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Ferrokinetic studies in acute myocardial infarction
Ferrokinetic infarction
studies
in acute
myocardial
Ionah Barash, M.D.* Meir Djaldetti, M.D. Petah-l&pa,
Israel
Decreased serum iron is frequently observed in patients with acute myocardial infarction (AMI). Feldthusen and Lassen’ reported in 1954 a decrease in the serum iron level in patients with AM1 who did not have infections, as did also Myhrman and Wilander,z Brucknerova and Pojer,” and Handjani and associates.J Bass and Shapira5 described a series of 122 male and 24 female patients with AM1 who displayed hypoferremia. The lowest serum iron level measured (47.8 pg/lOO ml.) was found on the third day after the infarction, although in some of the patients a decrease in serum iron was already noticeable the day following the event. The serum iron values in these patients returned to their normal levels, without any specific treatment, at day 9 following the infarction. In a control group of 62 patients complaining of chest pains, but without myocardial infarction, there was no decrease in the serum iron. Extension of the infarction, or additional pulmonary embolism, was accompanied by a further decrease in the serum iron leve1.6 In most of the series the maximal decrease in the serum iron was noted at day 3 after the infarction.‘. B The aim of the present study was to clarify the mechanism of the decrease in serum iron in patients with AMI. Materials
and methods
Patients. Sixteen patients with AM1 and five patients either receiving steroids or suffering from From the Department of Internal Medicine “B,” Hasharon Hospital, Petah-Tiqva, and Tel-Aviv University Medical School, Israel. Part of this work was supported by a grant from the Chief Bureau, ministry of Health, of which M. D. is an established tor. Received
for publication
Reprint Hospital,
requests: Prof. Petah-Tiqva,
* Part
of M.D.
August,
Thesis,
July
19, 1974.
M. Djaldetti, Israel. Hebrew
Scientist investiga-
Dept.
University,
of Medicine
“B,”
Jerusalem,
Israel.
1975, Vol. 90, No. 2, pp. 159-164
Hasharon
diseases acting as stress factors (the control group) were examined. The AM1 patients consisted of 12 men in the age range 37 to 70 years (average age, 56.8 years) and four 58 to 69-yearold women (average age, 60.7 years). All patients with AM1 were treated with anticoagulants, such as heparin administered intravenously immediately after admission to the hospital and coumadin given orally on the subsequent days. Five patients had mild diabetes, controlled by diet only, four had hypertension, and one had suffered a cerebrovascular accident prior to admission. In one patient polycythemia was detected on admission. The diagnosis of AM1 was established on the basis of typical clinical and electrocardiographic (ECG) findings as well as the observed increases in serum glutamic oxaloacetic transaminase (SGOT), creatinine phosphate kinase (CPK), and lactic dehydrogenase (LDH) values. The control group consisted of four men, 43 to 57 years old (average age, 49.2 years), and one 73year-old woman. Two were admitted because of severe bronchial asthma, treated with steroids, two suffered from severe renal colic, and one from paroxysmal atria1 tachycardia and chest pains, but without AMI. Patients having chronic diseases, infections, bleeding, and conditions which could affect the iron metabolism were excluded from the study. Methods. Repeated ECG and routine blood examinations were performed in the early morning hours. Blood volume was detected by the method of Crispell, Porter, and Neiset,” using radioiodinated serum albumin (RISA) with a Picker Hemolitre Detector. The normal values are as follows: total blood volume, 70 ml. per kilogram; plasma volume, 30 ml. per kilogram. SGOT was examined by the method of Babson and associates“’ (normal values, 5 to 30 U.); LDH by the method of King and Morris” (normal
American
Heart
Journal
159
Barash
Table
and
Djaldetti
I. Hematological findings in patients with AM1 and control subjects (range and mean values) AMIpatients Day
Hemoglobin (GmJlOO Hematocrit (%) WBC ( /mm.3)
ml.)
1
12.7-18.5 (14.6) 39-53 (44.5) 8,400-18,700
(12,7’J’)) Platelets
( /mm.3)
Total blood volume (ml./Kg.) Plasma volume (ml./Kg.) Red cell mass (ml./Kg.)
