Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
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.
Cas
e N
o.
1 2 3 4 5 6 7
Mea
n
S.D
.
8 9 10
11
12
Mea
n
S.D
.
13
14
15
16
Mea
n S
.D.
Ag
e
50
25
43
34
23
49
53
38
36
51
59
44
69
40
62
69
---
--··-
-------
-------
Sex
I
M
M
M
M
M
M
M
M
M
M
M
M
M
M
F M
TA
BL
E 1
. H
emat
olo
gic
al a
nd
Ferr
ok
ineti
cs
Dat
a o
n P
ati
en
ts w
ith
Res
pir
ato
ry I
nfe
ctio
n
Dia
gn
osi
s I
Hem
o-
1 g
lob
in
(%J
Pu
lmo
nar
y T
ub
ercu
losi
s,
Min
imal
10
8
II
Min
imal
10
7 II
,
Mo
der
atel
y
105
II
, M
od
erat
ely
98
II
,
Mo
der
atel
y
100
II
, M
od
erat
ely
11
2 II
,
Mo
der
atel
y
92
103.
1
Pu
lmo
nar
y T
ub
ercu
losi
s,
Far
adv
ance
d
85
II
' II
94
II
'
II
71
II
II
80
II
' II
88
I 83
.6
Pu
lmo
nar
y A
bsc
ess
70
II
82
II
71
II
72
I 73
.7
I
Hem
ato
-R
etic
ulo
-cri
t cy
te
(%)
(%o
)
41
7
48
5 43
6
45
9 52
5
46
14
41
8
45.1
7.
7
44
8
42
5 34
11
38
10
39
7
39.4
8.
2
35
5 39
8
32
-30
-
34.0
Iro
n
TJ..
Ser
um
I P
ID
(f.l
gfdl
) (mi~)
mg
jkg
/ d
ay
130
99
1.00
60
101
0.32
11
4 11
3 0.
44
114
125
0.38
11
6 91
0.
50
153
90
1.45
77
74
0.
50
109.
1 99
.0
0.66
14
.9
0.38
49
63
0.38
32
39
0.40
64
90
0.
33
52
71
0.3
7 38
42
0.
66
47.o
1
61.0
0.
43
I 18
.9
0.12
70
26
1.72
10
1 45
0.
96
34
48
0.37
85
58
0.
71
72.5
1 44
.3
0.94
l1
.6
0.49
PIT
mg
/10
0
ml
pla
sma
1.31
0.59
1.
01
0 91
1.
27
1.70
1.
04
1.12
0
32
0.78
0.82
0.
71
0.73
0.
90
0.79
0.
07
2.69
2.
24
0.71
1.
47
1.78
0.
76
RC
U
(%)
I R
CIT
( m
g/k
g/d
ay
)
97
100 98
99
99
10
0 89
97.4
3.
6
100 97
79
100
95
I I 94
.2
1
7.8
I 95
96
10
0 95
96.5
2.
1
0.97
0.32
0.
43
0.38
0.
50
1.45
0.
45
0.64
0.
38
0.38
0.39
0
26
0.
37
0.63
0.41
0.
12
1.64
0.
92
0.37
0
.67
0.90
0.
47
.... <0
.... ~
><: ~ ~ ~
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~
Cas
e N
o.
17
18
19
20
21
22
23
24
Mea
n
S.D
.
25
26
27
28
29
Mea
n
S.D
.
3 3 3 3 3 0 I 2 3 4
Ag
e S
ex
13
M
I 6t
i M
35
M
19
M
58
M
57
F
15
M
43
F
I
60
M
I 52
M
45
F
51
F
I
50
M
I I 57
M
63
M
50
F
64
F
38
F
I M
ean
I
S.D
. --
--
-
TA
BL
E 2
. H
emat
olo
gic
al a
nd
Fer
rok
inet
ics
Dat
a o
n P
atie
nts
wit
h M
alig
nan
t N
eop
lasm
Dia
gn
osi
s
Ho
dg
kin
's d
isea
se
., ,t,• rr !!
t!
t!
