Nagoya J. med. Sci. 30: 491-505, 1968

CLINICAL STUDIES ON IRON KINETICS

II. IRON KINETICS STUDIES IN PATIENTS WITH

MALIGNANT NEOPLASMS

-WITH SPECIAL REFERENCE TO FERROKINETICS AND 59Fe LABELED IRON-DEXTRAN STUDIES-

HIDEO YAMADA

1st Department of Internal Medicine, Nagoya University School of Medicine

(Director: Prof Susumu Hibino)

ABSTRACTS

Although extensive studies on the anemia and iron metabolism in patients

with malignant neoplasms have been made, the pathogenesis of the anemia ob·

served in cancer patients remains obscure.

The first purpose of this paper is to elucidate the functional impairment in

red cell production in patients with malignant neoplasm by means of ferrokinetic

studies. The second one· is to clarify how the reticulo-endothelial cells partici·

pate in alterations of iron metabolism in malignancy by means of 59Fe labeled

iron-dextran. The third one is to enumerate sideroblasts in bone marrow smears

of cancer patients for assessing stainable iron in erythroblasts.

The results obtained were as follows:

1) Ferrokinetic studies with 59Fe-citrate showed the increased rate of erythro­

poiesis in patients with malignant neoplasm. However, studies on cases with

infections gave results very similar to those in malignant neoplasms, suggesting

the· existence of a mechanism common in both conditions.

2) The studies with 59 Fe labeled iron-dextran revealed a significant decrease

of utilization of radioiron for hemoglobin synthesis from iron-dextran captured in

reticulo-endothelial cells in malignant diseases.

3) The percentage of bone marrow sideroblasts in patients with malignant

neoplasms showed a significant decrease with the mean value of 28 percent.

The evidences obtained above demonstrated that the erythropoietic activity in

patients with malignant neoplasms is maintained above normal, while there is

an evident impairment of iron release from reticulo-endothelial cells. However,

the mechanism responsible for the defect of iron release in malignancy is not

clear and required further study.

I. INTRODUCTION

Extensive studies on anemia and iron metabolism in patients with malig­

nant neoplasms have been made by many investigators1l-7l. The alterations in

the function of reticulo-endothelial system (RES) with which iron metabolism

~lj EE :9~ 1$ Received for publication September 16. 1967.

492 H. YAMADA

is closely related, have been found to be involved in cancer patients8>9>. One purpose of this paper is to delineate whether or not a common mechanism is involved in the erythropoietic activity in patients with malignant neoplasm as well as in patients with infection by means of ferrokinetic studies. And the second one is to elucidate the alteration of iron release from reticulo-endo­thelial cells in patients with malignant neoplasm by means of 59Fe labeled iron-dextran. Another one is to enumerate sideroblasts in bone marrow smears of cancer patients, although it may be of some limited help in detecting iron stores.

II. MATERIALS AND METHODS

Clinical Materials (1) Ferrokinetic studies. A. Controls: i) Normal subjects. Seven normal adults (from 26 to 56

years old) and seven aged subjects (from 63 to 75 years old) were studied for normal controls. ii) Patients with infections. Twelve patients with pulmonary tuberculosis and 4 patients with pulmonary abscess were studied.

B. Patients with malignant neoplasm: Eighteen patients with malignant neoplasm were studied. They were 5 lung cancer, 3 stomach cancer, 2 rectum cancer, 7 Hodgkin's disease and 1 reticulosarcoma patients. They had no complication such as blood loss, overt hemolysis and infection and had no treatment with radiation, chemotherapeutic drugs or blood transfusion which might change hemopoietic activity.

(2) Utilization studies with 59Fe labeled iron-dextran. Controls: Three normal subjects and 4 patients with iron deficiency anemia

were studied. Patients with malignant neoplasm: Fifteen patients with malignant neo­

plasms were studied. They were 4 lung cancer, 7 malignant lymphoma, 3 uterine carcinoma and one breast cancer patients. All patients were studied prior to institution of any treatment and the patients of far advanced or terminal stage were excluded. In addition, to check the influence of hemor­rhage on iron-dextran studies, 4 patients with stomach cancer or uterine cancer showing overt blood loss were studied as well.

(3) Sideroblast counting. Fresh bone marrow smears from 31 patients with various types of malig­

nant neoplasms as well as 12 normal subjects were used for sideroblast stain­ing. The materials from 7 patients with iron deficiency anemia and 9 patients with aplastic anemia were also stained for comparison.

Methods ( 1) Ferrokinetic studies.

