Hematopathology / ZINC-INDUCED COPPER DEFICIENCY
Zinc-Induced Copper Deficiency
A Report of Three Cases Initially Recognized on Bone Marrow
Examination
Monte S. Willis, MD, PhD,1 Sara A. Monaghan, MD,1 Michael L. Miller, DO,1
Robert W. McKenna, MD,1 Wiley D. Perkins, MD,2 Barry S. Levinson, MD,2
Vikas Bhushan, MD,2 and Steven H. Kroft, MD1
Key Words: Zinc toxicity; Copper deficiency; Cytoplasmic vacuoles; Sideroblastic anemia; Ringed sideroblasts
DOI: 10.1309/V6GVYW2QTYD5C5PJ
Copper deficiency is a rare cause of sideroblastic
anemia and neutropenia that often is not suspected
clinically. The morphologic findings in bone marrow,
while not pathognomonic, are sufficiently characteristic
to suggest the diagnosis, leading to further testing to
establish the correct diagnosis. Excess zinc ingestion is
among the causes of copper deficiency. We present 3
cases of zinc-induced copper deficiency in which the
diagnosis first was suggested on the basis of bone
marrow examination. The first patient was a 47-yearold man with a debilitating peripheral neuropathy that
had progressed during the previous 18 months, mild
anemia, and severe neutropenia. The second was a
21-year-old man receiving zinc supplementation for
acrodermatitis enteropathica in whom moderate
normocytic anemia and neutropenia developed. The
third patient was a 42-year-old man with anemia,
severe neutropenia, and a peripheral neuropathy that
had progressed during 8 months. The bone marrow
findings in all cases suggested copper deficiency, which
was confirmed by further laboratory testing and
determined to be due to zinc excess. The morphologic
features, clinical manifestations, differential diagnosis,
and pathogenetic mechanisms are discussed.
Copper deficiency is a rare cause of anemia and neutropenia that is characterized morphologically by cytoplasmic vacuolization in erythroid and myeloid precursors and
ringed sideroblasts. There are a variety of causes of copper deficiency, including dietary deficiency, hypoproteinemic states
(kwashiorkor, celiac disease, tropical and nontropical sprue,
idiopathic hypoproteinemia, and enteropathy in infancy),
excess excretion (nephrotic syndrome), Wilson disease,
Menkes syndrome, and excess ingestion of zinc.1 Given its
low prevalence and nonspecific hematologic and clinical manifestations, the diagnosis of copper deficiency might be
delayed. The bone marrow morphologic manifestations of
copper deficiency are not widely appreciated. While not
pathognomonic, the morphologic features are highly characteristic and might permit early diagnosis and correction of the
deficiency state. We describe 3 patients with zinc-induced
copper deficiency in whom the correct diagnosis first was suggested on the basis of bone marrow findings.
Case Reports
Case 1
A 47-year-old man initially sought care from his primary
care physician in December 1999 because of the onset of progressive numbness and weakness in his lower extremities.
Laboratory testing detected severe macrocytic anemia and
leukopenia, and the patient was hospitalized. A serum B12
level was found to be low, and, therefore, the hematologic and
neurologic manifestations were thought to be due to B12 deficiency. However, despite continued vitamin B12 treatment, he
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Abstract
Willis et al / ZINC-INDUCED COPPER DEFICIENCY
Copper supplementation for this patient was delayed for
3 months, and in August 2002, the patient’s blood counts had
not changed significantly from his previous visits, with a
WBC count of 1,800/µL (1.8 × 109/L), a hemoglobin concentration of 11.6 g/dL (116 g/L), an RBC distribution width of
19.8%, and a platelet count of 501 × 103/µL (501 × 109/L).
