Annals of Hematology

https://doi.org/10.1007/s00277-018-3407-5

REVIEW ARTICLE

Copper deficiency anemia: review article

Zin W. Myint 1,2 & Thein H. Oo 3 & Kyaw Z. Thein 4 & Aung M. Tun 5 & Hayder Saeed 1,2

Received: 7 April 2018 / Accepted: 20 June 2018

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Copper is a crucial micronutrient needed by animals and humans for proper organ function and metabolic processes such as
hemoglobin synthesis, as a neurotransmitter, for iron oxidation, cellular respiration, and antioxidant defense peptide amidation,
and in the formation of pigments and connective tissue. Multiple factors, either hereditary or acquired, contribute to the increase
in copper deficiency seen clinically over the past decades. The uptake of dietary copper into intestinal cells is via the Ctr1
transporter, located at the apical membrane aspect of intestinal cells and in most tissues. Copper is excreted from enterocytes into
the blood via the Cu-ATPase, ATP7A, by trafficking the transporter towards the basolateral membrane. Zinc is another important
micronutrient in animals and humans. Although zinc absorption may occur by direct interaction with the Ctr1 transporter, its
absorption is slightly different. Copper deficiency affects physiologic systems such as bone marrow hematopoiesis, optic nerve
function, and the nervous system in general. Detailed pathophysiology and its related diseases are explained in this manuscript.
Diagnosis is made by measuring serum copper, serum ceruloplasmin, and 24-h urine copper levels. Copper deficiency anemia is
treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride.
Hematological manifestations are fully reversible with copper supplementation over a 4- to 12-week period. However, neuro-
logical manifestations are only partially reversible with copper supplementation.

Keywords Copper . Anemia . Neuropathy . Optic disease . Zinc . Gastric-by-pass . Myelodysplastic anemia

Introduction neurotransmitter biosynthesis, cellular respiration, pig-

ment formation, antioxidant defense peptide amidation,
Copper, an essential micronutrient in animals and humans, and connective tissue formation [1, 2].
plays an important role in the cellular transporters, called Most adults obtain adequate copper levels from food con-
cuproenzymes, that serve as cofactors for a variety of im- sumption. The total recommended amount of copper for
portant enzymes. Thus, copper is critical in the human adults is 2 to 3 mg per day. [3] Pregnant women, infants,
body for the proper function of organs and metabolic pro- and children have a higher recommended dose than for adults.
cesses such as hemoglobin synthesis, iron oxidation, Infants and children up to 5 years of age need 20 μg/kg/day
maximum up to 300 μg/day and children above 5 years old
require 0.3 to 0.5 mg/day [4]. Foods rich in copper include
* Zin W. Myint vegetables, mushrooms, legumes, whole grains, barley, nuts,
[email protected] seeds, milk, liver, beef, crustaceans (crab, lobster, mollusk)
and chocolate [5].
1
Division of Hematology and Blood and Marrow Transplant,
University of Kentucky, Lexington, KY, USA
2
Markey Cancer Center, University of Kentucky, Epidemiology and causes of copper deficiency
Lexington, KY 40536, USA
3
Division of Hematology, University of Texas M.D. Anderson Cancer The epidemiology of copper deficiency usually depends on its
Center, Houston, TX, USA causes. The incidence and prevalence of copper deficiency
4
Division of Hematology, Texas Tech University of Health Sciences anemia in several retrospective and prospective studies will
Center, Lubbock, TX, USA be discussed later in each section. Although copper deficiency
5
Division of Hematology, Brooklyn Hospital Center, Brooklyn, New is an uncommon disease in the clinical setting, there have been
York, USA a number of cases reported in the last few decades. Multiple
 Ann Hematol