CLINICAL STUDIES ON IRON KINETICS (II) 493

Ten pc of 59Fe in the form of ferric citrate was diluted to 10 millilitre with isotonic saline solution and injected intravenously without incubation with plasma.

Plasma iron disappearance rate (PID, T!), plasma iron turnover rate (PIT), percent red cell utilization of 59Fe ( 9-G'RCU), and red cell iron turnover rate (RCIT) were calculated by the method of Huff and associates with some modifications10l.

Serum iron was measured by the method of Matsubarall). The unsaturated iron-binding capacity was measured by a modification of the radioiron method of Tauxe12l.

(2) Utilization studies by 59Fe labeled iron-dextran. 59Fe labeled iron-dextran complex was supplied by Eisai pharmaceutical

Co., Ltd. Tokyo, Japan. Radioactivity corresponded originally to 20 to 40 pc

per 10 ml of iron-dextran containing 50 mg of elemental iron. One mg per kg body weight of iron-dextran with an activity of 5 to 10 pc was injected intra­venously. Plasma iron-dextran disappearance rates and 9& utilization of the radioiron for hemoglobin formation were measured. Blood samples were ob­tained at certain intervals, usually 10 minutes, 1, 2, 3, 4 and 6 hours after injection. Half time ( T ~ ) in activity was calculated from the extrapolated line of exponential 59Fe labeled iron-dextran disappearance curve. Blood speci­mens for 9& utilization of radioiron for hemoglobin formation were collected at every 5th day intervals for 3 to 4 weeks. The percent utilization was calcu­lated from the activity of the injected dose and the activity in red cells. The blood volume was determined from the plasma volume obtained by 59Fe iron­dextran dilution method and venous hematocrit.

(3) Staining method of bone marrow sideroblasts. Sideroblasts in bone marrow smears were stained by the method of Kaplan

with our modification13l . Namely, in this method, Feulgen reaction was used as a counterstaining instead of basic fuchsin or safranin solution.

( 1) Ferrokinetic studies . A. Controls: i l Normal subjects.

III. RESULTS

The ferro kinetic data in 7 healthy adults were as follows: PID ( T !) 96.1 ± 19.3 minutes, PIT 0.45 ± 0.07 mg/kg/day, 9CRCU 92.1 ± 8.7?(, and RCIT 0.41 ± 0.06 mgjkgjday. On the other hand, ferrokinetic data in 7 normal aged subjects were as follows: the mean values of PID (T ~ l, PIT, 9CRCU and RCIT to be 89.9±19.5 minutes, 0.49±0.07 mg/kgjday, 84.6 ± 6.5% and 0.42 ± 0.06 mg/ kg/day, respectively. The mean values of PID ( T ! ), PIT, 9-G'RCU and RCIT show no statistically significant differences between normal adults and aged.

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CLINICAL STUDIES ON IRON KINETICS (Il) 495

ii l Patients with infection. Patients with pulmonary tuberculosis were classified into minimal, moder­

ately advanced and far advanced groups (NTA-classification). These patients

were further divided grossly into 2 groups: less advanced group consisting of

minimal and moderately advanced cases and far advanced group. As shown

in Table 1, the mean value of PID ( T !) on 5 patients in the far advanced

group was 61 minutes, while that of 7 patients in the less advanced group was

99 minutes. The mean value of PIT on the less advanced group was 0.66

mg/kg/day and that on the far advanced group was 0.43 mgjkg/day. The

percent RCU were all within the normal range. The PID ( T ~ ) was accelerated

in all of the 4 patients with pulmonary abscess and the PIT was raised except

one patient (case No. 15) who showed normal value. The percent RCU on

these patients were within normal limits.

B. Patients with malignant neoplasm : a) The hematological and ferrokinetics data on 8 patients with malignant

lymphoma were shown in Table 2. All patients studied were not at advanced

stage. Serum iron levels were low in 3 patients, subnormal in 2 and normal

in 3 patients. PID (T~) was faster in 6 patients (case No. 17, 18, 19, 20, 21

and 24) and normal in 2 patients (case No. 22 and No. 23). PIT was moder­

ately elevated in 5 patients (case No. 17, 18, 20, 21 and 23), normal in 2 (case

No. 19 and 24) and low in one (case No. 22). The mean value of PIT in 8

patients with malignant lymphoma was 0.64 mgjkg/day. Percent RCU was

normal in all patients. Accordingly, RCIT was normal or increased. The mean

value of RCIT in patients with malignant lymphoma was 0.57 mgjkg/day.

