IRON METABOLISM UTILIZATION OF INTRAVENOUS RADIOACTIVE IRON By CLEMENT A. FINCH, M.D., JOHN G. GIBSON II, M.D., WENDELL C. PEACOCK, PH.D., AND REX G. FLUHARTY, PH.D. T HE HUMAN body shows great economy in its handling of iron. Only small amounts of iron arefound in the excreta, and these amounts cannot be ap- preciably increased through loading body iron stores by oral ingestion,’ by paren- teral iron administration2 or by multiple blood transfusions.3 These observations imply that iron is rigidly conserved by the body and that no attention need be directed toward excretion of iron in the absence of blood loss. This conservation serves to emphasize the importance of the metabolic cycle in the body where iron is reused again and again for hemoglobin formation. With the exception of the red cell iron, any estimate of the distribution of iron in man is at best an approximation because of the difficulty in separating tissue from hemoglobin iron. Circulating erythrocytes account for the largest mass of body iron, some 2. to 3 grams. This includes all erythrocytes in the body other than those developing in the bone marrow, since there appear to be no reserve depots of erythrocytes.4 From analogy with animal data,5 tissue iron available for hemo- globin production is perhaps one-fourth as much. Myoglobin, cell enzyme iron, and fixed tissue iron represent even smaller fractions whose iron turnover is not known. However, the work of Hahn and Whipple would indicate that myoglobin iron remains relatively constant despite marked changes in red cell and storage iron.6 The following studies were undertaken to determine the dynamic relationship between storage and circulating iron in normal subjects and in patients with a variety of hematologic disorders. When single tracer doses of radioactive iron (Fe55 and Fe59) are given intravenously in man, he radioiron rapidly enters the hemoglobin cycle and “tagged” erythrocytes begin to appear in the circulation within twenty-four hours. Thereafter, the radioactivity of circulating red cells rises and reaches a plateau in from two to three weeks. Similar findings have been reported by Dubach, Moore, and Minnich.7 This procedure appears to offer a method of measuring the participation of injected iron in the hemoglobin cycle. In the subsequent discussion the term utilization curve refers specifically to the utilization of the injected radioiron for hemoglobin production. METHODS The preparation of the two isotopes employed (Fc’5and Fe59) by bombardment in the Massachusetts Institute of Technology cycletron, the separation of the isotopes from the targets and synthesis of the From the Department of Medicine, Harvard Medical School, and the Medical Clinic, Peter Bent Brigham Hospital, Boston, Massachusetts, Radioactivity Center, Department of Physics, Massachusetts Institute of Technology, Cambridge, Mass. This work was supported by a grant from the United States Public Health Service. 905 For personal use only. on January 5, 2019. by guest www.bloodjournal.org From
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IRON METABOLISM
UTILIZATION OF INTRAVENOUS RADIOACTIVE IRON
By CLEMENT A. FINCH, M.D., JOHN G. GIBSON II, M.D., WENDELL C. PEACOCK,
PH.D., AND REX G. FLUHARTY, PH.D.
T HE HUMAN body shows great economy in its handling of iron. Only small
amounts of iron arefound in the excreta, and these amounts cannot be ap-
preciably increased through loading body iron stores by oral ingestion,’ by paren-
teral iron administration2 or by multiple blood transfusions.3 These observations
imply that iron is rigidly conserved by the body and that no attention need be
directed toward excretion of iron in the absence of blood loss. This conservation
serves to emphasize the importance of the metabolic cycle in the body where iron
is reused again and again for hemoglobin formation.
