Copper Deficiency with Cow's Milk Diet

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Copper

Deficiency

with

Cow’s

Milk

Diet

Yehezkel Naveh, MD, Anna Hazani, MD, and Moshe Berant, MD

From the Departments of Pediatrics and Hematology, Rambam Medical Center, and Faculty of Medicine, Technion-lsrael Institute of Technology, Haifa, Israel

ABSTRACT. A 6-month-old full-term infant had severe

anemia and neutropenia. The patient was being fed cow’s

milk and a diet of corn flour. Thorough investigation

revealed low serum iron concentration, severe

hypocupre-mia, low ceruloplasmin, retardation of bone age, and

metaphysial irregularities and spurring. Bone marrow

aspirate revealed cytoplasmic vacuolization in precursors

of the erythroid and myeloid series and ringed

sidero-blasts. Therapy with oral iron, folic acid, and vitamin C

was futile. Administration of copper sulfate resulted in

brisk increase in neutrophils and reticulocytes. The child

maintained normal levels of hemoglobin, neutrophils,

Se-rum copper and ceruloplasmin, and serum iron one year

after copper therapy was discontinued. The probable role

of unrecognized copper deficiency in causing anemia in

infants more than 6 months of age is discussed, and the

importance of serum copper examination in refractory

iron deficiency anemia and neutropenia is stressed. To

the best of our knowledge, no such case has previously

been described in the literature. Pediatrics 68:397-400,

1981; anemia, copper, hypocupremia, neutropenia,

nutri-tion.

Copper deficiency has been reported in severely

malnourished infants with histories of chronic

diar-rhea who were rehabilitated on milk-based diets.”2

It has been reported also in malabsorptive states

resulting from disaccharidase deficiency,3 untreated

malnourished infants,4 premature infants fed

cop-per-deficient formulas,56 and infants, children, and

adults with or without short bowel syndrome

re-ceiving long-term parenteral nutrition without

cop-per supplementation.7’#{176}

Despite the lower concentration of copper in

cow’s milk as compared to human milk,” a review

of the literature did not reveal any reports of a

full-term, otherwise healthy infant who developed

cop-per deficiency on a low-copper diet such as

unmod-ified cow’s milk formula. Those who did had

expe-Received for publication Sept 29, 1980; accepted Jan 6, 1981.

Reprint requests to (Y.N.) Department ofPediatrics B, Rambam

Medical Center, Haifa, Israel.

American Academy of Pediatrics.

rienced protracted diarrhea which resulted in losses

of the element.

The present work describes a unique case of a

full-term infant who was fed an unmodified milk

diet, experienced no disease whatsoever, and

devel-oped copper deficiency.

CASE REPORT

A 6-month-old male infant was admitted to the

pedi-atric department with gradually developing pallor of

three week’s duration. Nothing in his history pointed to

a diagnosis.

The patient was the product of a normal pregnancy

and delivery. He was born to a healthy nonanemic

mother. Birth weight was 3.750 kg and his development

had been normal. The infant was mainly fed unmodified

cow’s milk, 150 ml/kg body weight. One month prior to

admission, approximately 8 gm of corn flour was added

daily to his diet.

Physical examination revaled a well-nourished

ex-tremely pale infant. His temperature was 37.5 C and pulse

at rest 180/mm; his weight was 7.600 kg (50th percentile

for age), length 68 cm (75th percentile for age), and head

circumference 43.5 cm (50th percentile for age). The liver

was palpable 2 cm below the right costal margin. The

spleen was not palpable. Otherwise, results ofthe physical

examination were normal.

Laboratory studies revealed a hemoglobin level of 4.5

gm/100 ml, reticulocytes 0.8% with hypochromia and

microcytosis in blood smear. The WBC count was 5,000/

cu mm with 1% metamyelocytes, 3% band forms, 3%

segmented neutrophils, 1% eosinophils, 8% monocytes,

and 84% lymphocytes. Platelets were normal. Serum iron

level was 34 ig and iron-binding capacity 360 g/100 ml.

The direct Coombs test was negative. Hemoglobin

elec-trophoresis revealed a hemoglobin A2 value of 2.8% and

a hemoglobin F value of 1.11% (normal values for age).

Glucose-6-phosphate dehydrogenase was normal. Total

protein concentration was 6.5 gm/100 ml with an albumin

level of 4.5 gm/100 ml. Serum biirubin, 1.0 mg/100 ml;

SGOT, 18 IU; serum calcium, 9.0 mg/100 ml; serum

phosphorus, 4.9 mg/100 ml; and alkaline phosphatase,

412 IU. Results of urinalysis were normal. Repeated stool

cultures and examination for parasites and occult blood

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398 COPPER DEFICIENCY

ml (normal 85 to 163 g/100 ml) and serum ceruloplasmin

concentration was 0.5 mg/100 ml (normal 27 to 37 mg/

100 ml). Bone marrow aspirate showed marked

cytoplas-mic vacuolization in the precursors of erythroid and

mye-bid cells and the presence of many sideroblasts and

ringed sideroblasts.