Table
150,000-307,OOJl (220,000) 55.0-87.5 (73.5) 32.5-50 (43.0) 22.5-43.5 (31.2)
Day
3
12.1-20.0 (14.4) 35-57 (44.5) 6,300-21,200
(11&W 157,000-440,000 (241,000)
Day
Day
12
13.0-16.2 (14.2) 39-50 (43) 7,000-15,800
11.6-15.8 (14.0) 36-47 (42.5) 6,100-14,800
WOO) 151,000-470,000 (254,000)
145,000-467,000 (292,000)
(8,750)
Day
15
12.2-16.0 (13.8) 36-47 (41.5) 4,800-16,300
W’W
13.5-15.1 (14.1) 41-48 (44) 6,900-9,000
(7,240)
207,000-380,000 (292,000) 53.5-90.5 (74.5) 33.0-51.5 (43.0) 22.0-42.5 (31.5)
170,000-256,000 (188,400) 64.5-78.3 (73.2) 38-44 (41.6) 26-38 (31.2)
II. Biochemical findings in patients with AM1 and control subjects (range and mean values) AMI Day
SGOT (U.) LDH (U.) Total proteins (GmJlOO Albumin (Gm./lOO ml.) Globulin (Gm./lOO ml.)
ml.)
30-215 71-570 6.7-8.0 3.7-5.2 2.0-4.2
1 (103) (252) (7.1) (4.5) (2.8)
Day
3
29-116 (64) 50-373 (229) 6.2-8.1 (6.9) 3.2-4.5 (3.9) 2.3-3.4 (2.8)
Ill. Plasma ll-OHCS values in patients with AM1 and control subjects
Table
AMI Day Morning (pg/ 100 ml.) Night @g/100
1
24.8 + 3.0 15.7 f 3.0
patients Day
15
16.0 + 4.2 7.7 + 2.84
Control subjects, day 1 17.5 f 4.4 6.2 + 1.8
ml.)
values, 30 to 120 U.) 11-Hydroxycorticosteroids (ll-OHCS) were determined by the method of de Moor and associates’* (normal morning values, 13 to 23 pg/lOO ml., evening values, 4 to 7 pg/lOO ml.). Serum iron and total iron-binding capacity were determined by the methods of Trinder13 and Ressler and Zak” (normal values, 80 to 120 and 230 to 350 pg/lOO ml., respectively) and 24 hour urine iron excretion by the method of Fisher and Pricels (normal values, 0.5 to 1.0 mg.). 59Fehalftime plasma clearance was detected by the method of Lajtha’” (normal values, within the range of 70 to 120 minutes) and its incorporation into the red blood cells was tested according to the method of Beierwaltes, Johnson, and Solari.17
160
9
Control subjects, day 1
Patients Day
20-35 55-194 6.2-7.4 3.4-4.5 2.4-3.4
9 (29) (105) (6.9) (3.9) (2.9)
Day
12
5-10 (7.8) 62-117 (82.5) 6.5-7.6 (7.1) 3.6-4.1 (3.75) 2.8-3.9 (3.3)
Day
15
12-15 (13) 52-104 (79) 6.6-7.8 (7.0) 3.5-4.8 (4.1) 2.3-3.3 (2.9)
Control subjects, day 1 20-25 (21.4) 49-86 (65.6) 6.6-7.4 (7.1) 4.1-4.5 (4.3) 2.5-2.9 (2.7)
Normally 75 to 85 per cent of the injected radioactive iron is detected in the red blood cells 8 to 12 days after the injection. The abovementioned tests, except for the blood volume, urine iron excretion, and ferrokinetics, were performed on days 3, 9, 12, and 15 following admission of patients with AMI. Blood volume and ferrokinetic studies were made on day 15. Patients of the control group were examined on day 1 after their admission. Results ECG. In 10 of the patients there were findings compatible with anterior wall MI; in four, posterior inferior; in two, posterior wall MI. Eight patients showed premature auricular or ventricular beats or conductive disturbances. Bradycardia of 35 beats per minute due to complete A-V block was noted in one patient. The ECG was normal in all but one patient of the control group; this patient had attacks of supraventricular tachycardia. Blood examinations. The results of routine blood examinations and the blood volume values in AM1 patients and control subjects are given in Table I. Except for an initial leukocytosis in most
August,
1975, Vol. 90, No. 2
Ferrokinetic
Table IV. Serum iron, total
iron-binding
capacity,
and iron excretion
studies
in acute myocardial
in urine in patients
infarction
with AM1
and control subjects 1
AMI patients Day I Iron (j&100 ml.) TIBC (pg/lOO ml.) Iron in urine (mgJ24
--
34.3 335
hr.)