With the exception of the red cell iron, any estimate of the distribution of iron
in man is at best an approximation because of the difficulty in separating tissue from
hemoglobin iron. Circulating erythrocytes account for the largest mass of body
iron, some 2. to 3 grams. This includes all erythrocytes in the body other than those
developing in the bone marrow, since there appear to be no reserve depots of
erythrocytes.4 From analogy with animal data,5 tissue iron available for hemo-
globin production is perhaps one-fourth as much. Myoglobin, cell enzyme iron,
and fixed tissue iron represent even smaller fractions whose iron turnover is not
known. However, the work of Hahn and Whipple would indicate that myoglobin
iron remains relatively constant despite marked changes in red cell and storage
iron.6
The following studies were undertaken to determine the dynamic relationship
between storage and circulating iron in normal subjects and in patients with a
variety of hematologic disorders. When single tracer doses of radioactive iron
(Fe55 and Fe59) are given intravenously in man, �he radioiron rapidly enters the
hemoglobin cycle and “tagged” erythrocytes begin to appear in the circulation
within twenty-four hours. Thereafter, the radioactivity of circulating red cells
rises and reaches a plateau in from two to three weeks. Similar findings have been
reported by Dubach, Moore, and Minnich.7 This procedure appears to offer a
method of measuring the participation of injected iron in the hemoglobin cycle.
In the subsequent discussion the term utilization curve refers specifically to the
utilization of the injected radioiron for hemoglobin production.
METHODS
The preparation of the two isotopes employed (Fc’5and Fe59) by bombardment in the Massachusetts
Institute of Technology cycletron, the separation of the isotopes from the targets and synthesis of the
From the Department of Medicine, Harvard Medical School, and the Medical Clinic, Peter Bent
Brigham Hospital, Boston, Massachusetts, Radioactivity Center, Department of Physics, Massachusetts
Institute of Technology, Cambridge, Mass.
This work was supported by a grant from the United States Public Health Service.
905
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blood were obtained in the morning; the patient was fasting in most instances. Hematologic studies were
done according to the following methods: Hematocrit determinations were performed in Wintrobe tubes
with centrifugation for one hour at 3,000 r.p.m. (International Centrifuge, Size I, Type C); hemoglobin
was determined in duplicate by the oxyhemoglobin method on an Evelyn colorimeter9; red counts were
done in duplicate pipets and were repeated if they did not check within � per cent. Reticulocyte counts
were done according to the method of Osgood and Wilhelm)0 Cell constants were determined and
reticulocyte counts were performed at least twice during the study of each patient. In all patients whose
blood picture was stabilized during the period of study, the figures were averaged in table � for the sake
of brevity. In the others, blood values at the initiation of the study are recorded.6 Bilirubin determina-
tions were made according to the method ofEvelyn and Malloy.#{176} Blood volumes were determined by the
method of Gibson and Evans)2 Four to six samples of blood were drawn between ten to thirty minutes
after injection of the dye and read in the Evelyn photo-electric microcolorimeter. The circulating red cell
volume was taken as 8� per cent of the cell volume calculated from the plasma volume and venous hema-
merit.’3 The radioactivity present in the blood stream, which was solely intracellular after the first day,
was expressed as per cent utilization of the total quantity given, according to the formula: Per cent‘. . (counts per minute/cc. red cells) X (red cell volume) . . . . .
utilization = -�--�- ‘ �;�;- . Since a dilution of the iron injectedTotal counts/minute injected
was run with the samples obtained from the patient, decay in radioactivity and variation in counting
efficiency were automatically corrected.
EXPERIMENTAL DATA
I. Normal subjects (Nos. 8, 9, 10, ;8, 87, 91, 93, 94)
Nine normal male volunteers between the ages of 2.4 and 30 were used as sub-
jects. None had recently given blood or suffered any other blood loss. Blood
volumes were determined at the beginning and in five instances at the end of the
experimental period. Hematologic data are recorded in table i. Utilization of
intravenously injected radioiron is recorded in figure i. Over a period of fifteen to
eighteen days, 8 of these subjects showed a utilization of between 68 and 83 per
Cent, averaging 74 per cent.t
Three subjects (71, 42., 43) with miscellaneous diseases not expected to alter iron
metabolism were studied in a similar manner. These included a 59 year old female
diabetic (‘i) recovering from mild diabetic acidosis, a 53 year old male with
typical myocardial infarction (42.) but without any fever or evidence of heart
failure during the period of study, and a 71 year old asthmatic (��) in no acute
distress. Their utilization curves shown in figure 2. were similar to the composite
curve of normal subjects.
