COPPER DEFICIENCY COMPLICATING SEVERE CHRONIC INTESTINAL MALABSORPTION

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CHRONIC

INTESTINAL

MALABSORPTION

Angel Cordano, M.D.,

and

George G. Graham, M.D.

Grace Department of Research, British American Hospital, Apartado 2713, Lima, Peru

(Received October 14, 1965; revision accepted for publication May 12, 1966.)

This work was supported by grants AM-04635, AM-05935 and AM-09137 from the National Institutes

of Health, U. S. Public Health Service, and by a grant from the United Nations Children’s Fund.

PRESENT ADDRESS: (CCC.) Baltimore City Hospital, 4940 Eastern Avenue, Baltimore, Mary’land

21224.

PEDIATRICS, Vol. 38, No. 4, Part I, October 1966

596

W

E HAVE previously reported the

oc-cunrence of copper deficiency in

se-verely malnourished infants rehabilitated on milk diets.’ Hypocupremia, anemia, neutropenia, and bone changes resembling

those seen in scurvy developed in manasmic infants with histories of chronic diarrhea and grossly inadequate intakes

appnoxi-mately 2 months after being placed on a high-calorie, low-copper diet. There was a prompt response to copper therapy. At that time we expressed doubt that copper

deficiency could occur with any frequency

in human beings but suggested that it

might vell occur in subjects with chronic intestinal malabsonption who were neceiv-ing milk diets. A previous report of

two

adults with anemia and hypocupremia com-plicating non-tropical sprue supports this

2 Recently we have seen a child

with severe chronic intestinal malabsonp-tion who developed intractable anemia,

in-termittent neutropenia, severe osteoporosis. and pathological fractures. We were not able to study hen until after copper

treat-ment had been given and we, thus, do not know the serum Cu level before treatment. The manifestations of Cu deficiency were so typical and the neponse to treatment so dramatic, including striking improvement in the malabsorption, that publication of her detailed history seems justified, panticu-larly as it suggests that chronic Cu deficiency can also affect intestinal enzyme activity.

CASE REPORT

P.L., a white female born on April 21, 1958,

was the fourth child of healthy parents of

Polish-Jewish extraction who are first cousins. Their first

child, a l)Oy born in 1945, and the second, a girl born in 1947, are both in good health. Their third child, a girl born in 1954, weighed 2.68 kg at

birth and died at the age of 53i months of

malnim-trition and diarrhea, weighing 3.4 kg. She was

breast-fed, almost exclusively, for 23 months. hilt very soon after birth became anoretic, vomited fre-quently, and had severe diarrhea which persisted

despite a change to a variety of formulas. Autopsy

was not performed.

P.L. weighed 3.1 kg at birth. She was breast-fed for 33i months (orange juice with some cane sugar

was started at 2 months) and, although she was

described as a poor eater and vomited on the

aver-age of once every 2 days, she regained her birth

weight in 2 weeks and gained 150 gm a week

thereafter. She had one normal stool daily and

reached a weight of 4.8 kg. Between 33 and 4

months of age she gained only 110 gm and a

physician advised a gradual change to an

evapo-rated cow’s milk and cane sugar formula. Within a

week she began to vomit three to four times daily

and to have bulky, loose stools three to four times daily. A gastric and pancreatic enzyme

prepara-tion and atropine were given and her diet was

changed to powdered whole milk. Stools improved

but she continued to vomit. Anorexia became more severe, and at 5 months her weight was 4.3 kg. Another physician advised the addition of solid

foods and forced feeding. Vomiting and anorexia continued; stools were large and contained undi-gested food. The diagnosis of celiac disease was suggested; solids were stopped; and she was given

a high-protein milk, Vitamin B2 and a lactobacil-lus preparation, intramuscular liver extract (20

doses) and desoxvcorticosterone (intermittently), and three whole blood transfusions. Over the next few months she received chloramphenicol, tetra-cycline, B complex injections, a testosterone