The sensory neuropathy in his legs and loss of strength continued to progress. In October 2002, 2 months after the initiation
of copper supplementation, his blood counts returned to normal, with a WBC count of 7,100/µL (7.1 × 109/L), a hemoglobin concentration of 14.1 g/dL (141 g/L), RBC distribution
width of 12.8%, and a platelet count of 322 × 103/µL (322 ×
109/L; down from 501 × 103/µL [501 × 109/L]). However, no
improvement in his peripheral neuropathy or loss of strength
was observed.
Case 2
This 21-year-old man was given a diagnosis of acrodermatitis enteropathica 5 years previously for which he was
receiving therapeutic zinc supplementation. He sought care at
the emergency department complaining of a 2- to 3-week history of fatigue and new onset fever (40.6°C). At the time of admission, the patient was taking approximately 600 mg/d of zinc,
which was several times the dosage prescribed by his physician.
❚Table 1❚
Initial Patient Laboratory Values
Test
WBC count, /µL (× 109/L)
Absolute count, /µL (× 109/L)
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count, × 106/µL (×1012/L)
Hemoglobin, g/dL (g/L)
Hematocrit, %
Mean corpuscular volume, µm3 (fL)
Mean corpuscular hemoglobin
concentration, g/dL (g/L)
RBC distribution width (%)
Reticulocyte count, %
Absolute reticulocyte count, × 103/µL
(× 109/L)
Platelet count, ×103/µL (×109/L)
Zinc, µg/dL (µmol/L)
Serum copper, µg/dL (µmol/L)
Urine copper (U/24 h)
Ceruloplasmin, mg/dL (mg/L)
Iron, µg/dL (µmol/L)
Total iron binding capacity, µg/dL
(µmol/L)
Transferrin saturation (%)
Ferritin, ng/mL (µg/L)
Vitamin B12, pg/mL (pmol/L)
Folate, serum, ng/mL (nmol/L)
Homocysteine, mg/L (µmol/L)
Case 1
Case 3
Reference Range
Case 2
Reference Range
2,100 (2.1)
2,100 (2.1)
4,100-11,100 (4.1-11.0)
1,600 (1.6)
4,000-11,000 (4.0-11.0)
388 (0.4)
1,313 (1.3)
252 (0.25)
42 (0.04)
105 (0.11)
3.22 (3.2)
9.8 (98)
36.1 (0.36)
101 (101)
29.8 (298)
483 (0.5)
945 (0.9)
546 (0.55)
105 (0.11)
21 (0.02)
3.44 (3.4)
0.8 (80)
30.8 (0.31)
89.4 (89)
32.3 (323)*
2,000-7,500 (2.0-7.5)
900-4,700 (0.9-4.7)
100-900 (0.10-0.90)
0-500 (0.00-0.50)
0-200 (0.00-0.20)
4.27-5.99 (4.3-6.0)
13.2-16.9 (132-169)
39.6-50.2 (0.40-0.50)
82-105 (82-105)
31.6-35.4 (316-354)
512 (0.5)
752 (0.8)
240 (0.24)
64 (0.64)
32 (0.03)
4.2 (4.2)
8.5 (85)
25.5 (0.25)
92 (92)
ND
2,400-7,400 (2.4-7.4)
1,000-4,000 (1.0-4.0)
100-800 (0.10-0.80)
0-450 (0.00-0.45)
0-180 (0.00-0.18)
4.27-5.99 (4.3-6.0)
13.5-17.5 (135-175)
39.6-50.2 (0.40-0.50)
80-100 (80-100)
—
21.7
1.3
41.9 (42)
16.2*
0.8*
27.9 (28)*
<14.5
0.5-2.8
32-147 (32-147)
ND
ND
ND
—
—
—
488 (488)
193 (29.5)
8 (1.3)
6
1.8 (18)
32 (5.7)
361 (64.6)
211 (211)
428 (65.5)*
<10 (<1.6)*
ND
1.1 (11)*
49 (8.8)*
589 (105.4)*
140-450 (140-450)†
66-110 (10.1-16.8)
70-145 (11.0-22.8)
15-60
22.9-43.1 (229-431)
60-200 (10.7-35.8)
262-474 (46.9-84.8)
209 (209)
145 (22.2)
<15 (<2.4)
ND
<2 (<20)
5 (0.9)
224 (40.1)
150-400 (150-400)
55-150 (8.4-23.0)
70-140 (11.0-22.0)
—
21-45 (210-450)
30-140 (5.4-25.1)
262-474 (46.9-84.8)
9
252 (252)
277 (204)
5.8 (13)
0.65 (4.8)
8*
170 (170)*
484 (357)*
17.9 (41)*
1.37 (10.1)*
20-50
22-300 (22-300)†
211-911 (156-672)
2.8-18.0 (6-41)†
0.68-2.03 (5.0-15.0)†
2
444 (444)
301 (222)
8.0 (18)
ND
20-50
18-300 (18-300)
211-911 (156-672)
2.8-18.0 (6-41)
—
ND, not done.