0.75
Day 3
-+ 19 f 4.2 f
28.6 361
2 15.7 f 45.8
Day 9 64.9 361
Day 15
Day 12
z!z 8.2
90
+ 20.5
2 34.8
399
rt 55.6
98.3 386
0.3
0.71
Control subjects, day 1
’
+ 26.8
f05.4
rt 22.5
t
10x
+ 69.6
t
35.9 0.11
0.48
-t
0.13
IWgo-
IRON
ml----------706050-
I
3
12
15
DAYS OF ADMk6ION Fig. 1. Serum iron levels of patients with days after admission. The dotted line marks serum iron in controls.
AM1 at different the lower limit of
of the patients with AM1 and elevated hemoglobin and hematocrit values in one patient, all results were within normal limits. In Table II data obtained from the biochemical tests are presented. The AM1 patients show elevated SGOT and LDH levels. Morning plasma ll-OHCS values (Table III) were slightly high in patients with AM1 on the day of admission and much higher than the values measured on day 15 in the same patients (54 per cent, p < 0.02). The night plasma ll-OHCS values were also higher than normal on day 1 and much higher (104 per cent) than the values found on day 15 after admission (p < 0.01). Serum iron, iron-binding capacity, and the 24 hour iron excretion in the urine are shown in Table IV. The lowest serum iron values were found at day 3 after the infarction; they rise to the lower limit of the normal at day 9 and to within the normal range at day 12. There was a highly significant statistical difference (p < 0.001) between the serum iron levels at days 1 and 15. Fig. 1 shows serum iron levels on
American Heart Journal
l.oi-i*D*y
-
-
-
-
-
---#-&
--
-__
Fig. 2. Serum iron and plasma cortisol levels and iron excretion in urine in five patients with AMI. The dotted lines mark the lower limit of serum iron and the range of iron excretion in urine in controls.
different days after admission in patients with AMI. There was no difference in the 24 hour iron excretion in the urine of patients with AM1 on days 1 and 15 after admission. Fig. 2 illustrates the relationship between serum iron, plasma llOHCS, and urine iron excretion. It is evident that the difference in serum iron levels on days 1 and 15 does not result from iron loss in the urine. The half time 59Fe plasma clearance values of patients with AM1 on days 1 and 15 are shown in Fig. 3. On day one, these values ranged from 45 to 98 minutes (mean, 72 + 15 minutes), that is, they were reduced immediately after the event but returned to normal 2 weeks thereafter-in all but one patient with polycythemia, where the value remained low. The difference between the mean half-time 59Fe plasma clearance values on days 1 and 15 was highly significant (p < 0.001). There was no relationship between the severity of clinical signs and iron clearance rates. The ““Fe
161
Barash
and
Djaldetti
::::‘.I .:: NORMAL RANSE E Y. I. PATIENTS -- --- MEAN MI. VALUE
HOURS
Fig. 3. Half-time
I ONSET
59Fe plasma
2 3 OF ADMISSION
clearance
4
in patients
I
5
2
IS DAYS
with
AM1
AFTER
at the onset
3
4
5
ADMISSION
and 15 days
after
admission.
Discussion
I
60-
4. 59Fe utilization compared with normal values are shown. Fig.
- ---
MEAN
NOWAL
-.-.-
MEAN
M.I.
curve in patients with AM1 as control subjects. The range and mean
utilization curve of patients with Ati1 is shown in Fig. 4. Ninety per cent of the radioiron was incorporated in the red blood cells by day 6. The plasma iron transport rate* is normally in the range of 20 to 40 mg. per day. In patients with AMI, this value on day 1 ranged from 20.0 to 70.24 mg. per day (mean, 36.92). The iron metabolism could be regarded as generally almost normal in these patients; the high value of 70.24 mg. per day is the exceptional one and it was found in the patient with polycythemia. * Calculated plasma half-time
162
from
the formula:
‘On (Pg’1oo m1.) clearance (min.)
x plasma
volume
(ml./Kg.)