factors, either hereditary or acquired, contribute to this in- accumulation of copper mainly in the liver and brain. When
crease in copper deficiency seen clinically (Table 1). copper reaches hepatocytes, protein metallochaperones serve
as transporters to uptake and assign the copper to different
specific pathways; this prevents the deposition of free intra-
Pathophysiology of copper deficiency and its cellular copper [13].
regulation For example, copper is delivered to the mitochondria of
enterocytes via metallochaperones such as Cox 17, Sco1.
The uptake of dietary copper into intestinal cells is through the Sco2 assists in the metalation of copper with cytochrome C
Ctr1 transporter, a polytrophic high affinity membrane trans- oxidase, an important enzyme in the electron transport chain
port protein, structurally related to channel proteins, and lo- (Fig. 1) [14]. Inherited deficiency of Sco2 results in fatal
cated at the apical membrane of intestinal cells and in most encephalo-cardiomyopathy from impaired respiratory chain
tissues [6]. function [15].Copper is released from the liver into the blood
In animal studies, copper is transported into the mucosal stream and binds with a variety of copper-dependent enzymes
surface of intestinal cells. It is then carried through each layer: such as ceruloplasmin, cytochrome C oxidase, lysyl oxidase,
submucosa, muscularis propria, subserosa, and finally the se- monoamine oxidases, and dopamine B-hydroxylase [16].
rosa surface by a saturation mechanism. This process suggests Copper-dependent enzymes cannot function adequately in
that there may be an intestinal copper pool [7]. Evans et al. copper-deficient patients, which results in hematological or
proposed that a copper pool is associated with metallothionein neurological manifestations.
proteins, which serve to regulate copper absorption [8]. Depending on the daily requirement and amount absorbed,
Copper is excreted from enterocytes into the blood via the there are number of ways that copper is excreted from the
Cu-ATPase, ATP7A, by trafficking of transporter towards the body, including biliary loss 0.5–1.3 mg/day, urinary loss
basolateral membrane (Fig. 1) [9, 10]. Menkes disease is (10–60 μg/day), saliva loss (0.38–0.47 mg/day) [ 17], menses
caused by mutation of the ATP7A gene resulting in an accu- (0.47 mg/period), gastrointestinal secretions (greater than
mulation of copper in enterocytes that cannot reach the blood 1.0 mg/day) [17], and sweat. If dietary copper intake is less
or any other organ systems. This defect results in a copper that the daily requirement, the body conserves, rather than
deficiency in different connective tissues (Fig. 1). excretes, copper.
Copper is mainly absorbed in the stomach and proximal
duodenum [11]. It enters the jejunum with the aid of metallo-
thionein, which is a metalloprotein that binds to divalent cat-
ions [12]. Once inside the jejunum, copper binds to albumin Diseases associated with copper deficiency
and is then transported via the portal circulation to liver cells
where it binds with ceruloplasmin receptors for storage in the Zinc-induced copper deficiency anemia
liver [12]. The majority of the copper is stored in hepatocytes,
which provides homeostasis in the body. Copper uptake into Zinc is another important micronutrient in the human body,
hepatocytes is not highly regulated, but release of copper from acting as a catalyst or cofactor for many enzymatic reactions
hepatocytes is highly regulated via Cu-ATPase ATP7B gene and playing a critical role in the structure of cell membranes,
(Fig. 1). Wilson disease, or hepatolenticular degeneration, is DNA, RNA and ribosomes [18]. Although zinc absorption
an autosomal recessive disorder caused by mutation of may directly interact with the Ctr1 transporter, its absorption
ATP7B gene in chromosome 13 and results in the is slightly different. Zinc is digested via pancreatic enzymes,

Table 1 Causes of copper

deficiency anemia Causes Diseases

Hereditary Menkes disease, familial hypoceruloplasminemia

Decreased/inadequate intake Anorexic patients, malnutrition, Kwashiorkor, poverty, vegetarian,
parenteral hyperalimentation
Increased demand Pregnant women, lactating women, premature infants, infants
Increase copper loss or Malabsorption conditions include inflammatory bowel disease, ulcerative
inadequate absorption colitis, Crohn’s disease, Celiac sprue, post-bariatric surgery,
gastrectomy, prolonged diarrhea, protein-losing enteropathy, spure,
tropical and non-tropical
Drug-related Excessive zinc ingestion (e.g., from dentures, or excessive oral
supplementation) or iron supplements
Iatrogenic Parenteral or enteral nutrition with inadequate copper supplements
Ann Hematol