* Performed 24 days after initial bone marrow examination.
† Reference ranges for case 3 were as follows: platelet count, 174-404 × 103/µL (174-404 × 109/L); ferritin, 10-322 ng/mL (10-322 µg/L); folate, 5.3-24.0 ng/mL (12-54 nmol/L);
homocysteine, 0.68-1.88 mg/L (5.0-13.9 µmol/L).
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continued to have difficulties with balance and numbness in
his lower extremities.
Between the December 1999 hospitalization and August
2000, the patient’s neuropathy progressed to the point at
which he became wheelchair-dependent. In May 2001, the
patient no longer ambulated and used a scooter owing to bilateral flexion contractures. During this time, he received regular
vitamin B12 injections, and his vitamin B12 levels were in the
normal range. A bone marrow biopsy performed in January
2001 demonstrated a mildly hypocellular bone marrow with
normal trilineage hematopoiesis.
The patient was seen again 1 year later, and at that time,
he had normocytic anemia with neutropenia ❚Table 1❚. A second bone marrow examination was performed in May 2002,
and, based on the morphologic findings, serum copper, ceruloplasmin, and zinc levels were obtained (Table 1). Marked
decreases in serum copper and ceruloplasmin levels were
detected, along with an elevated serum zinc concentration.
The results of antigliadin and antiendomysial antibody testing to rule out celiac sprue were negative. The results of vitamin B12 and folate studies were normal (Table 1). Serum
iron was low, but total iron-binding capacity and ferritin levels were within normal ranges (Table 1). The cause of the
zinc excess remains undetermined.
Hematopathology / ORIGINAL ARTICLE
Case 3
This 42-year-old man initially sought care from his primary care physician in August 2003 because of ascending tingling and numbness in his lower extremities, which later progressed to his fingertips. His symptoms continued to progress,
and by January 2004, he had difficulty walking with a steady
gait and holding objects in his hands owing to the lack of sensation. Nerve conduction studies revealed evidence of sensory
neuropathy. However, the patient was noted at this time to be
anemic and neutropenic (Table 1) and a bone marrow evaluation was performed in March 2004. After an initial interpretation of myelodysplastic syndrome was given at an outside hospital, the patient was referred to our institution for evaluation.
Based on our review of the bone marrow biopsy specimen,
additional laboratory testing was obtained, which revealed
serum copper levels below the detectable range, extremely low
ceruloplasmin levels, and high zinc levels (Table 1). The
patient was asked further about possible zinc ingestion, and it
was determined that he had been consuming an entire tube (68
g) of PoliGrip denture cream (containing polymethyvinylether
maleic acid calcium-zinc salt) daily for the past 4 to 5 years.
The patient was using the denture adhesive for his dentures and
additionally eating “pellets” of it from the tube. The patient
was advised to stop ingesting the denture cream, and copper
sulfate supplementation was initiated. Approximately 3 weeks
after the initiation of treatment, the patient’s serum copper levels increased to 20 µg/dL (3.1 µmol/L), and his hematologic
values normalized completely (hemoglobin level, 13.0 [130
g/dL]; hematocrit, 39.9 [0.40]; WBC count, 7,900/µL [7.9 ×
109/L]). However, the neuropathy showed no improvement.