Radiographic examination of the left hand revealed

retarded bone age and metaphysial irregularities and

spurring.

On the day of admission and before an accurate

diag-nosis was made, the patient was given 200 ml of packed

red cells which resulted in a rise of hemoglobin value to

10.6 gm/100 ml. In a few days, the infant was discharged

clinically well on a regimen of ferrous carbonate

equiva-lent to 50 mg of Fe2; vitamin C, 100 mg; and folic acid,

5 mg per day orally. He was followed up in our outpatient

clinic.

Following five weeks of iron, vitamin C, and folic acid

oral therapy and cow’s milk diet, hemoglobin value was

8.8 gm/100 ml, reticulocytes 1.6%, and WBC count was

4,600/cu mm, with 5% segmented neutrophils, 8%

mono-cytes, and 87% lymphocytes. Platelets were normal.

Meanwhile, results of serum copper test and bone

marrow aspiration had been received, at which time the

child was given copper sulfate solution, 2 mg/day, for

about five weeks. By the 17th day of copper therapy the

number of neutrophils had risen from 230/cu mm before

treatment to 3,572/cu mm (Figure) and reticulocytes from

1.6% to 8.8%.

One month after copper sulfate therapy was

discontin-ued, serum copper level was 262 g/100 ml and

cerulo-plasmin level was 37 mg/100 ml. The infant’s diet was

subsequently enriched with copper sources.

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FOLIC ACID

At age 18 months, the patient’s hemoglobin level was

11.4 gm/100 ml, hematocrit level 34.3%, reticulocytes

5.2%, and the WBC count was 8,500/cu mm, of which 9%

were band forms and 32% were segmented neutrophils.

Platelets were normal. Roentgenogram of the wrist was

normal. Serum copper level was 154 g/100 ml and

cer-uloplasmin level was 27.5 mg/100 ml.

DISCUSSION

The earliest reliable laboratory indicators of

cop-per deficiency seen on routine blood count are

neutropenia, and hypochromic anemia

unrespon-sive to oral iron therapy.’ The development of

scurvy-like bone lesions were noted by x-ray film

late in the course of copper deficiency.”3

Abnormalities in iron metabolism described in

copper-deficient swine are defective gastrointestinal

iron absorption, restricted flow of iron from

reticu-loendothelial cells to plasma, excessive iron within

hepatic parenchymal cells, and defective utilization

of iron to form heme within normoblasts.’2

Associ-ated deficiency of the plasma copper protein may

account for the first three of the aforementioned

abnormalities.’2 Neutropenia in copper deficiency

might be the result of a decrease in neutrophil life

span’ or the result of a disorder in development and

division of granulocytes.8 However, the exact cause

is still unknown.

This patient, who was initially seen with severe

anemia, had severe and persistent neutropema, low

TIME C DAYS)

Figure. Neutrophil and hemoglobin response to

differ-ent kinds of therapy. Addition of copper sulfate was

followed by complete recovery of peripheral blood

neu-trophils, and rise and maintenance of hemoglobin level.

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serum iron and copper levels, low ceruloplasmin

level, retardation of bone age, metaphysial

irregu-larities and spurring, and marked cytoplasmic

vac-uolization in the precursors of erythroid and

mye-bid cells with the presence of ringed sideroblasts.

The x-ray film changes in bone could not have

been due to deficiencies of vitamin D or vitamin C

as the patient had no clinical signs of rickets or

scurvy nor biochemical signs of rickets. Moreover,

administration

of

vitamin C did not result in any

improvement in radiologic signs. Folic acid, vitamin

C, and oral iron therapy did not result in significant

changes in the number of reticulocytes or

neutro-phils in peripheral blood (Figure). Following the

administration

of copper

sulfate

solution,

the

num-ber of neutrophils rose from 230 to 3,572/cu mm

and reticulocytes from 1.6% to 8.8% by the 17th day

of therapy. The prompt response to copper therapy

is also characteristic of the copper deficient state.’3

Copper deficiency is uncommon in human beings

unless it results from severe malnutrition with

chronic intestinal disease, prolonged total

paren-teral nutrition without supplementation of copper,

or very marked prematurity.’’#{176} Papers dealing with

copper deficiency state: “there is no evidence that

dietary deficiency of copper occurs in man,” “ and

“there has been no evidence that a full-term infant

or a prematue of more than 1500 gm at birth can

become copper deficient on a low copper diet

with-out first experiencing prolonged and significant

body losses of the element.’5 These concepts are

supported by failure of earlier experimental

at-tempts to produce copper deficiency in human

in-fants.’6”7 Our finding of unexplained severe copper

deficiency in an otherwise healthy infant has not

previously been reported in the literature.

Until his admission to our hospital, the patient

was a normally growing healthy boy; there is no

reason to suspect diminished copper stores at birth

as the patient was a full-term infant born to a

clinically and biochemically normal mother.

