OCCULT BLOOD LOSS IN IRON DEFICIENCY ANEMIA OF INFANCY

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OCCULT

BLOOD

LOSS

IN

IRON

DEFICIENCY

ANEMIA

OF

INFANCY

M. Silvi1a Hoag, M.D., Ralph 0. Wallerstein, M.D., and Myron Pollycove, M.D.

Hematology Research Laboratory, Children’s Hospital, San Francisco, and the Donner Laboratory, University of California, Berkeley

This study was supported in part by a grant (A-2887) from the National Institutes of Health.

ADDRESS: (R.O.W.) Children’s Hospital, 3700 California Street, San Francisco 18, California.

PEDIATRICS, February 1961

199

I

RON DEFICIENCY is the most frequent

cause of anemia in infancy. Its

diag-nosis and treatment are relatively simple,

but its etiology is more complex. Anemia

rarely develops before 4 to 6 months of age

because iron acquired prenatally, largely

in the form of hemoglobin, maintains ade-quate concentration of hemoglobin until

the infant reaches twice birth weight.’ Iron

deficiency anemia may develop earlier in

the premature infant, who has a smaller

neonatal hemoglobin mass.2 After the age

of 6 months, faulty diet becomes a common

cause of iron deficiency; a diet composed

primarily of milk, which contains only 1

mg/h, does not supply sufficient iron for

the hemoglobin mass to keep pace with the

growing body mass. Severe iron deficiency

anemia is seen occasionally in some

full-term infants before the age of 6 months;

others develop anemia later in spite of

ade-quate diet. These observations suggest iron loss as the cause of anemia. Since only

minute quantities of iron are excreted nor-mally, and even less in iron deficiency

anemia, the possibility of blood loss must be considered.

This investigation deals with the role of

gastrointestinal bleeding in the

develop-ment of iron deficiency anemia in infancy.

MATERIAL AND METHODS

Patients selected for this study were

be-tween 7 and 17 months of age. The diagnosis

of iron deficiency anemia was established in

every case by the characteristic erythrocyte

morphology and indices, low values for serum iron and absence of hemosiderin in the marrow. At the completion of the study the appropriate erythrocytic response to parenteral iron therapy

was obtained. Thirteen children with iron

de-ficiency anemia, but without clinical evidence of

bleeding, were studied. Only those infants were

selected whose parents agreed to have them

re-main in the hospital for 3 to 4 weeks prior to

treatment. Another requirement was

reason-ably

satisfactory veins for the determination of

the blood volume and ferrokinetic studies.

During the period of observation the

chil-dren were given normal hospital diets for this

age. No medicinal iron was given. The children

developed no complicating illnesses nor clinical

evidence of bleeding.

Hemoglobin was determined by the

oxy-hemoglobin method in a Beckman B

spectro-photometer. Bone marrow aspirations were

ob-tained from the iliac crest and stained for iron

by the

Prussian blue reaction.3 Iron in serum

and total iron-binding capacity were measured

according to the method of Peters

et al.

A

guaiac test for occult blood was performed

on three consecutive stools of 67 normal well

babies and of 58 iron-deficient children who

had received a meat-free diet for 3 days.

Eryth-rocyte volumes were determined directly by

the isotope-dilution technique, using 32 labeled

erythrocytes. Plasma volumes were calculated

using the measured erythrocyte volumes and

cor-rected venous hematocrit (body hct. = 0.92

x

venous hct.). Radioiron in tracer amounts (Fe59,

0.15 c/kg, specific activity approximately 2

c/g) was given intravenously. Erythrocyte

radioactivity was determined at weekly

inter-vals. Stools were collected continuously for

1-week periods in a single container. Radioiron

in erythrocytes and feces was measured with

scintillation crystal counters. All stools were

col-lected for the 3- or 4-week period immediately

following injection of radioiron since normally

there is negligible fecal loss of intravenously

ad-ministered tracer radioiron.6 During the first

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TABLE I

OCcULT BIoOn IN STOOLS OF

PAT! ENTS WIT!! IlION 1)EFICI ENCY ANEMIA

Infants (5-26 mo) Anemic Normal Total Pts. 64 67

(;iaiac Test .

_____________________ Positive

0 1+ 2to4+

27 6 31 57.7

6’2 5 0 7.5

TABLE II

* Studied for 3 weeks only.

at the end of the first week; subsequently,

aver-age labeling of ervthrocytes was obtained from

the mean of the values measured at the

be-guiDing and end of the weekly collections.