The results of the present study confirm previous observations of a decrease in serum iron in patients with AMI.‘-” We were able to show that this decrease in the acute phase of the disease is due to rapid iron plasma clearance. The normal iron plasma transport rate does not support the possibility of imparied iron metabolism; the rapid iron plasma clearance and the early incorporation of iron into the red blood cells show that the plasma iron in patients with AM1 is mostly cleared by the cells of the bone marrow. It cannot be excluded that some of the iron is incorporated into the reticuloendothelial cells of other organs, such as the liver and spleen. The patients’ condition did not permit a more detailed tracing of the radioiron. We can find no explanation for the decrease in serum iron in patients with AMI. Myhrman and Wilander’ suggested that it is a result of the inflammation which usually accompanies infarctions. It has been shown that producing a sterile abscess in animals by injection of therebentine decreases serum iron by 50 per cent.18 The decrease of serum iron in our patients with AM1 cannot be explained by the mechanism of inflammation, principally because of the increased iron incorporation into the red blood cells, which is not the case in patients with inflammation. Lajtha16 reported low serum iron with rapid iron clearance and low incorporation into the red blood cells in cases of inflammation. Kampschmidt and UpchurchS9 proposed a humoral mechanism activated by endotoxins. Although the urinary excretion of iron in AM1 patients was slightly higher than in control subjects, the amount of iron excreted was still in
August,
1975, Vol. 90, No. 2
Fermkinetic
the normal range and could not explain the lower serum iron in these patients. To the best of our knowledge, heparin administration has no effect on ferrokinetics. As for the coumadin, its effect on the ferrokinetics may be excluded, since the different results of these studies at the onset and 15 days after admission were obtained when the patients were on continuous anticoagulant treatment. Steroids have been shown to have a sideropenic effect. Prinzie and Lederer*” demonstrated a 64 per cent decrease in serum iron 16 days after cortisone administration to rats. A similar effect was found by Lederer?’ in patients treated with 10 mg. of prednisone per day for 3 to 5 months. Increase of plasma cortisol has been demonstrated in patients with AMI. Logan and Murdoch” reported a threefold increase of plasma cortisol in the majority of their 46 patients with AM1 during the first 10 hours following the event. The values had fallen to normal 90 hours later. Patients with AM1 in the present series showed an increase in ll-OHCS which occurred mainly in the evening hours. Although this increase was not as pronounced as the cases quoted in other reports, Z2it is possible that it caused a decrease in the serum iron, Patients in the present study receiving steroids or with diseasesacting as stress factors did not show sideropenia, but these conditions differ in many aspects from the stress accompanying AMI.
We are indebted to Dr. Lubin. from the Radioisotope Institute, for his helpful advice: to the heads of medical departments of Beilinson Hospital, Petah-Tiqva, for the opportunity to study some of t,heir patients; and to Drs. J. Ben-Bassat and A. Hershko for their helpful sl[ggestions.
REFERENCES I.
2.
3. 4.
5.
6.
7.
8.
American
Heart
Journal
infarction
ferrokinetics were within the normal Eirnits at, all times. Since in AM1 patients the ll-OHCS values were found to be significantly higher on the day following the infarction than on day i5 after the event, it is suggested that the decrease in iron concentration in these patients may braconnected with changes in plasma ll..OHC”S Irv+;l~.
Summary
Serum iron levels were determined in 16 patients with AM1 at different days following the event and in five patients either treated with steroids or suffering from diseasesacting as stress factors. Patients with AM1 showed a marked decrease in serum iron concentrations, the lowest value being recorded at day 3 after the event; serum iron returned to normal level at day 12. These alterations in iron concentration were not accompanied by changes in the 24 hour urine excretion of iron. On the other hand, a significant shortening of the half-time 59Feplasma clearance and an early increase in 5”Fe incorporation into the red blood cells were found immediately after the event. These values returned to normal in all but one patient, who had in addition polycythemia. In the five patients comprising the control group, serum iron, iron excretion in urine, and
.studies rn acute mv~c~~rdi~ri
9.
10.
11. 12.
13. 14. 15.