Diagrammatic Representation Copper

of Copper Absorption

Gut
Liner
Ctr1 Transporter

Enterocyte

Cytoplasma
Cu-ATPase ATP7A Menkes Disease

Cu ##
Blood

Cu is Absorbed into Blood and Binds to Albumin

Hepatocytes

Cu SOD1
COX
Mitcochondria
SCOI/II

Cu-ATPase ATP7B Wilson Disease

Ceruloplasmin + Cuproenzymes

Fig. 1 Diagrammatic representation of copper absorption. Abbreviation: CTr1 copper transporter 1, Cu++ copper, COX cytochrome C oxidase, SOD1
superoxide dismutase 1

and then binds to amino acids, phosphates, organic acids, and lower alkyl vinyl ether-maleic acid blends. [24]A lack of reg-
histidines [19]. These complexes are absorbed through active ulation in denture adhesives for excessive zinc supplementa-
and passive processes [6]. Zinc is mainly absorbed in the tion along with zinc treatment in certain diseases can lead to
jejunum by metallothionein, similar to copper’s absorption hematological abnormalities—copper deficiency anemia. In
[20] and then transported to the liver [21]. instances of copper deficiency anemia, Wiley et al. [ 8] sug-
High zinc intake can cause an up-regulation of metallothio- gested that an adult needed 3 to 4 months of total zinc avoid-
nein, which, in enterocytes, has a greater affinity for copper than ance to recover from anemia and to restore normal hemato-
zinc. This situation results in decreased copper entry into the poiesis before a copper supplementation was re-initiated.
plasma since copper is likely to be bound to metallothionine, However, neurological manifestations were not completely
resulting in increased zinc absorption [22]. recovered, even after the extended abstinence [25].
Copper deficiency anemia may also be related to denture
adhesive that contains zinc. Denture use is increasing among Copper deficiency after gastric bypass surgery
adults in the United States (U.S), a group that makes up 13%
of the total population. It is estimated up to 37.9 million will Obesity is increasing worldwide; approximately 15 million
use dentures by 2020 [23]. Shah et al. invented denture adhe- people in the U.S are obese [26]. With this increase, and the
sives by adding zinc salts to stabilize copolymer mixtures of comorbidities associated with this condition, a large number
 Ann Hematol