(le-rivative, pancreatic extracts, a low-fat diet and a

protein milk, all without effect. A lactic acid,

low-fat milk with added dextri-maltose was given for

most of the following year. At 6 months,

roughen-ing of the skin was noticed, with an apparent good

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a banana-base formula for a few days; she took it well but the number of stools increased and it

was stopped. Blood examinations apparently re-vealed anemia and she received 22 blood trans-fusions (approximately every 10 days), 20 to 25

plasma transfusions (at similar intervals) and 80

injections of liver extract. This treatment,

how-ever, was apparently intended as general

suppor-tive therapy more than as a specific treatment for

anemia. Her general condition remained

precani-oils with anorexia, vomiting, and diarrhea always

prominent; at 15 months her length was 61 cm and weight was 4 kg. A 2-week course of vitamin

E was associated with improved appetite, a 450

gm weight gain, and eruption of her first tooth,

but was soon followed by a return to the previous

state. At the age of 19 months she was taking about 25 oz per day of the lactic acid milk. She vomited occasionally, had intermittent abdominal

distention, and usually had one or two stools

daily-some formed, some undigested. Although

she recognized her family, smiled, and had head

control, she could not turn over or sit, even with

support. She was markedly emaciated, feeble and irritable, moderately pale, weighed 4 kg, and mea-sured 63 cm in length. Circumference of the head was 41.9 cm, of the chest 38.1, and of the

ab-domen 39.4 cm. She had an enlarged clitoris but no additional significant findings. She was ad-mitted to The Children’s Medical Center in Boston for 33 months, during which time extensive studies were carried out. Sweat electrolytes and stool trypsin were normal as were liver and adrenal

function studies. Routine urinalyses yielded 10 to

80 mg of albumin/100 ml but were otherwise

normal, including screening for amino acids. Re-peated 3-day stool fat determinations were within normal limits. Duodenal intubation demonstrated

normal trypsin, chymotrypsin and lipase, decreased amylase. Hemoglobin was 7.3 gm/100 ml,

hema-tocrit 24%, and WBC 8,200/mm’ with 81% lvmpho-cytes, 4% monocytes, 1% eosinophils, 1% basophils,

6% metamvelocvtes, 3% non-segmented neutrophils,

and 4 segmented neutrophils. Blood smear re-vealed marked hypochromia, moderate anisocytosis and poikilocvtosis, a mixed population with

marked microcytosis and moderate macrocvtosis and normal platelets. After transfusion of 100 ml

of whole blood, hemoglobin and hematocrit

con-tinued to rise to normal levels and the neutropenia

disappeared. After a few weeks, the hemogram gradually reverted to mixed anemia and

neutro-penia. Reticulocytes were found to be 3.0, 1.6, and 5.2% on three different occasions, platelets 350,000/mm’. Red blood cell indices 10 days

after transfusion were within normal limits.

Bone marrow aspiration 5 days aftr

transfu-sion revealed a cellular marrow with erythroid

hyperplasia and slight tendency of red cell

pre-cursors toward earl type nucleus. Giant

meta-myelocytes were present, with some bizarre

shaped nuclei. Serum iron was found to be 73

tg/100 ml. Fasting serum carotene was 4 g/1O0

ml and Vitamin A 9.6 tg/100 ml. Four hours after

an oral dose of oleum percomorphum, serum

Vita-mm A was 19 tg/100 ml.

Repeated blood sugar determinations were within

normal limits, with no significant postprandial rise.

Oral glucose tolerance tests on two occasions

showed a marked rise in 1 hour with a return to normal by 3 hours. Following the finding of

lac-tose in the urine, oral galactose and lactose toler-ance tests were done. Galactose did not produce diarrhea, and total blood sugar rose from a fasting

value of 36.4 to 190 in 1 hour, 195 at 2 hours

and 1 15 mg/100 ml at 3 hours. Fermentable sugar

fell to 0 at 2 hours, and non-fermentable sugar

rose from a fasting value of 4.9 to 195 at 2 hours

and 75 mg/100 ml at 3 hours.