RESULTS

Hemoglobin varied from 4.1 to 10.2 gm/ 100 ml and changed little during the 3 to 4

weeks of observation, except in three

in-fants (C-39, 1, 5-46) with blood loss

exceed-ing 11% blood volume. The average iron

level in serum was 20 i.g/100 ml with a

range of 5 to 35 s.g/100 ml. Stools were

guaiac positive in

57.7% of the

iron-deficient

children but only in 7.5% of the normal well

babies (Table I). Blood volumes

deter-mined in eight of the infants varied from 46.9 to 91.8 mI/kg, with an average of 68.4

ml/kg. The radioactivity of the stool ex-pressed as percentage of radioiron in

circu-hating erythrocytes varied from 1.15 to 18.6%, with a mean of 6.66%; the percentage of

total Fe59 administered that was recovered

in the stools varied between 0.75 and 16.4%,

with a mean of 5.73%. This represented loss of whole blood in the stool varying from 7 to

107 ml, with a mean of 41 ml in the 4-week

observation period (Table II, Fig. 1).

Ten of the infants maintained normal

hemoglobin values for the year following

correction of the iron deficiency anemia by

iron therapy. Three of the infants relapsed but eventually maintained normal

hemo-globins after repeated iron therapy.

Pa-tient C-39 had radiologic investigation of

the upper and lower gastrointestinal tract

and a sigmoidoscopy; no lesion was found.

By comparison, two normal children lost

0.73% and 1.96% of erythrocyte radioiron in

the stools, representing 4 and 12 ml of whole

blood (Table II).

BIooD Loss IN IRON DEFICIENCY ANEMIA OF INFANCY

Case Age (en) Jib Si Jg//) ifl 779 TIJ?C (g/100 in

,

RB( (mi/kg) Plasma (mi/kg)

Blood Fe59 in Stool Blood

(ml/kg) Percent of Percent of

/ Total Dose RRCAcliv.

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LOQ D

100

eo

60

40

20

0

- IRON DEFICIENCY ANEMIA

(,OT C- 39, AGE 10 MOS.)

-- NORMAL

(CASE 853, AGE 9 MOS.)

0 1 2

WEEKS

3

Fic. 1. Distribution of radioactive iron after intravenous administration.

TABLE III

SEVERE IRON DEFICIENCY IN INFANCY

Case Age

(mo)

Jib

m/10O ml)

. IIeight

g

Birth

Weight (kg)

I

17 17 2.4 9.1 3.8

493 11 3.0 8.2 3.6

C-23 7 3.6 9.5 4.2

642 10 4.1 9.5 3.9

519 8 4.2 6.8 3.7

364 8 4.4 8.1 4.1

S-145 11 4.6 8.5 3.7 II

S-283 14 2.8 9.3 3.2

526 6 3.0 6.4 3.0

819 9 3.6 7.2 3.2

35 6 4.8 8.5 3.3

484 6 5.1 7.1 3.2

III

S.318 12 2.3 9.5 2.7

32 8 3.3 7.8 ‘2.4

9 10 3.3 7.4 2.5

223 7 4.0 7.0 2.8

102 6 4.5 6.9 2.7

14 7 5.1 6.6 2.9

125 8 5.4 6.6 2.9

215 8 5.4 6.8 2.3

ARTICLES

201

Ill

0

‘U I)

‘U

0,

DISCUSSION

Blood volume at birth has been estimated

by Mollison

et al.

using an isotope dilution

method : in 34 normal infants they found

a mean value of 84.7 mI/kg and a range

from 70 to 100 ml/kg. Mollison

et

al.

ex-pected on theoretic grounds that blood vol-ume would increase with venous hemato-crit, that is, larger infants would tend to have higher hemoglobin concentrations. In

a study of 133 normal infants they found a

mean hemoglobin concentration in blood

from the umbilical cord of 16.55 gm/100 ml,

with a range of 13.6 to 19.6 gm/100 ml.8

In a series of infants with severe iron

deficiency anemia (Table III) we estimated

the maximum hemoglobin mass at birth from Mollison’s figures, then compared them with the hemoglobin masses at the

time of anemia (calculated from the

hemo-globin concentrations and our average fig-ure for the blood volume of 71.2 ml/kg). Figure 2 shows that the anemic children’s

total hemoglobin masses were considerably

smaller than their estimated hemoglobin

masses at birth in most cases. Storage iron is

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I

TOTAL

HEMOGLOBIN

AT

BiRTH

AT

TIME

OP

ANEMIA

It

nI

3.’fr4.2

3.O3.6

2.32.4

BIRTH

WEIGHT

IN

KG

FIG. 2. The bars represent the total hemoglobin mass at birth’ for the given weight

groups. The cross-hatched area indicates the range. The dots represent the total

calculated hemoglobin mass in individual patients with anemia.