of patients have been referred for bariatric surgery. Roux-en-Y dysphagia, any brain injury, or short bowel syndrome. Not all
gastric bypass surgery (RYGB) has proven to be the most parenteral nutrition fluids include a copper supplement.
effective for weight loss [27]. This particular surgery usually Reports found that the serum copper level can decline at a rate
results in a 65 to 80% weight loss during the first year post- of 11 μg/dl/week, resulting in copper deficiency [40]
surgery [10]. These results are achieved by stomach restriction Additionally, when zinc was added in some nutrition regi-
(reducing the stomach size more than 90%), which results in mens, a zinc-induced copper deficiency anemia resulted
malabsorption. Nutritional deficiencies are common after by- [41]. Malnutrition guidelines recommend checking zinc and
pass surgery, even with supplementation [28]. In a 2004 study, copper levels before replenishing zinc to malnourished patient
the incidence of anemia following bypass surgery was esti- or patients with enteral or parenteral nutrition.
mated to be from 12 to 30% by Alvarez-Leite et al. [29]
Malnutrition etiologies could develop from reduced absorp- Copper deficiency in celiac disease
tion of multiple micronutrients including iron, vitamin A, B1,
B12, K, D, and E. Copper deficiency has been reported as well Copper deficiency associated with Celiac disease is uncommon;
[30, 31]. One prospective study consisted of 136 patients who however, Sternlieb et al. studied 50 patients with malabsorption
underwent RYGB. In this study, investigators measured serum from variable causes [42]. Copper deficiency was found in eight
copper, zinc, and ceruloplasmin levels at three points during out of 24 patients with Celiac disease. The true incidence or
the study: (1) before surgery, (2) 6 months following surgery, prevalence of copper deficiency in patients with Celiac disease
and (3) 24 months following surgery. The prevalence of cop- is unknown due to a general intestinal malabsorption. The he-
per deficiency after RYGB was 9.6% and the incidence was matological abnormality is completely resolved after copper
18.8%. Plasma copper and ceruloplasmin levels decreased at 6 supplementations together with a gluten-free diet [42].
and 24 months following surgery relative to the baseline levels
(p < 0.05) [32]. In a recent cross-sectional analysis of 78 pa-
tients who had undergone RYGB, the prevalence of copper Clinical features
deficiency was reported to be 15.4% [33]. Other retrospective
reviews of copper deficiency in patients who underwent Hematological effects
RYGB or the more malabsorptive bariatric procedures, such
as jejuno-ileal by pass or biliopancreatic diversion procedure, Copper deficiency anemia was first recognized in 1930. [43]
have been reported but the prevalence was insufficient to gen- The disorder impairs normal hematopoiesis resulting in ane-
erate valid statistics [34–37]. mia and leukopenia, neutropenia being the most common. The
In two case series that studied serum copper levels in mor- median time to diagnose copper deficiency anemia from initial
bidly obese patients who underwent biliopancreatic diversion, presentation with either neurology or hematology is 1.1 years,
23% (14 out of 64) developed hypocupremia within 6 months ranging from 10 weeks to 23 years in one retrospective review
of the procedure and 70% (98 out of 141) developed [36]. Latent copper deficiency occurs 3 months after the start
hypocupremia within 3 years [12]. Studies showed that the of enteral nutrition intake of this form of nutrition. [44] The
serum copper level was significantly decreased and incidence median time to diagnose zinc-induced copper deficiency ane-
of copper deficiency increased with time after bariatric surgery. mia is 12 months [45].
In one retrospective study, researchers used a different approach Huff et al. studied patients with unexplained anemia that
and focused on 55 hypocupremic patients to determine the were followed over a 23-month period. [46] From a total of
onset of symptoms. It was found that symptom onset ranged 126 serum copper levels measured, 8 were found to have
from 5 to 26 years in bariatric patients and 10 to 46 years in copper deficiency. In this study, patients were treated with oral
non-bariatric patients [38].Prodan et al. studied serum copper, copper gluconate and all hematological conditions were
serum ceruloplasmin, and zinc levels in 20 patients from a completely reversed within 4 weeks. For one patient, the bone
single institution who had partial gastric resection performed marrow response required 8 months of copper replacement.
either for peptic ulcer disease or for obesity to determine copper [46] In one retrospective study, 40 patients with copper defi-
deficiency, and compared levels to 50 control patients. The ciency and hematological manifestations were reviewed:
study reported that 15% (three out of 20 patients) had undiag- 52.5% presented with both anemia and leukopenia, 30% pre-
nosed hypocupremia with a mean interval of 20.7 years [39]. sented with isolated anemia, 10% presented pancytopenia,
and 2.5% presented with neutropenia [47].
Copper deficiency in parenteral or enteral nutrition Copper deficiency anemia can be present as microcytic or
normocytic or macrocytic. Mean corpuscular volume can
Parenteral or enteral (nasopharyngeal, gastrotomy, or range from 70.3 to 114.1 fL. Anemia followed by leukopenia
jejunostomy tube feeding) nutrition is an important means of is reported in more than 50% of cases. Occasionally, copper
providing nutritional support to patients with malnourishment, deficiency can present with thrombocytopenia [48].
Ann Hematol