b) Ferro kinetics data on patients with lung cancer were also shown in

Table 2. In most patients with lung cancer, levels of hemoglobin and serum

iron were normal or subnormal. PIT was increased in all patients. The mean

value of PIT was 0.88 mg/kgjday which is about twice normal. Percent RCU

was normal in all patients.

c) The lower column of Table 2 depicts the ferrokinetics data with hema­

tological data on patients with cancer of gastrointestinal tract. Patients with

overt blood loss were not included among the patients studied. Serum iron

levels were markedly low in most patients. Patients with cancer of the

gastrointestinal tract showed accelerated PID ( T ~ ), normal or increased PIT

and normal 9b'RCU. The mean value of PIT on these patients was 0.61 mg/

kg/ day and 0. 76 mg 1100 ml plasma. It is of great interest that the PIT in

mgjkg/day was elevated, while that in mg/100 ml plasma was within normal

range in patients with cancer of the gastrointestinal tract.

d) Fig. 1 illustrated the PIT on the patients with various kinds of malig­

nant neoplasms described above. The significant correlation between PID ( T ~ )

ilPQ. seru,:rn i.rop. level~ was fou,p<;l in patients with mali~nant neoplasPls. Th~

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CLINICAL STUDIES ON IRON KINETICS (II)

PIT

m;lk;/day

I. 5

1.0

... 0.5 ...

0 z 0

ii .. (') .. ~ !!. y

E !!. .. " .. " ~ :1 -g. 0 :1 ..

Plasma I ron Turnover R1les PIT

m;/looml. plaama

3.0

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=

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(')

" " n .. FIG. I. Plasma iron turnover rates in patients

with malignant neoplasm.

497

correlation coefficient was + 0. 71. Fig. 2 illustrated the ferro kinetics data ob· tained on patients with infections or malignant neoplasms. These ferrokinetics data demonstrated normal or increased rate of erythropoiesis in both infection and malignancy.

Lung Abscess and Tuberculosis Malignancy

S.l. I f. . 'II I : . ·I (l!ldil - .. . .. . =· "' "' ···:- .... : I I I I o I I I I 0 I

0 20 40 60 BO 100 !20 ~~ 20 40 ro HO 100 120 140

PI 0 T0t1 .. . . • h.· II . ~""'" .. . jl I I flO 0 I I I I I < .. in) 0 20 40 80 100 120 1400 20 40 60 80 100 120 140

PIT --+· II ··i .• ···•··· ·. .. I I I ' ' I

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<"I 0 1)0 100 0 60 100

Average of Normal Controls

FIG. 2. Ferrokinetics data in infection and malignancy.

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GLINICAL STUDIES ON IRON KINETICS (II) 499

( 2) Utilization studies by 59 Fe labeled iron-dextran

a) Table 3 depicts the results of 59Fe labeled iron-dextran studies with

hematological data on 15 patients with various kinds of malignant neoplasms

as well as those of the controls. The plasma iron-dextran disappearnce rate

( T ~ ) was quite different from that of 59Fe-citrate. No significant difference

in plasma iron-dextran disappearance rate was observed among the normal

subjects and patients with iron deficiency anemia or with malignant neoplasms

(Table 3). b) As shown in Fig. 3, the curves of 9C utilization of radioiron of iron­

dextran for hemoglobin synthesis is significantly lower in the patients with

malignant neoplasm than that of normal controls. The difference of 9C utili­

zation between the patients with malignant neoplasm and normal controls

is readily seen on the fifth day and becomes more evident later. Percent

utilization in normal subjects was 30.39C on the fifth day, 53.7 9C on the lOth

day and 63.0% on the 15th day, whearas that on patients with malignant neo­

plasm was 17.0% on the fifth day, 37.2% on the lOth day and 44.7% on the

15th day. No correlation among hemoglobin concentration, plasma iron-dextran

disappearance rate and % utilization for hemoglobin synthesis was observed

in patients with malignant neoplasms.

c) The results on patients with malignant neoplasm having overt blood

loss showed the % utilization more than that of the normal controls (Fig. 3

and Table 4).

% 100

75

50

25

0 5 10

---··· ·f··::_ I ron deficiency anemia

________ -------r- M oli 11 non c y w i I h

__./___. Blood loss

Nqrmal Controls

Malignant Neoplasm.s

15 Days after injection

FIG. 3. Percent incorporation of 59Fe (59Fe-dextran)

into circulating red blood cells.