II. Iron Deficiency and Blood Loss Anemia (j, 7, 19, 20, 24, 26)
Six patients with acute or chronic blood loss were given radioiron (Fe55) intra-
venously. The patients represented varying degrees of iron deficiency as shown in
table i by their degree of microcytosis and hypochromia. Slight increases in mean
cell size found in acute blood loss are undoubtedly due to the appearance of
younger cells which are larger. Some patients had continued bleeding, some were
* In the reprints of this article, charts are included portraying the clinical course of these patients
similar to those shown in figure 7. While a correlation of the clinical factors affecting erythropoiesis and
the utilization curve was thought to be important, space did not permit its inclusion in the Journal.
t Subject 93 was excluded because of his variation from the others and because of the finding of a
decreased amount of iron binding protein in his serum.
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Over the days following injection, the radioiron passes through the serum to the
bone marrow. The functional integrity of the erythropoietic tissue is the final link
in the incorporation of the radioiron into the red cell.
The curve of radioiron utilization for hemoglobin production in normal subjects
is approximately exponential in character. When normalized to 100 per cent, this
curve extrapolates to a theoretic lag period of i.8 days. Actually there is an ap-
preciable uptake during this two day period, considerably greater in certain patho-
logic states. This is at least partially explained by the observation that reticulo-
cytes in vitro will take up radioiron. It might be presumed that the reticulocytes
in the circulation and the cells just leaving the marrow would begin to assimilate
radioiron immediately after its injection. In addition, the composite normal curve
is derived from the numerical average of eight subjects and shows a straggling
effect which in part explains this initial rise in the utilization curve.
Interpretation of the Utilization Curve
In interpretation of the utilization curve there are two components of impor-
tance: the size of iron stores, and bone marrow function. The influence of enlarged
iron stores was demonstrated experimentally in dogs (table 3). Utilization curves
done after iron injections showed marked depression although erythropoiesis was
unaffected. A similar reduction in utilization has been produced in experimental
subjects by oral ingestion of iron over a period of six months. This again occurred
without change in peripheral blood or in serum iron levels. The effect of bone
marrow dysfunction is self evident from previous discussion.
The normal curve shows the localization of about 2.5 per cent of the radioiron
extravascularly and 75 per cent in circulation as hemoglobin. This pattern may be
taken as representative of the average storage iron compartment size and normal
bone marrow function. The extravascular iron admittedly represents iron incor-porated in cell enzymes and myoglobin as well as storage iron. With a decrease in
storage iron as in iron deficiency, there may be increased demands of tissue for iron.
This would make it unlikely that decreased iron stores would be accurately detected
by the per cent utilization of radioiron. In conditions of iron excess, however, it
seems definite that increased stores have a clear-cut effect in depressing utilization
of radioiron for hemoglobin production’
In iron deficiency and blood loss anemia, initial utilization is more rapid and com-
plete than in normal subjects. Comparing the curve in figure 3, it will be seen that
Patients 2.0 and 2.6 show a greater utilization than the others. This is explainable
on the basis of a greater bone marrow activity in these cases, one showing a
reticulocytosis of 17 per cent, and the other responding with a rise in hematocrit to
iron therapy. It is of some interest that blood production in patients 2.5, �, and
7 was not increased during the first week, as judged by the riematocrit. With
the hyperplastic marrow found in iron deficiency and therefore an increase in
total red cell elements, the cell turnover would be slower than normal. The iron
given, o to 0.5 mg, as compared with a daily breakdown and reutilization of
about 2.0 mg., would not be expected to accelerate cell production. We must con-
clude that the increased speed of utilization in these cases represents a decrease in
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CLEMENT A. FINCH, JOHN G. GIBSON II, WENDELL C. PEACOCK and REX G. FLUHARTY IRON METABOLISM: UTILIZATION OF INTRAVENOUS RADIOACTIVE IRON
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