Materials and Methods
Bone marrow core specimens were fixed in B-5 or Zenker
solution, washed, decalcified, and processed. Paraffin-embedded
sections of the core biopsy (4 µm sections) were stained with
H&E. Direct smears, particle crush, buffy coat, and touch
preparations were prepared and stained with Wright or WrightGiemsa and Prussian blue stains as previously described.3,4
Results
Peripheral Blood Smears
The peripheral blood smears in all cases demonstrated
RBC changes. In case 1, the RBCs exhibited dimorphism with
a minor population of microcytic, hypochromic RBCs, as well
as scattered dacryocytes, target cells, and elliptocytes ❚Image
1A❚. The peripheral blood sample in case 2 showed less distinct RBC dimorphism but more pronounced anisopoikilocytosis, including variable hypochromia, dacryocytes, elliptocytes, and target cells ❚Image 1B❚. The peripheral blood sample in case 3 demonstrated nonspecific anisopoikilocytosis
with occasional elliptocytes and dacryocytes. Although each
patient was neutropenic, the WBC morphologic features were
normal. The platelets in all cases were numerically and morphologically normal.
Bone Marrow Aspirates
In all 3 cases, the bone marrow aspirates demonstrated
left-shifted granulocytic maturation with vacuolization of
early granulocytes (myelocytes and promyelocytes) ❚Image 2❚.
The shift to immaturity was most pronounced in case 1, in
which there was little maturation beyond the myelocyte stage.
The vacuoles ranged from 1 to 3 µm in size and were present
in 18%, 21%, and 20% of granulocytes (mainly myelocytes)
in cases 1 through 3, respectively. We found 3 to 12 vacuoles
present in a given cell, generally 5 to 7 per cell in case 1 and
7 to 10 in cases 2 and 3. Myeloblasts were not increased in any
case. However, subtle morphologic abnormalities were present in the maturing granulocytes, consisting mainly of dyssynchronous maturation with chromatin maturation lagging
behind nuclear conformation.
Left-shifted maturation, mild megaloblastoid changes,
and mild terminal dyserythropoiesis were identified in the erythroid lineage in the bone marrow aspirates in each case
(Image 2). The myeloid/erythroid ratios were 1.1:1, 2.1:1, and
1.3:1 in cases 1 through 3, respectively. Vacuoles ranging from
1 to 2 µm, mostly restricted to basophilic normoblasts and
pronormoblasts, were present in 11%, 7%, and 37% of the
erythroid precursors in cases 1 through 3, respectively. The
number of vacuoles per erythroid cell ranged from 2 to 12 and
most commonly numbered around 5 per cell.
Megakaryocytes were normal in number and morphologic features in all cases. Iron staining of the aspirate smear with
Prussian blue demonstrated the presence of storage iron and
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Laboratory testing revealed moderate normocytic anemia,
leukopenia with severe neutropenia, and a normal platelet count
(Table 1). Based on the morphologic examination of a bone marrow specimen, serum ceruloplasmin, copper, and zinc levels were
obtained. The serum copper and ceruloplasmin were found to be
extremely low, and the zinc level was high normal (Table 1).