500 H. YAMADA

TABLE 4. 59 Fe labeled Iron-Dextran Studies in Patients with Malignant Neoplasm Complicating Overt Blood Loss

I Hemo- Hemato- Serum PID Red Cell Case Utilization No. Age Sex Diagnosls I globin crit Iron T ~ --------------.

··-

I <%> (%) (pg/dl) (min) 5th lOth 20th( day )

23 24 25 26

Mean S.D.

62 72 45 37

M M F F

Gastric Cancer 73 30 II 75 33

Uterine Cancer 48 31 II 58 34

63.5 32.0

89 236 38 58 88 83 284 40 62 85 30 112 45 70 98 34 270 38 80 95

-59.0 225.5 1 40.3 67.5 91.5

2.9 8.4 5.3 ----------··-~------

( 3) Percentage of bone marrow sideroblast Table 5 and Fig. 4 show the percent of bone marrow sideroblasts in

patients with malignant neoplasms which varied from 7 to 52 percent with the mean value of 28.7 ± 12.7 %. The decrease in bone marrow sideroblasts was observed in patients with malignant neoplasm, as compared with those of normal controls, but was not so remarkable as seen in patients with iron de­ficiency anemia. The mean values of percent sideroblasts in iron deficiency anemia and aplastic anemia were 0.6 ± 0.9 .% and 86.0 ± 5.5% respectively.

TABLE 5. Data of Bone Marrow Sideroblasts (% )

Diagnosis

Malignant neoplasms (total) Pulmonary cancer !Malignant lymphoma Gastric cancer Uterine cancer Breast cancer

Normal controls !ron deficiency anemia Aplastic anemia ·

I. No. of I Mean cases Range S.D.

i 31 28.7 8 30.8

8-52--~--~2.7 - --

23-42 7.1 12 28.1 10- 51 14.1

3 21.0 10- 31 8.6 4 30.5 7-52 16.3 4 30.5 8- 51 15.7

--'--- -----------12 7 9

46.4 0.6

86.0

28-65 0- 2

79- 94

10.2 0.9 5.5

_______________ ___!_ __ __]_ ____________ _ _ __ _

IV. DISCUSSION

A number of investigations have been carried out to elucidate the patho­genesis of the anemia on patients with malignant neoplasm, which is not attributable to blood loss, infection and treatments with myelodepressive agents but appears to have inherent linking with some primary malignant process. It is a matter of course that the incidence and the degree of such anemia are quite varied according to kinds and spread of neoplasms or the stage of the diseases. Many investigators attributed the anemia to the shortening of the red cell life span. Although shortened erythrocyte suvival is a frequent find­ing in advanced carcinomas14', leukemia and lymphomas15 ' , hemolysis is usually

CLINICAL STUDIES ON IRON KINETICS (II)

'Yo 100

80

60

40

20

.. . . ----- ... ----.. .

: . . ·.·. : . .. . .. . .

·: -----.----. ...

. . 0~------~--~-~-~-~--~-.-~--~------~----__J

Norma I I ron Malignant Aplastic deficiency .Neoplasms Anemia

Anemia

FIG. 4. Sideroblasts (%) in malignant neoplasms.

501

not evident in the early stage of the diseases. The low serum iron concen­tration and the low levels of total iron-binding capacity were observed in the majority of patients in this study. The increased PIT and normal % RCU were two prominent features on ferrokinetic measurements in malignancy, as shown in the present study. The PIT was about 1.5 times normal and% RCU varied between 76 and 100%. The similar results to the present study were reported in two studies by Hyman and coworkers1> and Miller and coworkers21 •

There is no reason to believe that the age factor has decisive influence upon the results of ferrokinetic study, because ferrokinetic data on the aged were consistent with that of normal adults subjects. The similar results of ferro­kinetics on the aged were reported by Maekawa16 ' and Takaku17 1 •

Heilmeyer and associates reported a moderate depression of % RCU in malignant tumor as well as in infection and that a great portion of the in­creased PIT was routed to storage iron pool. On the contrary, the present study and the studies by Hyman1> and Miller2' showed no significant decrease of % RCU in malignant neoplasms. Be that as it is, the increased PIT is a characteristic feature for iron metabolism in patients with malignant neoplasm. Thus the results of ferrokinetic studies would indicate that there is no im­pairment in the utilization of iron by the precursors of erythrocytes in malig-

504 H. YAMADA

ACKNOWLEDGMENT

The author wishes to express cordial thanks to Professor S. Hibino for his sincere guidance and encouragement throughout this study and also to Dr. H. Ohta and Dr. M. Kubo for their kind advice and cooperation.

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