Hematologic findings can mimic myelodysplastic anemia. erythropoiesis through hypoxia-inducible factor 2 alpha,
These two conditions have a similar clinical presentation and which stimulates the expression of the duodenal divalent met-
bone marrow morphology. Bone marrow findings in both al transporter located on the apical membrane of enterocytes to
conditions may show dysplastic erythroid precursors such as increase iron absorption. Iron uses ferroportin to cross into
the presence of ring sideroblasts, nuclear budding, and blood vessels, then binds to transferrin to produce mature
multilobulation with large size. One significant characteristic red blood cells. Alternatively, iron is absorbed into hepato-
finding in copper deficiency is the presence of cytoplasmic cytes for storage. Erythropoiesis decreases expression of
vacuolization within erythroid and myeloid precursors. This hepcidin, which releases of iron from enterocyte (Fig. 2)
feature is the key to differentiate between these two conditions [51]. Copper is an important component in the ferroxidase
[49]. The formation of ringed sideroblast is thought to stem enzymes, hephestin and ceruloplasmin. Hephestin is located
from reduced levels of superoxide dismutase, a copper- in the duodenal mucosa and helps in the oxidation of ferrous
dependent enzyme that has as an important role in antioxidant iron, released from enterocyte ferroportin, to ferric iron. The
and free radical scavenging [50]. Reduction of this enzyme ferric iron then binds to apo-transferin and enters the blood
level or function can cause iron accumulation in the circulation, and finally binds to transferrin and plays a role in
mitochondria. hemoglobin synthesis (Fig. 2). Ceruloplasmin is essential for
iron transfer from monocyte-macrophage to plasma [52–54].
Mechanisms of anemia in copper deficiency Copper deficiency leads to impaired ferroxidase enzymes,
which causes impaired hemoglobin synthesis. Leukopenia is
The exact mechanism of anemia in copper deficiency is un- the most common manifestation of neutropenia. The exact
clear. Copper is important in iron homeostasis. Iron homeo- mechanism for leukopenia/neutropenia remains elusive.
stasis is mainly regulated by expression of hepcidin and eryth- However, it can result from decreasing the rate of maturation
ropoiesis. An increase in erythropoiesis suppresses the pro- and differentiation of CD34-positive bone marrow stem cells
duction of hepcidin. Anemia from any etiology stimulates [55]. Platelet counts are typically normal or mildly depressed.

Mechanism of
Copper
Deficiency Anemia Fe2

Gut
Liner
DMT1
Hepcidin Unblocks Iron
Absorption by Releasing
Iron From Enterocyte
Enterocyte Hephaestin

Cytoplasma
Ferroportin

Hepcidin
Ferroportin
f
Cytochrome C
HIF 1
Oxidase
Fe2 Erythropoiesis
Fe3
Blood
Hb
Synthesis
Apotransferrin Transferin

Copper Deficiency Decreased Oxidation of Decreased in Hb Synthesis

Fe2+ to Fe3+
Fig. 2 Mechanism of copper deficiency anemia. Abbreviation: Fe2+ ferrous ions, DMT1 divalent metal transporter 1, HIF 1 hypoxia-inducible factors
alpha 1, Fe3+ ferric ions, Hb hemoglobin
 Ann Hematol

Neurology effects: copper deficiency myelopathy Hematological manifestations can be fully reversible with
copper supplementation over the course of 4 to 12 weeks of
Although the mechanism of copper deficiency myelopathy is therapy [45]. However, neurological manifestations are only
unclear, it is well-known that copper is also required for nervous partially reversible with copper supplementation. In one ret-
system development and function. The first copper deficiency rospective study of 40 copper-deficient patients associated
myelopathy was published in 2001 [56]. The clinical features with bariatric surgery, 57% had complete normalization of
mimic subacute combined degeneration (SCD). Copper defi- their hematologic symptoms with copper replacement [47].
ciency affects methylation dysfunction similar to that seen in Monitoring the patient’s blood copper levels every few
SCD and caused by B12 deficiency. Others symptoms include months for the first year to confirm normal serum levels is
myeloneuropathy (spastic paraparesis or tetraparesis, spasticity important to establish the appropriate dose. A national retro-
produced by posterior and lateral column dysfunction, respec- spective study in Scotland investigated the treatment of 16
tively). This condition can involve optic neuropathy, central copper-deficient patients over a 5-year time period. The study
nervous system demyelination, myelo-optico-neuropathy, and showed that 93% of hematological abnormalities were
motor neuron disease [57]. Magnetic resonance imaging (MRI) completely improved with copper supplements, while only
of spinal cord usually shows an increased signal T2-weighted 25% of neurological symptoms were improved [14].
imaging confined to the region of dorsal columns in the cervical
regions from C1 to C5 [23].