The patient stopped taking the zinc supplements before his
hospital discharge and had a spontaneous recovery of his WBC
count and hemoglobin level. One week after discharge, he had
a WBC count of 2,100/µL (2.1 × 109/L) with 48% neutrophils
(0.48), a hemoglobin concentration of 8.4 g/dL (84 g/L), and a
platelet count of 297 × 103/µL (297 × 109/L). The patient was
followed up by the gastrointestinal service to ensure a safe
level of zinc supplementation. After 6 weeks, all hematologic
values were within the normal range. This case has been
reported previously in the ASCP Check Sample Program.2
Willis et al / ZINC-INDUCED COPPER DEFICIENCY
A
B
A
B
❚Image 2❚ Example of morphologic changes in marrow
precursors in copper deficiency. A, Vacuolization of immature
granulocytes. Mild dyssynchrony in nuclear maturation also is
present. B, Vacuolization of an early myelocyte (lower left) and
an early basophilic normoblast (upper right). In addition, mild
megaloblastoid/macronormoblastic changes are evident in
several late-stage erythroid precursors. C, Vacuolization in 2
pronormoblasts (A-C, Wright-Giemsa, ×330).
C
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❚Image 1❚ Peripheral blood RBC morphologic features in patients with copper deficiency. A (Case 1), Dimorphic RBC morphologic
features are evident, with a minor population of microcytic/hypochromic erythrocytes. There also is mild anisopoikilocytosis with
scattered elliptocytes and dacryocytes (Wright-Giemsa, ×165). B (Case 2), Although RBC dimorphism is not apparent, there is more
pronounced anisopoikilocytosis with scatted elliptocytes and dacryocytes (Wright, ×165).
Hematopathology / ORIGINAL ARTICLE
sideroblastic iron with scattered ringed sideroblasts (5% and
4% of erythroid precursors in cases 1 and 2, respectively)
❚Image 3❚. No stainable storage iron was identified in several
particles in case 3, but sideroblasts were identified easily, and
ringed sideroblasts constituted 2% of the erythroid precursors.
A
B
Trephine Biopsy Specimens
The trephine biopsy specimen from case 1 was mildly
hypocellular for age (~35%-40% cellularity; age 47 years) but
otherwise was morphologically unremarkable with the exception of the presence of multiple lipogranulomas. The trephine
biopsy specimen from case 2 was unavailable for review. The
trephine biopsy specimen from case 3 was normocellular for
age (~50% cellularity; age 42 years) and was morphologically unremarkable.
We describe 3 patients with zinc-induced copper deficiency in whom the diagnosis first was suggested based on
characteristic bone marrow findings. These findings include
vacuolization of granulocytic and erythroid precursors and the
presence of ringed sideroblasts. The serum copper level was
decreased in each patient. In addition, an increased serum zinc
level or a history of excessive zinc intake was present, implicating zinc-induced copper deficiency as the likely cause of
the neutropenia and anemia.
The hematologic findings that have been reported in copper deficiency include anemia with neutropenia5 and pancytopenia.6-8 Microcytic, normocytic, and macrocytic anemias
have been described.9-15 The 3 cases presented herein demonstrated normocytic (cases 2 and 3) and macrocytic (case 1) anemia at initial examination. In the cases in which trephine biopsy specimens were available, mild hypocellularity (case 1) and
normal marrow cellularity (case 3) were noted. As in the present cases, previous reports have described various hematologic
abnormalities in zinc-induced copper deficiency, including vacuolization of erythroid and myeloid precursors, megaloblastic
changes, and ringed sideroblasts.14,15 Dyserythropoiesis, dysmyelopoiesis, and prominent hemosiderin characteristic of
myelodysplastic syndrome also have been reported.15 One of
the patients described herein initially was given a diagnosis of a
myelodysplastic syndrome. Bone marrow biopsy specimens in
zinc-induced copper deficiency might be hypercellular, normocellular, or hypocellular,14 although hypercellularity has been a
rare finding among the reported cases.16
Copper has an essential role in several enzymatic reactions in RBCs, and copper deficiency interferes with iron
transport and utilization and, therefore, with heme synthesis.