90

accumulation of parenchymal iron is insuffi-cient to explain a decrease of circulating he-moglobin mass well below the neonatal amount; parenchymal iron may be de-creased in iron deficiency anemia.9 Occult

blood loss, or possibly unrecognized neo-natal anemia, may be important factors in the development of this anemia. Dietary

de-ficiency, which may be responsible for the

failure of the infant’s hemoglobin mass to increase, cannot explain this decrease.

Five milliliters of blood is required to give a positive guaiac test with the stools and five or six times this amount to render

the stools black. The loss of 2 ml of blood per day may well escape detection by or-dinary means. This blood loss is equivalent

to the loss of 1 mg of iron, more than is absorbed normally each day from the diet

in the first 12 months of life, and this may lead to a negative iron balance and iron

defi-ciency anemia.

The infant’s dietary iron, which may

vary from a fraction of a milligram to 1.5 mg/kg/day. does, of course, influence the

development of anemia. With only slight

bleeding, but a good diet, normal concen-tration of hemoglobin can be maintained; but with the same amount of bleeding and a deficient diet, there will be anemia. With

sizable blood loss, even optimal oral iron in-take cannot prevent the development of iron deficiency anemia.

Evidence that significant blood loss

actu-ally occurs is presented here in two ways:

1) Table I compares the results of stool guaiac tests in normal infants with those in iron-deficient children. A high incidence of occult blood was found in the latter; in 2) tracer studies with Fe59 showed varying amounts of blood loss in the iron-deficient

children

during

the

4-week

observation

period.

SUMMARY

Blood loss from the gastrointestinal tract

was measured in 13 infants with iron defi-ciency anemia, using radioiron as a tracer.

The

radioiron was given intravenously;

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ARTICLES

was measured for the following 3 to 4

weeks.

The percentage of total Fe59 adminis-tered that was recovered in the stools varied between 0.75 and 16.4%, with a mean of 5.75%. This represents loss of whole blood in

the stools varying from 7 to 107 ml, with a

mean of 41 ml during the observation

pe-riod.

Occult blood loss from the gastrointestinal tract appears to be a significant factor in the development of iron deficiency in early childhood.

REFERENCES

1. Sturgeon, P.: Iron metabolism. PEDIATRICS,

18:267, 1956.

2. Schulman, I., Smith, C. H., and Stem, C. S.:

Studies on the anemia of prematurity.

Amer.

J.

Dis. Child., 88:567, 1954.

3. Rath, C. E., and Finch, C. A.: Sternal

marrow hemosiderin.

J.

Lab. Clin. Med.,

33:81, 1948.

4. Peters, T., Grovanniello, T.

J.,

Apt, L., and

Ross,

J.

F.: New method for determination

of serum iron-binding capacity; and,

Sim-ple improved method for determination of

serum iron.

J.

Lab. Clin. Med., 48:274,

and 280, 1956.

5.

Berlin, N. I., Lawrence,

J.

H., and Gartland,

J.:

Blood volume in polycythemia as

de-termined by 32 labeled red blood cells.

Amer.

J.

Med., 9:747, 1950.

6. Pollycove, M. Unpublished data.

7. Mollison, P. L., Veall, N., and Cutbush, M.:

Red cell and plasma volume in newborn

infants. Arch. Dis. Child., 25:242, 1950.

8. Mollison, P. L., and Cutbush, M.: A method

of measuring the severity of a series of

cases of hemolytic disease of the newborn.

Blood, 6:777, 1951.

9. Beutler, E.: Iron enzymes in iron deficiency.

I. Cytochrome C. Amer.

J.

Med. Sci., 234:517, 1957.

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1961;27;199

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1961;27;199

Pediatrics

M. Silvija Hoag, Ralph O. Wallerstein and Myron Pollycove

OCCULT BLOOD LOSS IN IRON DEFICIENCY ANEMIA OF INFANCY

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