16. 17
Feldthusen, LJ., and Lassen, N. A.. Serum iron after coronary occlusion and traumatic inlurks. Acta Med. &and. 150:53, 1954. Myhrman, G., and Wilander, 0.: Inflammatory anemia and serum iron changes in myocardial infarction, Acta Med. Stand. 151:407, 1955. Brucknerova, O., and Pojer. J.: Serum iron levels in congestive heart failure, Cor Vasa 5:177. 1963. Handjani, A. M., Banihashemi, A., Rafiee. f-t., and Tolou, H.: Serum iron in acute myocardial infarction. Blut 23:363, 1971. Bass, D., and Shapira, J.: The values of serum iron levels as a diagnostic aid in acute myocardial infarction, M.D. Thesis, Hadassah Medical School &The Hebrew IJniversity, Jerusalem, 1965. Gibson, I. I.. Kelly, A. M., and Wang, 1. Serum iron values following acute myocardial inf’arcti~m. Scot. Med. ,J. 14:1X, 1969. Nitter-Hauge, S.: Serum iron, total iron binding capacity and transferrin following acute tnyocardial infarction, Arta Med. Stand. 190:337, 1971. Syrkis. I., and Machtey, I.: Hypoferremin in acute myocardial infarction, Am. Geriatr. Sot. 21:2&X, 197:I. CrispelI, K. R., Porter, B., and Neiset. R. ‘I’.: Studies of plasma volume using human serum albumm tagged with radioactive iodine-131. J. Clin. Invest. 29:51X 1950. Babson, A. L., Shapiro, P. 0.. Williams, P. A.. and Philips, G. E.: The use of diazonium salt for the determination of glutamic oxaloacetic t,ransaminasr in seruln. (Yin. Chim. Acta 71199, 1962. King, J., and Morris, M. B.: Serum enzyme act.lvity in the normal newborn infant,, Arch. Dis. Child. 36:604, 1961. de Moor, P.. Steeno, 0.. Raskin, M., and Hendrix. A.: Fiuorometric determination of free plasma 11 -hydroxycorticosteroids in man, Acta Endocrinol. 33:297, 1960. Trinder, I’.: The improved determinatic~n :)I’ iron in serum, ,J. Clin. Pathol. 9:170, 1956. Ressler, N., and Zak, B.: Serum unsaturalcd non binding capacity, J. Clin. Pathol. 30:RT, 195X. Fisher, D. S., and Price, D. C.: A simple serum iron method using the new sensitive chromogen tripyridyl-sthiazine, Clin. Chem. 10:21, 1964. Lajtha, I,. G.: The use of isotol:+ iti hematology. Toronto, 1961, Ryerson Press, p. 49. Beierwaltes, W. H., Johnson, P. C’.. and Solari. A. J.: Clinical use of radioisotopes, Philadelphi:1, 1957, W.B. Saunde1-s Company. p. 288.
163
Barash
18.
19.
20.
164
and
Djaldetti
Quastel, M. R., and Ross, J. F.: The effect of acute inflammation on the utilization and distribution of transfer-r-in bound and erythrocyte radioiron, Blood 28:738, 1966. Kampschmidt, R F., and Upchurch, H. F.: Lowering of plasma iron concentration in the rat with leukocytic extracts, Am. J. Physiol. 216:1287, 1969. Prinzie, A., and Lederer, J.: Endocrine control of iron metabolism. VIII. Influence of cortisone on the plasma
21.
22.
level of iron male and female rabbits, Ann. Endocrinol. 21:158,1969. Lederer, J.: Endocrine control of iron metabolism. XV. Endocrine origin of the difference in the composition of blood in men and women, Ann. Endocrinol. 2:249, 1962. Logan, R. W., and Murdoch, W. R.: Blood levels of hydrocortisone, transaminases, and cholesterol after myocardial infarction, Lancet 2521, 1966.
August,
1975, Vol. 90, No. 2
studies
in acute
myocardial
Ionah Barash, M.D.* Meir Djaldetti, M.D. Petah-l&pa,
Israel
Decreased serum iron is frequently observed in patients with acute myocardial infarction (AMI). Feldthusen and Lassen’ reported in 1954 a decrease in the serum iron level in patients with AM1 who did not have infections, as did also Myhrman and Wilander,z Brucknerova and Pojer,” and Handjani and associates.J Bass and Shapira5 described a series of 122 male and 24 female patients with AM1 who displayed hypoferremia. The lowest serum iron level measured (47.8 pg/lOO ml.) was found on the third day after the infarction, although in some of the patients a decrease in serum iron was already noticeable the day following the event. The serum iron values in these patients returned to their normal levels, without any specific treatment, at day 9 following the infarction. In a control group of 62 patients complaining of chest pains, but without myocardial infarction, there was no decrease in the serum iron. Extension of the infarction, or additional pulmonary embolism, was accompanied by a further decrease in the serum iron leve1.6 In most of the series the maximal decrease in the serum iron was noted at day 3 after the infarction.‘. B The aim of the present study was to clarify the mechanism of the decrease in serum iron in patients with AMI. Materials
and methods
Patients. Sixteen patients with AM1 and five patients either receiving steroids or suffering from From the Department of Internal Medicine “B,” Hasharon Hospital, Petah-Tiqva, and Tel-Aviv University Medical School, Israel. Part of this work was supported by a grant from the Chief Bureau, ministry of Health, of which M. D. is an established tor. Received
for publication
Reprint Hospital,
requests: Prof. Petah-Tiqva,
* Part
of M.D.