Optic neuropathy Conclusion

Copper-induced optic neuropathy typically presents with uni- Copper and zinc are essential micronutrients for metabolic
lateral symptoms and can develop years after any type of processes and tissue functions for major organs. However,
gastric bypass surgery. The disease has an indolent course these micronutrients can be harmful if the amount is excessive
and can lead to blindness if not treated early. Copper replace- or deficient for the body’s need. Copper deficiency is an un-
ment was shown to have no effect in reversing visual acuity in common and under-recognized disease that is fatal if not di-
published case reports. However, it could prevent further pro- agnosed and treated early. Other than residual neurological
gression if recognized and treated promptly. symptoms, most symptoms can be reversed by replacing cop-
per. For copper-deficient patients with risk factors, clinicians
should consider a strong clinical suspicious setting.
Diagnosis
Acknowledgements The authors thank Heather N. Russell-Simmons and
the Markey Cancer Center Research Communications Office for assis-
Copper deficiency anemia can be diagnosed by measuring
tance with manuscript preparation.
serum copper, serum ceruloplasmin, or from a 24-h urine cop-
per specimen; deficiency is demonstrated by low levels by any
Compliance with ethical standards
method utilized. Folate and vitamin B12 levels must be
checked for other causes of pancytopenia. A bone marrow Not applicable.
biopsy can confirm the diagnosis. Zinc levels should be
checked for suspected zinc toxicity. Cytogenetic studies can Conflict of interest The authors declare that they have no conflict of
rule out myelodysplastic syndrome as well as anti-tissue interest.
transglutaminase and anti-endomysial antibodies for Celiac
disease.

References
Treatment
1. Balamurugan K, Schaffner W (2006) Copper homeostasis in eu-
karyotes: teetering on a tightrope. Biochim Biophys Acta 1763(7):
Copper deficiency anemia is treated with oral or intravenous 737–746
copper replacement in the form of copper gluconate, copper 2. Prohaska JR (2012) Copper. In: Present knowledge in nutrition.
sulfate, or copper chloride. For severe copper deficiency ane- Wiley-Blackwell, pp 540–553
mia, the American Society for Metabolic and Bariatric Surgery 3. Chambers A, Krewski D, Plunkett L (2010) An exposure-response
curve for copper excess and deficiency. J Toxicol Environ Health B
Clinical Practice guidelines recommend 2–4 mg/day of intra-
Crit Rev 13(7–8):546–578
venous copper for 6 days followed by 3–8 mg/day of oral 4. Bhutta ZA, Nizami SQ, Isani Z (1999) Zinc supplementation in
copper until levels normalize. For mild to moderate anemia, malnourished children with persistent diarrhea in Pakistan.
the routine copper supplement is 2 mg/day [58]. Pediatrics 103(4):e42
Ann Hematol