Oral lactose tolerance test produced a recur-rence of diarrhea and lactosuria, and total blood sugar rose from 57 to only 90 mg/100 ml at 1 and 2 hours. Stools were guaiac positive, as on a number of other occasions.

On a lactose-free protein hydrolysate diet there

was some clinical improvement: stools became smaller and less frequent and her disposition im-proved but there was no significant weight gain. Subsequently, sucrose was also found in the urine and she was then placed on a diet of casein, corn-oil emulsion, and glucose, with improvement in her stools but continued failure to gain weight.

Radiologic bone age was 3 months when she

was 20 months old. The long bones showed

marked osteoporosis on admission. Fifty-one days

later, shortly after a trial course of ACTH, it was noted that both knees were swollen and tender.

X-rays revealed pathological compression

frac-tures through the distal shafts of the left femur,

proximal metaphysis of the left tibia, proximal shaft

of the right tibia (Fig. 1) and compression frac-tures of both radial heads without evidence of dis-alignment. Despite the gross osteoporosis and little

or no maturation, x-rays taken subsequently

showed good healing of the fractures.

Upon discharge from the hospital, she was kept on a diet of protein hydrolysate and casein with

added fat and glucose, bananas, and carrot juice.

During the following 23 months her course was somewhat more favorable, with periods of little or no diarrhea alternating with acute episodes of

large, foul-smelling stools every 2 or 3 weeks.

During the last 5 of these 23 months she had

bouts of unexplained fever. In February 1962 she

weighed 8 kg and measured 80 cm in length; head

circumference was 46.5 cm; bone age was 12 months. Hemoglobin was 12 gm/100 ml,

hema-tocrit 40, WBC 10,100 (44% neutrophils). Five

months later she began to require transfusion

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_::&:.

.

F

Fic. 1. Lateral x-rays of both knees at the age of 22 months revealing pathological compression

fractures through the metaphyses of the left femur and both tibiae.

hemoglobin to below 5.0 gm/100 ml. Leukopenia

and neutropenia was repeatedly found as well. In

February 1963 she suffered a supracondylar

frac-hire of the left arm.

At the age of 5 years she was re-admitted to

The Children’s Medical Center in Boston for

re-evaluation. Her weight was 8.8 kg and she mea-sured 83.8 cm in length. Routine urinalyses were

unremarkable except for the finding of 45 mg

albumin/100 ml. Sweat electrolytes were again

normal as were serum electrolytes, with the

ex-ception of acidosis and hypokalemia during an

episode of diarrhea and dehydration.

Hemoglobin was 10.5 gm/l00 ml, WBC 7.900 (14% non-segmented neutrophils and 52%

seg-mented neutrophils). Smear revealed moderate to

marked anisocvtosis, macrocytosis and microcv-tosis, moderate hvpochromia, slight poikilocvtosis,

and polychromatophilia. One week later hemo-globin had risen to 12.5 gm, hematocrit was 39,

RBC 3.28 million/mm’, the morphology was

near-ly normal, and there was 4% reticulocytosis.

Aspiration of the bone marrow yielded fairly

cellular material. A tendency to myeloid

hyper-plasia was apparent with a shift to the left in the myeloid series. Erythroid elements were generally

morphologically normal and megakarvocytes were

moderately numerous. Occasional histiocytes were

seen. The impression was: shift to the left in the myeloid series suggesting either a response to

leu-kocytosis or an early partial myeloid maturation

arrest.

Precipitins to milk and wheat could not be

demonstrated. Stool trvpsin and fat content were

repeatedly normal. Fasting serum carotene was 10 Lg and Vitamin A was 34.9 tg/100 ml.

Oral glucose and maltose tolerance tests were

normal. Oral lactose tolerance revealed a fasting

total blood sugar of 48 mg/100 ml with no rise in

4 hours. It produced a marked lactosuria,

moder-ate galactosuria, explosive diarrhea, and a

posi-tive stool guaiac. Sucrose tolerance test produced a rise in blood sugar from 68 to 135 in 3 hour, with a return to 57 mg/100 ml at 2 hours. There

was a marked sucrosuria, moderate glucosuria and

fructosuria, and positive stool guaiac, but no

diar-rhea.