Ret
icu
losa
rco
ma
Pu
lmo
nar
y C
ance
r !/
1/ " r:
Sto
mac
h C
ance
r 1/
., R
ecta
l C
ance
r f/
glo
bin
cri
t cy
te
Iro
n
T ~
I Hem
o-
Hem
ato
-R
etic
ula
· S
eru
m
I P
ID
PIT
(%J
(,%")
<%
ol
(pg
fdl)
(m
in)
mg
jkg
/day
m;t
;~~:
l
73
32
-12
0 77
33
14
52
73
36
2
25
43
20
-33
71
44
-
77
88
43
5 58
10
5 45
-
13.:l
72
32
5
23
75.2
35
.6
65.1
75
29
8 90
75
36
5
60
78
35
3 65
79
35
-
129
88
34
12
85
79.0
33
.8
7 84
.2
74
38
5 35
99
43
2
23
47
23
-33
75
29
2
63
86
32
11
24
76.2
33
5
I
66
41
43
4ti
42
86
113 18
56.9
28
.2
48
32
53
93
61
57.4
20
.2
74
27
42
77
27
49.4
22
.0
0.95
0.
82
0.39
0.
86
0.63
0.
33
0.64
0.
51
0.64
0
.21
1.14
1.
17
0.60
0.
76
0.71
0.88
0.
23
0.40
0.
60
0.74
0.
76
0.54
0.61
0.
13
1.82
1.
27
0.58
0
72
1.
83
0.67
1.
18
1.28
1.17
0.
46
1.88
1.
88
1.23
1.
39
1.39
1.55
0.
24
0.47
0.
8.5
0.79
0.
82
0.89
0.76
0.
15
37.6
I
~--------'--------
·-----~----'-----------
RC
U
I R
CIT
(9
b)
(mg
fkg
/day
)
90
93
82
76
97
85
89
98
88.8
7.
1
98
89
- 90
100
94.2
4.
8
95
95
100 79
100
93.8
7.
7
0.86
0.
76
0.32
0.
65
0.61
0.
28
0.57
0.
50
0.57
0.
16
0.39
0.
53
-0.
68
0.54
0.54
0.
10
1.08
1.
11
0.60
0.
60
0.71
0.82
0.
23
.. «::
Q) ;r: ~
:> ~
:>
tj :>
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
2.0
1.0 ...
0 ... "' z E " ~ ~ !!. :1 :1 c 0 .. " " " .. ..
(') n :. ... =o" .. ~ ~ n •" .. n n :1
" -· 0
:: .. ~ . -g. niP 0
~ :1 " ... ;:
=
..
;p "' .. 3
y
0
" " .. (')
~ .. (') " =on .. . . " n ~ n ~CP ~
(')
" " 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
llllg/f~Wd)J 0,5 1.0 1.6 2.0 0 o.o 1.0 I.& 2.0
'lfoRCU I ' ·+. II I ······i;~
<"I 0 1)0 100 0 60 100
Average of Normal Controls
FIG. 2. Ferrokinetics data in infection and malignancy.
... <.D
0
0
TA
BL
E 3
. D
ata
of
Iro
n U
tili
zati
on
Stu
die
s b
y 5
9F
e·la
bel
ed I
ron
-Dex
tran
·-·
----
-·
\Hem
og
lob
in H
emat
:cri
t s;
r~m I
---
---·
Cas
e P
ID
Red
Cel
l U
t ili
zati
on
of
59 F
e (
%)
No
. A
ge
Sex
D
iag
no
sis
T~
I <%
> <%
) (p
~/~1
) I (
min
) 5
th
lOt h
15
th
20
th
(Day
)
1 34
M
I N
or1~a
l I
88
46
135
I 22
2 26
57
64
69
2
19
M
96
40
78
216
26
41
58
3 31
M
II
10
2 45
84
I
201
39
63
67
_ .. _
Mean
I I
95.3
43
.7
99.0
I 21
3.0
30.3
53
.7
63.0
S
.D.