5. USDA National Nutrient Database for Standard Reference, Release 28. Bernert PC, Ciangura C, Coupaye M, Czernichow S, Bouillot JL,
28, Copper Cu(mcg) content of selected foods per common mea- Basdevant A (2007) Nutritional deficiency after gastric bypass:
sure. Accessed October 28, 2015 diagnosis, prevention and treatment. Diabetes Metab 33(1):13–24
6. Nose Y, Rees EM, Thiele DJ (2006) Structure of the Ctr1 copper 29. Alvarez-Leite JI (2004) Nutrient deficiencies secondary to bariatric
trans’PORE’ter reveals novel architecture. Trends Biochem Sci surgery. Curr Opin Clin Nutr Metab Care 7(5):569–575
31(11):604–607 30. Haddad AS, Subbiah V, Lichtin AE, Theil KS, Maciejewski JP
7. Crampton RF, Matthews DM, Poisner R (1965) Observations on (2008) Hypocupremia and bone marrow failure. Haematologica
the mechanism of absorption of copper by the small intestine. J 93(1):e1–e5
Physiol 178:111–126 31. Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF (2009)
8. Evans GW (1976) LeBlane FN: copper binding protein in rat intes- Acquired copper deficiency: a potentially serious and preventable
tine: amino acid composition and function. Nutr Rept Intern 14:281 complication following gastric bypass surgery. Obesity (Silver
9. Monty JF, Llanos RM, Mercer JF, Kramer DR (2005) Copper ex- Spring, Md) 17(4):827–831
posure induces trafficking of the menkes protein in intestinal epi- 32. Gletsu-Miller N, Broderius M, Frediani JK, Zhao VM, Griffith DP,
thelium of ATP7A transgenic mice. J Nutr 135(12):2762–2766 Davis SS, Sweeney JF, Lin E, Prohaska JR, Ziegler TR (2012)
Incidence and prevalence of copper deficiency following Roux-
10. Ravia JJ, Stephen RM, Ghishan FK, Collins JF (2005) Menkes
en-y gastric bypass surgery. Int J Obes (Lond) 36(3):328–335
copper ATPase (Atp7a) is a novel metal-responsive gene in rat
33. Ernst B, Thurnheer M, Schultes B (2009) Copper deficiency after
duodenum, and immunoreactive protein is present on brush-
gastric bypass surgery. Obesity (Silver Spring, Md). 17(11):1980–
border and basolateral membrane domains. J Biol Chem 280(43):
1981
36221–36227
34. Atkinson RL, Dahms WT, Bray GA, Jacob R, Sandstead HH
11. Mason KE (1979) A conspectus of research on copper metabolism
(1978) Plasma zinc and copper in obesity and after intestinal by-
and requirements of man. J Nutr 109(11):1979–2066
pass. Ann Intern Med 89(4):491–493
12. Cox DW, Roberts EA. Wilson disease. In: Feldman M, Friedman 35. Faber J, Randolph JG, Robbins S, Smith JC (1978) Zinc and copper
LS, Brandt LJ, eds. Sleisenger & Fordtran’s Gastrointestinal and status in young patients following jejunoileal bypass. J Surg Res
Liver Disease: Pathophysiology, Diagnosis, Management. 8th ed.: 24(2):83–86
Saunders; 2006:P 1601 36. Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ (2008)
13. Culotta VC, Yang M, O’Halloran TV (2006) Activation of super- Hematological manifestations of copper deficiency: a retrospective
oxide dismutases: putting the metal to the pedal. Biochim Biophys review. Eur J Haematol 80(6):523–531
Acta 1763(7):747–758 37. de Luis DA, Pacheco D, Izaola O, Terroba MC, Cuellar L, Martin T
14. Cobine PA, Pierrel F, Winge DR (2006) Copper trafficking to the (2008) Clinical results and nutritional consequences of
mitochondrion and assembly of copper metalloenzymes. Biochim biliopancreatic diversion: three years of follow-up. Ann Nutr
Biophys Acta 1763(7):759–772 Metab 53(3–4):234–239
15. Bohm M, Pronicka E, Karczmarewicz E (2006) Retrospective 38. Jaiser SR, Winston GP (2010) Copper deficiency myelopathy. J
multicentric study of 180 children with cytochrome C oxidase de- Neurol 257(6):869–881
ficiency. Pediatr Res 59:21–26 39. Prodan CI, Bottomley SS, Vincent AS, Cowan LD, Meerveld BGV,
16. Turnland JR (2000) Copper. In: Modern nutrition in health and Holland NR, Lind SE (2009) Copper deficiency after gastric sur-
disease. Lippincott, Philadelphia gery: a reason for caution. Am J Med Sci 337(4):256–258
17. Cartwright GE, Wintrobe MM (1964) Copper metabolism in nor- 40. Fleming CR, Hodges RE, Hurley LS (1976) A prospective study of
mal subjects. Am J Clin Nutr 14:224–232 serum copper and zinc levels in patients receiving total parenteral
18. King JCKC (2000) Modern nutrition in health and disease. nutrition. Amer J Clin Nutr 29:70–77
Lippincott, Philadelphia 41. Dembinski K, Gargasz AE, Dabrow S, Rodriguez L (2012) Three
19. Sandstrom B (1997) Bioavailability of zinc. Eur J Clin Nutr distinct cases of copper deficiency in hospitalized pediatric patients.
51(Suppl 1):S17–S19 Clin Pediatr 51(8):759–762
20. Weigand E (1983) Absorption of trace elements: zinc. Int J Vitam 42. Sternlieb I, Janowitz HD (1964) Absorption of copper in malab-
Nutr Res Suppl 25:67–81 sorption syndromes. J Clin Invest 43:1049–1055
43. Jaiser SR, Winston GP (2010 Jun) Copper deficiency myelopathy. J
21. Cousins RJ, Lee-Ambrose LM (1992) Nuclear zinc uptake and
Neurol 257(6):869–881
interactions and metallothionein gene expression are influenced
44. Ito Y, Ando T, Nabeshima T (2005) Latent copper deficiency in
by dietary zinc in rats. J Nutr 122(1):56–64
patients receiving low-copper enteral nutrition for a prolonged pe-
22. Fosmire GJ (1990) Zinc toxicity. Am J Clin Nutr 51:225–227
riod. JPEN J Parenter Enteral Nutr 29:360–366
23. Douglass CW, Shih A, Ostry L (2002) Will there be a need for 45. Gabreyes AA, Abbasi HN, Forbes KP, McQuaker G, Duncan A,
complete dentures in the United States in 2020? J Prosthet Dent Morrison I (2013) Hypocupremia associated cytopenia and mye-
87(1):5–8 lopathy: a national retrospective review. Eur J Haematol 90(1):1–9
24. Shah NB GM, Holeva KT, Inventor; Richarson-Vicks, Inc, assign- 46. Huff JD, Keung YK, Thakuri M, Beaty MW, Hurd DD, Owen J,
ee. Denture stabilizing zinc and strontium salts of AVE/MA copol- Molnár I (2007) Copper deficiency causes reversible
ymer. US patent 4758630. July 19, 1988, 1988 myelodysplasia. Am J Hematol 82(7):625–630
25. Wiley JS, Moore MR. Heme biosynthesis and its disorders: 47. Halfdanarson TR. Kumar N, Li CY. Hematological manifestions of
porphrias and sideroblastic anemias. In: Hoffman R, Benz EJ Jr, copper deficiency: a retrospective review. Eur J Hematol ISSN
Shattil SJ, eds. Hematology: basic principles and practice. 5th ed. 0902-4441
Philadephila (PA): Churchill Livingstone Elsevier; 2009:P.488 48. Green R (2012) Anemias beyond B12 and iron deficiency: the buzz
26. Alberti KG, Zimmet P, Shaw J (2006) Metabolic syndrome—a new about other B’s, elementary, and nonelementary problems.
world-wide definition. A consensus statement from the Hematology / the Education Program of the American Society of
International Diabetes Federation. Diabetic Federation. Diabet Hematology American Society of Hematology Education Program
Med 23(5):469–480 2012:492–498
27. Livingston EH (2007) Bariatric surgery in the new millennium. 49. Willis MS, Monaghan SA, Miller ML, McKenna RW, Perkins WD,
Arch Surg 142(10):919–922 Levinson BS, Bhushan V, Kroft SH (2005) Zinc-induced copper
 Ann Hematol