Specifically, ceruloplasmin (which incorporates copper) is a
ferroxidase that converts ferrous (+2) to ferric (+3) iron,
allowing it to bind transferrin and be transported. The copperdependent enzyme cytochrome-c oxidase also is required for
the reduction of ferric iron to incorporate it into the heme molecule.17,18 In addition to interference with heme synthesis,
there is approximately 85% reduction of superoxide dismutase in the RBC membrane in copper deficiency, which
decreases RBC survival time.19 The mechanism for neutropenia in copper deficiency is unknown; neutropenia has been
demonstrated experimentally in copper-deficient mice and is
associated with arrested maturation.20
Knowledge of the details of the mechanism(s) by which
copper is absorbed from the diet is incomplete. In physiologic ranges of intake, absorption occurs in the small intestine,
and the amount absorbed depends on the copper content in
the diet.21 Copper absorption occurs by the ATP7A protein on
the basolateral surface of enterocytes; it is this protein that is
defective in patients with Menkes disease, who cannot absorb
copper.21 When large doses of copper are ingested over long
periods, other mechanisms of uptake occur, involving the
intracellular ligand metallothionein (MTO). MTO has a high
affinity for transition metals, forming mercaptide bonds by its
multiple cysteine residues.22 Multiple mechanisms have been
proposed for the ability of zinc to interfere with the absorption of copper in enterocytes of the small intestine. Excess
zinc levels induce the synthesis of the intracellular ligand
MTO in enterocytes, which then binds zinc. The excess zinc
bound to MTO then is excreted in the feces through enterocyte shedding. However, copper, with its higher affinity for
MTO, displaces zinc and also is excreted, reducing the
amount of copper delivered to the enterocyte.23 The exact
mechanisms by which copper is absorbed, however, are just
beginning to be elucidated.
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Discussion
❚Image 3❚ Two late-stage ringed sideroblasts (A and B,
Prussian blue, ×330).
Willis et al / ZINC-INDUCED COPPER DEFICIENCY
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causes of SA, including copper deficiency. Resolution of the
hematologic changes found in alcoholic patients after alcohol
abstinence occurs in days to weeks.38
Treatment with the tuberculosis medications isoniazid,
pyrazinamide, or cycloserine also can result in an SA. A
microcytic anemia and dimorphic RBC population also might
accompany SA in this setting. Although most patients taking
isoniazid are given supplemental vitamin B6, this finding is
not seen commonly. Chloramphenicol can cause a reduction
in erythropoietic activity and maturation. Bone marrow evaluation might identify vacuolization of the erythroid and granulocytic precursors with a maturation arrest at the proerythoblast stage. Aplastic anemia also can occur due to chloramphenicol use, with resultant pancytopenia.
RARS is characterized by the insidious onset of moderate
macrocytic or normocytic anemia with hypochromic or normochromic, often dimorphic, RBCs. It generally is found in
patients older than 50 years. By definition, neutropenia and
thrombocytopenia are not features of RARS, and, in fact,
thrombocytosis sometimes is identified.40 Dyserythropoiesis
with normal granulopoiesis and megakaryocytopoiesis generally are present.40 By definition, myeloblasts are fewer than
5% and ringed sideroblasts represent at least 15% of erythroid
precursors; bone marrow iron stores usually are increased.
We reported 3 cases of zinc-induced copper deficiency
resulting in neutropenia, anemia, and severe progressive
peripheral neuropathy (cases 1 and 3). The bone marrow manifestations of copper deficiency are characteristic, although
not pathognomonic. It is important for pathologists to be
aware of these rather subtle morphologic features in order to
initiate timely laboratory evaluation to help reverse the
cytopenias and prevent the progression of the neuropathy.
From the Departments of 1Pathology and 2Internal Medicine,
University of Texas Southwestern Medical Center, Dallas.
Address reprint requests to Dr Kroft: Dept of Pathology,
University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas,
TX 75390-9072.
References
1. Lee GR, Herbert V. Nutritional factors in the production and
function of erythrocytes. In: Lee GR, ed. Wintrobe’s Clinical
Hematology. 10th ed. Baltimore, MD: Lippincott Williams &
Wilkins; 1999:228-266.