August,
Thesis,
July
19, 1974.
M. Djaldetti, Israel. Hebrew
Scientist investiga-
Dept.
University,
of Medicine
“B,”
Jerusalem,
Israel.
1975, Vol. 90, No. 2, pp. 159-164
Hasharon
diseases acting as stress factors (the control group) were examined. The AM1 patients consisted of 12 men in the age range 37 to 70 years (average age, 56.8 years) and four 58 to 69-yearold women (average age, 60.7 years). All patients with AM1 were treated with anticoagulants, such as heparin administered intravenously immediately after admission to the hospital and coumadin given orally on the subsequent days. Five patients had mild diabetes, controlled by diet only, four had hypertension, and one had suffered a cerebrovascular accident prior to admission. In one patient polycythemia was detected on admission. The diagnosis of AM1 was established on the basis of typical clinical and electrocardiographic (ECG) findings as well as the observed increases in serum glutamic oxaloacetic transaminase (SGOT), creatinine phosphate kinase (CPK), and lactic dehydrogenase (LDH) values. The control group consisted of four men, 43 to 57 years old (average age, 49.2 years), and one 73year-old woman. Two were admitted because of severe bronchial asthma, treated with steroids, two suffered from severe renal colic, and one from paroxysmal atria1 tachycardia and chest pains, but without AMI. Patients having chronic diseases, infections, bleeding, and conditions which could affect the iron metabolism were excluded from the study. Methods. Repeated ECG and routine blood examinations were performed in the early morning hours. Blood volume was detected by the method of Crispell, Porter, and Neiset,” using radioiodinated serum albumin (RISA) with a Picker Hemolitre Detector. The normal values are as follows: total blood volume, 70 ml. per kilogram; plasma volume, 30 ml. per kilogram. SGOT was examined by the method of Babson and associates“’ (normal values, 5 to 30 U.); LDH by the method of King and Morris” (normal
American
Heart
Journal
159
Barash
Table
and
Djaldetti
I. Hematological findings in patients with AM1 and control subjects (range and mean values) AMIpatients Day
Hemoglobin (GmJlOO Hematocrit (%) WBC ( /mm.3)
ml.)
1
12.7-18.5 (14.6) 39-53 (44.5) 8,400-18,700
(12,7’J’)) Platelets
( /mm.3)
Total blood volume (ml./Kg.) Plasma volume (ml./Kg.) Red cell mass (ml./Kg.)
Table
150,000-307,OOJl (220,000) 55.0-87.5 (73.5) 32.5-50 (43.0) 22.5-43.5 (31.2)
Day
3
12.1-20.0 (14.4) 35-57 (44.5) 6,300-21,200
(11&W 157,000-440,000 (241,000)
Day
Day
12
13.0-16.2 (14.2) 39-50 (43) 7,000-15,800
11.6-15.8 (14.0) 36-47 (42.5) 6,100-14,800
WOO) 151,000-470,000 (254,000)
145,000-467,000 (292,000)
(8,750)
Day
15
12.2-16.0 (13.8) 36-47 (41.5) 4,800-16,300
W’W
13.5-15.1 (14.1) 41-48 (44) 6,900-9,000
(7,240)
207,000-380,000 (292,000) 53.5-90.5 (74.5) 33.0-51.5 (43.0) 22.0-42.5 (31.5)
170,000-256,000 (188,400) 64.5-78.3 (73.2) 38-44 (41.6) 26-38 (31.2)
II. Biochemical findings in patients with AM1 and control subjects (range and mean values) AMI Day
SGOT (U.) LDH (U.) Total proteins (GmJlOO Albumin (Gm./lOO ml.) Globulin (Gm./lOO ml.)
ml.)