Biopsy of the duodenal mucosa was reported to

show flattening of the mucosa and clubbing of the

villi with the relative length of the vil!i to depth of the crypts about 1 to 3 and the striated border of the epithelium intact. Scattered along the

sur-face and glandular epithelium, the nuclei of the

columnar cells tended to be large and juicy. The

Paneth cells were adequate and the lamina

pro-pria was markedly infiltrated by plasma cells. The villi were adequately vascularized. The lacteals

were dilated and the muscularis mucosa and glands of Brunner showed no remarkable change. Diagnosis was: Grade III atrophy of the

duo-clenal mucosa with plasmacvtosis and

lvmphangi-ectasia.

Enzyme studies of the duodenal biopsy revealed

no detectable lactase and a decrease in alkaline

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ARTICLES

599

most of the changes found microscopically and in

the enzymes could be secondary rather than

pri-mary.

X-ravs of the long bones (Fig. 2) showed

marked generalized loss of density with a rather coarse trabecular architecture evident in most of the metaphyses. The epiphyseal plates, however, had a normal size and were fairly sharply defined.

There was a buckle-type fracture of the distal lat-eral cortex of the left femur with a small amount

of periosteal new bone formation, and the

frac-ture was thought to have occurred several weeks

previously. Many growth disturbance lines were

evident. The bone age was between the standards

of 18 and 24 months; the chronologic age was 5 years. X-ray examination of the upper gastroin-testinal tract revealed intermittent severe gastro-esophageal regurgitation, probably accompanied by a sliding hiatus hernia. Irregular clumping of barium in the small bowel was also demonstrated.

During the following year she continued to

have repeated bouts of large, foul-smelling stools and did not gain weight. She received

transfu-sions every 2 to 3 nionths, when hemoglobin

dropped below 7 grn/100 ml.

From May to August 1964, she continued to have frequent bouts of diarrhea and in June edema of the eyelids and legs was noted for a few days. The

anemia became much more severe, falling below

4 gm/100 ml and making transfusion necessary

with much greater frequency. She received more

than 20 transfusions (100 ml of whole blood each) during this short time. Neutropenia was

intermit-tently noted.

On August 24, 1964, hematocrit was 10%, red

blood cell count 1.2 million/mm’, hemoglobin 3.6 gm/100 ml, WBC 3,900/mm’ with 2%

non-seg-mented and 7% segmented neutrophils.

Reticulo-cytes were 0.2%, normoblasts, 1%, and blood smear

revealed moderate hypochromia, microcytosis and

anisocytosis; MCV was calculated as 83.3, MCH

30, MCHC 36. Macroscopically the bone marrow

appeared moderately hypoplastic. Microscopically,

cellularity seemed diminished with a slight

in-crease in fat. Megakaryocvtes were normal or slightly increased. The erythroid elements were

diminished with most cells being of the

normo-blastic type. The granulocytic series was well rep-resented with a moderate degree of maturation arrest, as most elements were at the level of metamyelocytes and mature myelocytes. Very few non-segmented or segmented neutrophils were present. The impression was that of moderate

erythroid hypoplasia and moderate granulocytic

maturation arrest.

At this point her case was described to one of

us (AC.), who suggested that part of her picture

might be due to copper deficiency. A blood sam-plc for serum Cu determination was requested but, unfortunately, was not drawn, and on Au-gust 30, 1964, she was placed on 10 drops daily

of 1% Cu sulfate solution yielding 2.5 mg of Cu daily. On September 5 RBC was up to 1.66

mi-lion/mm’, hemoglobin to 5.8 gm/100 ml, \VBC to 12,400 with 7% non-segmented and 38% segmented neutrophils, reticulocytes to 4.5%. Nine days later, hematocrit was 32, RBC 3.36 million/mn’, hemo-globin 9.2 gm/100 ml, WBC 9,000/mm3 with 3%

non-segmented, 64% segmented neutrophils, retic-ulocytes 4%. The blood picture returned to

nor-mal in another month and she has not required

transfusion in over 18 months, hemoglGbin

remain-ing above 12 gm/100 ml. Table I summarizes the

pertinent hematologic data.

