cause of sideroblastic anemia that can sometimes,
as in our patient, be particularly severe. The diagnosis may
not be suspected in patients not receiving nutritional support, since
one recent hematology textbook's discussion of hematologic
complications of copper deficiency contains the statement that copper
deficiency occurs "only in malnourished premature infants or patients
receiving long-term parenteral nutrition."14 Our case
illustrates the nonspecificity of the morphologic abnormalities and
shows that copper deficiency should be considered a possible cause of
RARS, even in patients not receiving parenteral nutrition. It also
demonstrates that RARS may respond transiently to cytokine therapy.
| |
Footnotes |
Submitted January 31, 2002; accepted April 1, 2002.
Prepublished online
as Blood First Edition Paper, May 17, 2002; DOI
10.1182/blood-2002-01-0256.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Josef T. Prchal, Baylor College of Medicine, One
Baylor Plaza, 802E, Houston, TX 77030; e-mail: jprchal{at}bcm.tmc.edu.
| |
References |
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Top
Abstract
Study design