30-215 71-570 6.7-8.0 3.7-5.2 2.0-4.2
1 (103) (252) (7.1) (4.5) (2.8)
Day
3
29-116 (64) 50-373 (229) 6.2-8.1 (6.9) 3.2-4.5 (3.9) 2.3-3.4 (2.8)
Ill. Plasma ll-OHCS values in patients with AM1 and control subjects
Table
AMI Day Morning (pg/ 100 ml.) Night @g/100
1
24.8 + 3.0 15.7 f 3.0
patients Day
15
16.0 + 4.2 7.7 + 2.84
Control subjects, day 1 17.5 f 4.4 6.2 + 1.8
ml.)
values, 30 to 120 U.) 11-Hydroxycorticosteroids (ll-OHCS) were determined by the method of de Moor and associates’* (normal morning values, 13 to 23 pg/lOO ml., evening values, 4 to 7 pg/lOO ml.). Serum iron and total iron-binding capacity were determined by the methods of Trinder13 and Ressler and Zak” (normal values, 80 to 120 and 230 to 350 pg/lOO ml., respectively) and 24 hour urine iron excretion by the method of Fisher and Pricels (normal values, 0.5 to 1.0 mg.). 59Fehalftime plasma clearance was detected by the method of Lajtha’” (normal values, within the range of 70 to 120 minutes) and its incorporation into the red blood cells was tested according to the method of Beierwaltes, Johnson, and Solari.17
160
9
Control subjects, day 1
Patients Day
20-35 55-194 6.2-7.4 3.4-4.5 2.4-3.4
9 (29) (105) (6.9) (3.9) (2.9)
Day
12
5-10 (7.8) 62-117 (82.5) 6.5-7.6 (7.1) 3.6-4.1 (3.75) 2.8-3.9 (3.3)
Day
15
12-15 (13) 52-104 (79) 6.6-7.8 (7.0) 3.5-4.8 (4.1) 2.3-3.3 (2.9)
Control subjects, day 1 20-25 (21.4) 49-86 (65.6) 6.6-7.4 (7.1) 4.1-4.5 (4.3) 2.5-2.9 (2.7)
Normally 75 to 85 per cent of the injected radioactive iron is detected in the red blood cells 8 to 12 days after the injection. The abovementioned tests, except for the blood volume, urine iron excretion, and ferrokinetics, were performed on days 3, 9, 12, and 15 following admission of patients with AMI. Blood volume and ferrokinetic studies were made on day 15. Patients of the control group were examined on day 1 after their admission. Results ECG. In 10 of the patients there were findings compatible with anterior wall MI; in four, posterior inferior; in two, posterior wall MI. Eight patients showed premature auricular or ventricular beats or conductive disturbances. Bradycardia of 35 beats per minute due to complete A-V block was noted in one patient. The ECG was normal in all but one patient of the control group; this patient had attacks of supraventricular tachycardia. Blood examinations. The results of routine blood examinations and the blood volume values in AM1 patients and control subjects are given in Table I. Except for an initial leukocytosis in most
August,
1975, Vol. 90, No. 2
Ferrokinetic
Table IV. Serum iron, total
iron-binding
capacity,
and iron excretion
studies
in acute myocardial
in urine in patients
infarction
with AM1
and control subjects 1
AMI patients Day I Iron (j&100 ml.) TIBC (pg/lOO ml.) Iron in urine (mgJ24
--
34.3 335
hr.)
0.75
Day 3
-+ 19 f 4.2 f
28.6 361
2 15.7 f 45.8
Day 9 64.9 361
Day 15
Day 12
z!z 8.2
90
+ 20.5
2 34.8
399
rt 55.6
98.3 386
0.3
0.71
Control subjects, day 1
’
+ 26.8
f05.4
rt 22.5
t
10x
+ 69.6
t
35.9 0.11
0.48
-t
0.13
IWgo-
IRON
ml----------706050-
I
3
12
15
DAYS OF ADMk6ION Fig. 1. Serum iron levels of patients with days after admission. The dotted line marks serum iron in controls.
AM1 at different the lower limit of
of the patients with AM1 and elevated hemoglobin and hematocrit values in one patient, all results were within normal limits. In Table II data obtained from the biochemical tests are presented. The AM1 patients show elevated SGOT and LDH levels. Morning plasma ll-OHCS values (Table III) were slightly high in patients with AM1 on the day of admission and much higher than the values measured on day 15 in the same patients (54 per cent, p < 0.02). The night plasma ll-OHCS values were also higher than normal on day 1 and much higher (104 per cent) than the values found on day 15 after admission (p < 0.01). Serum iron, iron-binding capacity, and the 24 hour iron excretion in the urine are shown in Table IV. The lowest serum iron values were found at day 3 after the infarction; they rise to the lower limit of the normal at day 9 and to within the normal range at day 12. There was a highly significant statistical difference (p < 0.001) between the serum iron levels at days 1 and 15. Fig. 1 shows serum iron levels on
American Heart Journal
l.oi-i*D*y
-
-
-
-
-
---#-&
--
-__
Fig. 2. Serum iron and plasma cortisol levels and iron excretion in urine in five patients with AMI. The dotted lines mark the lower limit of serum iron and the range of iron excretion in urine in controls.