Following the administration of Cu there was a remarkable improvement in her appetite, he: weight rose from 8 kg in August 1964 to 9.25 kg in November 1964, to 11.25 kg in March 1r65, to

12.78 kg in August 1965, and to 15.2 kg in

De-cember 1965. During the same time she grew 14.5

cm (to 98.5 cm) and her head circumference

in-creased 1.6 cm (to 48.1 cm). Her progress in growth and bone age is depicted in Fig. 3.

During January, February, and March 1965 sl: had an unexplained fever (as on previous

occa-sions), but this disappeared without specific treat-ment and has not recurred in 10 months.

In Mawh 1965, at the age of 611/i2 years, she

FIG. 2. A-P x-ray of both legs at the age of 5 years revealing marked osteoporosis, multiple lines

of growth arrest, and a recent fracture of the left

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walked for the first time in her life and the

fol-lowing month sustained a linear fracture of the shaft of the left tibia which healed normally, never having had the characteristics of a pathological

fracture. Her disposition improved strikingly and her mental age was estimated at close to 5 years when she was 7 years old.

In November 1964, less than 3 months after the

start of Cu treatment, x-rays of the long bones

re-vealed considerable new bone formation at the metaphyses, but bone age was still 18 months. In

another 5 months (Fig. 4) there was radiologic evidence of considerable growth with dense new

bone formation. In July 1965 radiologie bone age

had advanced to 27 months and in January 1966

to 5 years.

Q

uite unexpectedly, there has been a remark-able improvement in her stools, the bouts of

diar-rhea becoming less and less frequent. Since Oc-tober 1964 she has had voluminous stools no more

than tsvice weekly and from early July 1965 to late January 1966 there had not been a single

episode of severe diarrhea. Until March 1965 she

remained on a diet of protein hydrolysates, medi-um-chain triglycerides, glucose, and a few

vege-tables. At that time, cautious additions to her

diet were started and by July she was taking

daily: 20 oz of whole milk, a variety of cereals,

noodles, chicken, beef, a wide variety of

vege-tables, baked apples and bananas. Excessive milk intake still produces an increase in stool weight. Serum Cii on Max’ 8, 1965, was 130 sg/100 ml, a normal value in our laboratory.

Oral lactose tolerance test in December 1965

revealed a fasting blood sugar of 97 mg/100 ml;

at 3 hour the blood sugar was 127, at one hour 107,

and at 2 hours 97 mg/100 ml. There was no di-arrhea, but the urine was positive for a reducing sugar which was not glucose.

Oral sucrose tolerance test, also in December,

revealed a fasting blood sugar of 77, a 3-hour

value of 195, a 1-hour value of 137, and a 2-hour value of 77 mg/100 ml. The urine was positive

for glucose.

Stool disaccharidase activities in 8 consecutive

stool samples obtained in December 1965 were determined by Dr. Harold M. Nitowsky and Dr. Andrew Grunfeld of the Sinai Hospital of

Balti-more. In micromoles of glucose released/gm of

fecal protein/hour the results were as follows:

lactase 44.0-1 21 .2 tmoles/gm/hour; saccharase

59.4-300.4 smoles/gm/hour; maltase

860.8-1,138.1 smoles/gm/hour. These values all fell within the normal range for their laboratory.

DISCUSSION

The primary diagnosis in this child ne-mains unclean; the family history strongly suggesting a genetic disorder. Cystic

fibro-I

CNRONOLOIC AGt (YRS)

Fic. 3. Evolution of developmental age for height,

weight, and bone maturation from birth until the age of 7 years, 8 months. The 50th percentile of the Stuart Growth Curves has been used as the standard of reference. Shortly after the

adminis-tration of copper there was a notable spurt in all

three measures.

sis of the pancreas and celiac disease were

adequately ruled out.