10.8
6.
1 9.
3 3.
7
4 33
F
I Iro
n D
efic
ien
cy A
nem
ia
I 32
24
24
I
183
60
94
99
5 26
F
30
19
18
I 16
2 45
77
8
6
II
I 6
19
F I
II
I 38
30
35
22
4 65
90
94
7
16
F I
II
33
18
15
I 19
5 85
95
10
0 -
~
I -----,--
-I
----
>< M
ean
33
.3
22.8
23
.0
192.
0 63
.8
89.0
94
.8
-~
S.D
. 23
.9
14.3
7.
7 5.
6 -
;;:::
I -~-.----____
_ ,._
tJ>
8 5
5
M
Pulm
ona~
y C
ancer
I
90
46
59
153
6 13
20
26
t1
tJ>
9
42
F 76
32
48
20
1 4
28
36
10
58
M
II
88
38
51
306
30
52
55
11
58
M
r1
(meta
stati
c)
68
35
75
207
0 3
5.0
8
12
71
M
Ret
i cu
losa
rco
ma
83
41
30
264
23
44
54
13
35
M
Ho
dg
kin
's
Dis
ease
75
40
80
21
9 12
39
49
14
16
M
I I
10
5 44
-
180
14
42
54
15
60
M
II
66
33
23
234
32
53
57
16
75
M
Ret
icu
losa
rco
ma
72
30
98
21
0 11
24
30
17
27
M
! I
72
39
24
16
7 25
50
62
18
53
M
H
od
gk
in's
D
isea
se
I
108
46
45
236
28
45
52
54
19
46
F
Ute
rin
e C
ance
r 63
35
12
4 24
8 22
45
53
20
32
F
II
55
30
48
165
17
38
45
47
21
45
F II
73
39
54
11
2 21
47
55
56
22
51
F
Bre
ast
Can
cer
I 65
29
29
25
2 10
35
43
- -
I ---
Mea
n
I 77
.3
37.1
56
.3
207.
3 17
.0
37.2
44
.7
S.D
. !
48.2
9.
5 14
.0
15.2
--
---
---------~
-~-----
-~-
-~-
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.
REFERENCES
1) Hyman, G. A. and Harvey, J. E., The pathogenesis of anemia in patients with carci·
noma, Amer. ]. Med., 19, 350, 1955. 2) Miller, A., Chodos, R. B., Emerson, C. P. and Ross, J. F., Studies of anemia and iron
metabolism in cancer, ]. Clin. Invest., 25, 1248, 1956. 3) Giannopoulos, P. P. and Bergsagel, D.E., The mechanism of the anemia associated
with Hodgkin's disease, Blood, 14, 856, 1959. 4) Lockner, D., Klinische Untersuchungen zur Krebsanaemie, Acta Haemat., 24, 186, 1961.
5) Heilmeyer, L. nnd Keiderling, W., Der Turnover des Haemoglobin- und des Nicht· haemoglobineisens beim Gesunden, beim Infekt und bei Malignen Tumoren, Dtsch. Med. Wschr., 84, 724, 1959.
6) v. Hevesy, G., Die Krebsanaemie. Naturwiss. Rundschau 1958, 247.
7) Keiderling, W. und Schmidt, H. A. E., Die infektioese und neoplastische Eisenstoff· wechsellstoerung. In Eisenstoffwechsel. Georg Thieme Verlag. Stuttgart., 1959, pp. 155.
8) Noyes, W. D., Bothwell, T. H. and Finch, C. A., The role of the reticuloendothelial
cell in iron metabolism, Brit. ]. Haemat., 6, 43, 1960. 9) Stern, K., Investigations on reticulo-endothelial function of cancer patients, ]. Lab.