2. Smith TA, Overmoyer BA, Miller ML. Sideroblastic anemia
due to zinc-induced copper deficiency. Clinical Hematology
Check Sample CH 98-6. Chicago, IL: ASCP Press; 1998;4:8195.
3. Brynes RK, McKenna RW, Sundberg RD. Bone marrow
aspiration and trephine biopsy: an approach to a thorough
study. Am J Clin Pathol. 1978;70:753-759.
4. Kaplan E, Zuelzer WW, Mouriquand C. Sideroblasts: a study of
stainable nonhemoglobin in marrow normoblasts. Blood.
1954;9:203-213.
© American Society for Clinical Pathology
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Acrodermatitis enteropathica, which patient 2 had, is a
rare autosomal recessive disorder characterized by the inability to absorb sufficient zinc from the diet. The most dramatic
manifestations of acrodermatitis enteropathica are vesiculobullous, eczematous, dry, scaly, or psoriasiform skin lesions
and kinky hair. Typically prescribed dosages of zinc range
from 50 to 150 mg/d. Patient 2 reported ingesting an average
of 600 mg/d of zinc to “control his symptoms.”
Excess zinc ingestion also can occur in patients taking
zinc therapeutically for decubitus ulcer healing, celiac disease,
glucagonoma, hepatic encephalopathy, acne,24,25 and for
reducing the duration of symptoms of the common cold.26-28
The ingestion of coins by psychiatric patients also has been
reported as a source of increased zinc ingestion (leached from
the coins) and subsequent copper deficiency.25,29,30 Since
1982, pennies have been composed of 97.6% zinc and 2.4%
copper; other US coins do not contain zinc.29 Copper deficiency due to long-term hyperalimentation without trace mineral
supplementation has been reported,7,31-34 as have 3 cases due
to intestinal malabsorption after partial gastrectomy.15,35,36
Idiopathic hyperzincemia and hypocupremia associated
with extensive central nervous system demyelination, similar
to that seen in case 1, recently was reported for the first time.37
Furthermore, irreversible demyelination has been reported
even after copper levels were stabilized through supplementation, although serum zinc levels remained high (unknown
cause). In addition, 2 previous descriptions of patients with
copper deficiency and concomitant severe progressive peripheral neuropathy have been reported.15,36 In both of these cases,
copper supplementation improved the hematologic symptoms; however, the neuropathies were irreversible.
The differential diagnosis of copper deficiency with
ringed sideroblasts includes other forms of sideroblastic anemia (SA). SAs are a group of disorders having in common
defects in iron utilization and heme synthesis, resulting in the
accumulation of storage iron and abnormal iron deposition in
mitochondria; inherited and acquired forms have been
described. Inherited forms are rare and have variable but persistent manifestations throughout life. Acquired SA can be
caused by chronic alcohol abuse, medications used to treat
tuberculosis, chloramphenicol toxicity, lead poisoning, and
copper deficiency. Moreover, refractory anemia with ringed
sideroblasts (RARS; a myelodysplastic syndrome) also is
classified as an SA. A patient’s history and hematologic
parameters, as well as blood and bone marrow morphologic
examination, are important in distinguishing these types of
SAs, because all except RARS are reversible if accurately
diagnosed and treated.
It is estimated that approximately 25% of alcoholic
patients have ringed sideroblasts.38,39 In SA due to the toxic
effects of ethanol, erythroid but not granulocytic precursors
can show vacuolization, helping to differentiate it from other
Hematopathology / ORIGINAL ARTICLE
24. Porea TJ, Belmont JW, Mahoney DH Jr. Zinc-induced anemia
and neutropenia in an adolescent. J Pediatr. 2000;136:688-690.
25. Broun ER, Greist A, Tricot G, et al. Excessive zinc ingestion: a
reversible cause of sideroblastic anemia and bone marrow
depression. JAMA. 1990;264:1441-1443.
26. Mossad SB, Macknin ML, Medendorp SV, et al. Zinc
gluconate lozenges for treating the common cold: a
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