The fact that she tolerated hen mother’s milk relatively well for

33

months and is now able to tolerate fairly lange amounts of

whole cow’s milk suggests that, if she had

primary lactase deficiency, this was incom-plete at first and at present, and that it was

aggravated by a secondary disorder which

also resulted in a temporary but severe deficiency of other disacchanidases. Her sibling’s history suggests primary lactase deficiency.

The aggravation of her difficulties almost immediately after the introduction of a modified evaporated cow’s milk formula containing sucrose suggests either an intol-erance on allergy to cow’s milk protein or a

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Fic. 4. Lateral x-ray of both knees at the age of 7 years approximately 7 months after the start of copper therapy. There is considerable dense new bone formation and evidence of striking growth in the length

of the bones.

very low invertase activity found in the du-odenal biopsy, she had normal sucrose tol-enance. At 72 years of age sucrose

tol-enance was normal and the stool bad a nor-mal saccharase activity. Multiple secondary disaccharidase deficiencies have been

ne-ported in most cases of primary invertase deficiency,’ although apparent lactase

deficiency has been reported only twice.4”

It is possible that hen basic problem is one of primary lactase deficiency, albeit

in-complete, but aggravated by secondary changes brought on by the chronic loss of

nutrients in her stool and

by

hen very re-stnicted diet. Alternatively, the lactase

deficiency may also be secondary to an

un-determined primary condition.

It is probable that l)v 7 or 8 months of age P.L. had developed Cu deficiency, con-trolieci temporarily 1w tranfusions.

By

the age of 19 months, after 3 months without

transfusion, she had all the manifestations

of Cu deficiency which we have previously described : anemia, neutropenia, and marked osteoporosis, soon adding patholog-ical fractures. The first bone marrow exam-med probably showed some response to the copper in the whole blood received 5 days previously. During the next 5 years, the man-ifestations were quite variable. It is

proba-ble that not only the transfusions but

possi-bly also the short episodes of improvement in her malabsorption and in her diet

result-ed in temporary remissions of the hemato-logic manifestations and in short periods of normal bone formation. Between March 1960 and July

1962

she showed enough

im-provement in hen basic disease to allow the

probable absorption of enough Cu to pre-vent anemia. Then, however, the full-blown

hematologic picture recurred; she started

receiving transfusions again and by the date of her second hospital admission she

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mar-row showed only partial maturation arrest of the granulocytic series. She relapsed

again and at 6 years of age hen copper deficiency had become most severe, with an apparent significant decrease in the life span of erythrocytes, such as that de-scnibed in swine who were made copper

2 There was now only a very

tran-sitory response to blood transfusion.

The hematologic and radiologic response to the administration of Cu was most

dna-matic. The fact that there has

simultaneous-ly been a striking improvement in the

intes-tinal enzyme deficiencies suggests that a significant pant of these were indeed due to

Cu deficiency, something we have not

en-countered before. The only parallel to this in the experience with animals is the severe

diarrhea or “scours” which develops in calves and possibly lambs who graze on soils which are low in Cu and high in mo-lybdenum and which respond promptly to

Cu supplementation.6

It is interesting that, although transfusion produced improvement in her erythroid and granulocytic picture, it seemingly had no effect on whatever part of her intestinal enzyme deficiency

was

due to Cu deficiency. On the other hand, the oral

ad-ministration of copper produced dramatic improvement in nearly all aspects of her disease.

This child developed chronic and severe diarrhea and maldigestion, and dietary treat-ment was almost entirely based on milk

derivatives, notoriously low in copper. She developed anemia early, probably due to

copper deficiency and possibly to folic acid and B,, deficiencies as well. She re-sponded in pant to transfusion but by 19 months of age had all the manifestations of Cu deficiency. Thereafter, transfusion and dietary manipulation resulted in partial and transient remission. Our experience’

sug-gests that response to therapy is first appar-ent as a prompt increase in neutrophils and

reticulocytes, followed soon by correction of the anemia and later by improvement in the bone lesions. It is likely that this child

had never been in remission long enough

for improvement in the osteoporosis and

radiologic bone age to become apparent. Once she was placed on oral Cu therapy

her neutropenia and anemia disappeared promptly and the formation of healthy new bone soon became evident. Her intestinal enzyme activity improved and she had a dramatic spurt of gain in weight, height, and radiologic bone age, and was able to tolerate most foods.