Full-term newborn infants are endowed with large stores

of copper in their livers.’8

The proposed recommended dietary allowance

for copper is 80 jzg/kg body weight per day for

full-term infants. The mean copper concentration of

cow’s milk is 135 pg/liter, much lower than that of

breast milk.’9 This makes cow’s milk a poor source

of the recommended daily copper requirement in

infant nutrition. Yet, the diet of hundreds of

mil-lions of infants all over the world is based mainly

on cow’s milk. The peak incidence of copper

defi-ciency anemia is at 7 to 9 months of age 2 and iron

deficiency anemia is common in infants more than

6 months of age. The question raised is whether

unrecognized copper deficiency contributes to

hy-pochromic microcytic anemia in some infants after

the first six months of life. Subsequent enrichment

of the diet with copper sources may result in

spon-taneous improvement. Studies will have to be

con-ducted to explore this hypothesis.

Copper stores in livers of premature infants may

be unable to meet the demands for rapid growth on

a diet based on cow’s milk.’8 We doubt whether

these stores are always capable of meeting the

demands for rapid growth in the first six months of

life in all full-term infants receiving cow’s milk

alone.

Transient specific inability to synthesize

apocer-uloplasmin at the normal rate has been described

in the newborn and the question is whether such a

mechanism could persist up to the age of 6 months.

Finally, we feel that copper deficiency is probably

undiagnosed in some full-term, otherwise healthy,

infants suffering from hypochromic microcytic

ane-mia.

The ability of the copper-deficient infant to

re-spond to infection with a significant neutrophil

response ‘ can mask the characteristic neutropenia

and divert the pediatrician’s attention from the

correct diagnosis.

We would strongly suggest that routine

investi-gation of infants with hypochromic microcytic

ane-mia unresponsive to oral iron therapy, or anemia

associated with persistent neutropenia erroneously

attributed to an intercurrent viral infection or folic

acid deficiency, should include serum copper

ex-amination.

REFERENCES

1. Cordano A, Baertl JM, Graham GG: Copper deficiency in

infancy. Pediatrics 34:324, 1964

2. Graham GG, Cordano A:Copper depletion and deficiency in

the malnourished infant. Johns Hopkins Med J 124:139,

1969

3. Cordano A, Graham GG: Copper deficiency complicating

severe chronic intestinal malabsorption. Pediatrics 38:596, 1966

4. Holtzman NA, Charache P, Cordano A, et al: Distribution of

serum copper in copper deficiency. Johns Hopkins Med J

126:34, 1970

5. Al-Rashid RA, Spangler J: Neonatal copper deficiency. N

Engi J Med 285:641, 1971

6. Ashkenazi A, Levin 5, Djaldetti M, et al: The syndrome of

neonatal copper deficiency. Pediatrics 52:525, 1973

7. Karpel JT, Peden VH: Copper deficiency in long-term

par-enthral nutrition. J Pediatr 80:32, 1972

8. Dunlap WM, James GW, Hume DM: Anemia and

neutro-penia caused by copper deficiency. Ann Intern Med 80:470,

1974

9. Zidar BL, Shadduck RK, Zeigler Z, et a!: Observations on

the anemia and neutropenia of human copper deficiency.

Am J Hematol 3:177, 1977

10. Heller RM, Kirchner 5G. O’Neill JA, et al: Skeletal changes

of copper deficiency in infants receiving prolonged total

parenteral nutrition. J Pediatr 92:947, 1978

11. Fomon SJ: Infant Nutrition, ed 2. Philadelphia, WB

Saun-ders Co, 1974, p 363

12. Lee GR, Williams DM, Cartwright GE: Role of copper in

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Ob-400 COPPER DEFICIENCY

erleas D (eds): Trace Elements in Human Health and

Disease. New York, Academic Press, 1976, vol 1, pp 373-390

13. Cordano A, Placko RP, Graham GG: Hypocupremia and

neutropenia in copper deficiency. Blood 28:280, 1966

14. Davidson 5, Passmore R: in Human Nutrition and Dietetics,

ed 4. Edinburgh, Livingstone, Ltd, 1969, p 180

15. Graham GG, Cordano A: Copper deficiency in human

sub-jects, in Prasad AS, Oberleas D (eds): Trace Elements in

Human Health and Disease. New York, Academic Press,

1976, vol 1, pp 363-372

16. Bush JA: The role of trace elements in hemopoiesis and in

the therapy of anemia. Pediatrics 17:586, 1956

17. Wilson JF, Lahey ME: Failure to induce dietary deficiency

of copper in premature infants. Pediatrics 25:40, 1960

18. Morrison DB, Nash TP Jr: The copper content of infant

livers. J Biol Chem 88:479, 1930

19. Wairavens PA: Nutritional importance of copper and zinc in

neonates and infants. Clin Chem 26:185, 1980

WORLD VISION’S WORK IN REFUGEE CAMPS

World Vision International, a Christian humanitarian organization working

in 85 countries around the world, now has medical teams working in Kampuchea,

Thailand, Somalia, and Ethiopia. In Kampuchea, WVI is running a pediatric

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Robert W. Latta

US Ministry Group

World Vision Inc

919 West Huntington Drive

Monrovia, CA 91016

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1981;68;397

Pediatrics

Yehezkel Naveh, Anna Hazani and Moshe Berant