Clin. Med., 26, 809, 1941. 10) Ohta, H. and Yamada, H., Ferrokinetic studies in blood disorders, ]ap. ]. Clin. Hemat.,
4, 125, 1963 (in Japanese). 11) Matsubara, T., Studies on the method for determination of iron in biological materials,
especially serum and whole blood-a new proposal for the standardization of the method, Acta Haemat. ]ap., 24, 434, 1961.
12) Yamada, H., Studies on the radioisotopic determination of the unsaturated iron-binding capacity of serum, ]ap. ]. Nucl. Med., 2, 146, 1965 (in Japanese).
13) Yamada, H., Kubo, M., Kawabata, S. and Takikawa, K., The application of the Feulgen reaction to the counterstaining of sideroblasts in bone marrow films and sections, Acta Haemat: jap., 28, 491, 1965.
14) Hyman, G. A., Studies on anemia of disseminated malignant neoplastic disease. I. The hemolytic factor, Blood, 9, 911, 1954.
15) Ross, J. F., Crokett, C. L. Jr. and Emerson, C. P., The mechanism of anemia in leukemia and malignant lymphoma, ]. Clin. Invest., 30, 668, 1951.
16) Maekawa, T. and Kinukasa, K., Hematologic studies on the aged, Acta Haemat. ]ap., 20( 3), Suppl., 105, 1957.
17) Takaku, F., Studies on the anemia in the aged-with a special reference to the pro
duction and destruction of erythrocytes, Acta Haemat. ]ap., 22, 464, 1959.
18) Cline, M. J. and Berline, N· I., Anemia in Hodgkin's disease, Cancer, 16, 526, 1963.
19) Kampschmidt, R. F. and Schultz, G. A., Absence of toxohormone in rat tumors free of bacterial contaminations, Cancer Res., 23, 751, 1963.
20) Kampschmidt, R. F. and Upchurch, H. F., Effect of bacterial contamination of the tumor on tumor-host relationships, Cancer Res., 23, 756, 1963.
21) Kampschmidt, R. F. and Clabaugh, W. A., Indications of involvement of the reticulo
endothelial system in alterations of iron metabolism produced by tumor extracts, J. tyqt. Cqnt;er lnst., 2;;, 713. 1960,
CLINICAL STUDIES ON IRON KINETICS (II) 505
22) Biozzi, G., Stiffel, C., Halpern, B. N. and Mouton, D., Etude de !a fonction phagocytaire du S. R. E. au cours du developpement de tumeur malignes experimenta les chez le rat et !a souris, Ann. lnst Pasteur (Paris), 94, 681, 1958.
23) Old, L. J., Clarke, D. A., Benacerraf, B. and Goldsmith; M., The reticulo-endothelial system and the neoplastic process, Ann. N. Y. Acad. Sci., 88, 264, 1960.
24) Hansen, H. A. and Weinfeld, A., Hemosiderin estimations and sideroblast counts in the differential diagnosis of iron deficiency and other anemias, Acta Med. Scand., 165, 333, 1959.
25) Saito, H., Studies on storage iron. The dynamic behavior of hemosiderin and ferritin under various experimental conditions, Nagoya]. Med. Sci., 21, 288, 1958.
26) Freireich, E. J., Miller, A., Emerson, C. P. and Ross, J. F., The effect of inflammation on the utilization of erythrocyte and transferrin bound radioiron for red cell production, Blood, 12, 972, 1957.
27) Haurani, F. I, Young, K. and Tocantins, L. M., Reutilization of iron in anemia com· plicating malignant neoplasms, Blood, 22, 73, 1963.
28) Urushizaki, 1., Studies of the anemia and iron metabolism in cancer, Metabol. Dis., 1, 28. 1964 (in Japanese).
29) Cruz, W. 0., Hahn, P. F. and Bale, W. F., Hemoglobin radioactive iron liberated by erythrocyte destruction (Acetyl phenylhydrazine) promptly reutilized to form new hemoglobin, Amer. ] . Physiol., 135, 595, 1942.