Copper is an essential part of many en-zymes and acts as a catalyst for many

meta-bolic reactions. A significant amount is present in bile and other intestinal secre-tions, being effectively reabsorbed with the

products of digestion.#{176} In the absence of an adequate food intake, but particularly in the presence of chronic diarrhea and/or malabsorption, a good deal of this copper is lost from the body and eventually the deficiency may become severe enough to affect intestinal enzymes as well as erythro-cytes, granulocytes, and osteoblasts.

It is logical to assume that the intestinal epithelium has first call on any copper coming from the diet, thus effectively pre-venting deficiency of the activity of

intesti-nal enzymes. If, on the other hand, copper is administered by vein, already bound to

cenuloplasmin and in blood cells, it is possi-ble that the bone marrow would make first use of it, as seems to have happened in this child after transfusion.

In humans with chronic intestinal maldi-gestion or malabsorption, copper deficiency might contribute to the anemia and

osteo-ponosis which are often encountered, par-ticularly if the diet is low in copper. This would set up a vicious nutritional cycle of malabsonption causing deficiency of a nu-trient which in turn causes further

malab-sorption which cannot be corrected until an adequate supply of the missing nutrient is provided.

SUMMARY

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months, this had resulted in marked copper deficiency Witil anemia, neutropenia, osteo-ponosis, pathological fractures and probably aggravation of intestinal enzyme activity deficiency. At years of age copper

therapy produced a dramatic improvement

in all manifestations, including the maldiges-tion, and there was a striking growth re-sponse.

REFERENCES

1. Cordano, A., Baertl, J. M., and Graham, C. C.:

Copper deficiency in infancy. Pmwrrncs, 34:324, 1964.

2. Cartsvright, C. E. : The relationship of copper,

cobalt and other trace elements to hemopoe-sis. Amer. J. Clin. Nutr., 3:11, 1955.

3. Nordio, S., and Lamedica, C. M. : Intolerance

to sucrose, maltose, isomaltose and starch.

In P. Durand, ed. : Disorders Due to

Intes-tinal Defective Carbohydrate Digestion and

Absorption. Rome: II Pensiero Scientifico, p.

181, 1964.

4. Delaitre, Fontv, Varlet, and Fourrier: Diarrhea

chronique chez un nourrisson par intolerance

au saccharose. Arch. Franc. Pecliat., 18:1202, 1961.

5. Gorouben, J., Beder, J., La Balle, J.,

Crum-bach, R., Yonger, J., Weill, J., and Kaplan,

M.: L’intolerance au saccharose. Etude

clini-que et biologique de 5 cas. Arch. Franc. Pediat., 20:253, 1963.

6. Underwood, E. J.: Copper. In Trace Elements in Human and Animal Nutrition. New York:

Academic Press, pp. 48-99, 1962.

Acknowledgment

The authors are indebted to Dr. Harry

Shwachman of the Boston Children’s Hospital

Medical Center, who was responsible for this

pa-tient’s care from 19 months to slightly over 5 years of age and studied her extensively; and to Drs. L. K. Diamond and Kurt Isselbacher, who

saw this child in consultation while she was

hos-pitalized in Boston, and who have allowed us to quote extensively from their records. We are also indebted to Dr. Celestino Sanchez for referring

this case to us and making available the results of his studies. We are particularly grateful to Drs. Harold Nitowsky and Andrew Grunfeld of the

Sinai Hospital of Baltimore for the stool enzyme

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1966;38;596

Pediatrics

Angel Cordano and George G. Graham

MALABSORPTION