deficiency: a report of three cases initially recognized on bone mar- 55. Peled T, Glukhman E, Hasson N, Adi S, Assor H, Yudin D, Landor
row examination. Am J Clin Pathol 123(1):125–131 C, Mandel J, Landau E, Prus E, Nagler A, Fibach E (2005)
50. Williams DM, Loukopoulos D, Lee GR (1976) Role of copper in Chelatable cellular copper modulates differentiation and self-
mitochondrial iron metabolism. Blood 48:77–85 renewal of cord blood-derived hematopoietic progenitor cells.
51. Deloughery TG (2014) Microcytic anemia. N Engl J Med 371: Exp Hematol 33(10):1092–1100
1324–1331 56. Schleper B, Stuerenburg HJ (2001) Copper deficiency-associated
52. Linder MC, Hazegh-Azam M (1996) Copper biochemistry and mo- myelopathy in a 46-year-old woman. J Neurol 248(8):705–706
lecular biology. Am J Clin Nutr 63(5):797s–811s 57. Gregg XT, Reddy V, Prchal JT (2002) Copper deficiency
53. Ames BN, Atamna H, Killilea DW (2005) Mineral and vitamin masquerading as myelodysplastic syndrome. Blood 100(4):1493–
deficiencies can accelerate the mitochondrial decay of aging. Mol 1495
Asp Med 26(4–5):363–378 58. Mechanick KI, Youdim A, Jones DB (2013) Clinical practice
guidelines for the perioperative nutritional, metabolic, and nonsur-
54. Bleackley MR, Wong AY, Hudson DM, Wu CH, Macgillivray RT
gical support of the bariatric surgery patient 2013 update:
(2009) Blood iron homeostasis: newly discovered proteins and iron
cosponsored by American Society for Metabolic & Bariatric
imbalance. Transfus Med Rev 23(2):103–123
Surgery. Obestiy 21(01):S-27