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
IRON 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-ablysatisfactory 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 thePrussian blue reaction.3 Iron in serum
and total iron-binding capacity were measured
according to the method of Peters
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
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
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 .
0 1+ 2to4+
27 6 31 57.7
6’2 5 0 7.5
* 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.
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
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.
- IRON DEFICIENCY ANEMIA
(,OT C- 39, AGE 10 MOS.)
(CASE 853, AGE 9 MOS.)
0 1 2
Fic. 1. Distribution of radioactive iron after intravenous administration.
SEVERE IRON DEFICIENCY IN INFANCY
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
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
Blood volume at birth has been estimated
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
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
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.
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
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
Blood loss from the gastrointestinal tract
was measured in 13 infants with iron defi-ciency anemia, using radioiron as a tracer.
Theradioiron was given intravenously;
was measured for the following 3 to 4
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
Occult blood loss from the gastrointestinal tract appears to be a significant factor in the development of iron deficiency in early childhood.
1. Sturgeon, P.: Iron metabolism. PEDIATRICS,
2. Schulman, I., Smith, C. H., and Stem, C. S.:
Studies on the anemia of prematurity.
J.Dis. Child., 88:567, 1954.
3. Rath, C. E., and Finch, C. A.: Sternal
J.Lab. Clin. Med.,
4. Peters, T., Grovanniello, T.
J.,Apt, L., and
J.F.: New method for determination
of serum iron-binding capacity; and,
Sim-ple improved method for determination of
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.
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.
RETICULOENDOTHELIAL SmucTi.nu AND
FUNCTION, edited by John H. Heller,
M.D. New York, the Ronald Press
Com-pany, 1960, 473 pp., $12.00.
The traditional courses on anatomy leave the
physician with only the vaguest notion of one
of the most important and interesting systems
of the body. If all other tissues could be made
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