different days after admission in patients with AMI. There was no difference in the 24 hour iron excretion in the urine of patients with AM1 on days 1 and 15 after admission. Fig. 2 illustrates the relationship between serum iron, plasma llOHCS, and urine iron excretion. It is evident that the difference in serum iron levels on days 1 and 15 does not result from iron loss in the urine. The half time 59Fe plasma clearance values of patients with AM1 on days 1 and 15 are shown in Fig. 3. On day one, these values ranged from 45 to 98 minutes (mean, 72 + 15 minutes), that is, they were reduced immediately after the event but returned to normal 2 weeks thereafter-in all but one patient with polycythemia, where the value remained low. The difference between the mean half-time 59Fe plasma clearance values on days 1 and 15 was highly significant (p < 0.001). There was no relationship between the severity of clinical signs and iron clearance rates. The ““Fe
161
Barash
and
Djaldetti
::::‘.I .:: NORMAL RANSE E Y. I. PATIENTS -- --- MEAN MI. VALUE
HOURS
Fig. 3. Half-time
I ONSET
59Fe plasma
2 3 OF ADMISSION
clearance
4
in patients
I
5
2
IS DAYS
with
AM1
AFTER
at the onset
3
4
5
ADMISSION
and 15 days
after
admission.
Discussion
I
60-
4. 59Fe utilization compared with normal values are shown. Fig.
- ---
MEAN
NOWAL
-.-.-
MEAN
M.I.
curve in patients with AM1 as control subjects. The range and mean
utilization curve of patients with Ati1 is shown in Fig. 4. Ninety per cent of the radioiron was incorporated in the red blood cells by day 6. The plasma iron transport rate* is normally in the range of 20 to 40 mg. per day. In patients with AMI, this value on day 1 ranged from 20.0 to 70.24 mg. per day (mean, 36.92). The iron metabolism could be regarded as generally almost normal in these patients; the high value of 70.24 mg. per day is the exceptional one and it was found in the patient with polycythemia. * Calculated plasma half-time
162
from
the formula:
‘On (Pg’1oo m1.) clearance (min.)
x plasma
volume
(ml./Kg.)
The results of the present study confirm previous observations of a decrease in serum iron in patients with AMI.‘-” We were able to show that this decrease in the acute phase of the disease is due to rapid iron plasma clearance. The normal iron plasma transport rate does not support the possibility of imparied iron metabolism; the rapid iron plasma clearance and the early incorporation of iron into the red blood cells show that the plasma iron in patients with AM1 is mostly cleared by the cells of the bone marrow. It cannot be excluded that some of the iron is incorporated into the reticuloendothelial cells of other organs, such as the liver and spleen. The patients’ condition did not permit a more detailed tracing of the radioiron. We can find no explanation for the decrease in serum iron in patients with AMI. Myhrman and Wilander’ suggested that it is a result of the inflammation which usually accompanies infarctions. It has been shown that producing a sterile abscess in animals by injection of therebentine decreases serum iron by 50 per cent.18 The decrease of serum iron in our patients with AM1 cannot be explained by the mechanism of inflammation, principally because of the increased iron incorporation into the red blood cells, which is not the case in patients with inflammation. Lajtha16 reported low serum iron with rapid iron clearance and low incorporation into the red blood cells in cases of inflammation. Kampschmidt and UpchurchS9 proposed a humoral mechanism activated by endotoxins. Although the urinary excretion of iron in AM1 patients was slightly higher than in control subjects, the amount of iron excreted was still in
August,
1975, Vol. 90, No. 2
Fermkinetic
the normal range and could not explain the lower serum iron in these patients. To the best of our knowledge, heparin administration has no effect on ferrokinetics. As for the coumadin, its effect on the ferrokinetics may be excluded, since the different results of these studies at the onset and 15 days after admission were obtained when the patients were on continuous anticoagulant treatment. Steroids have been shown to have a sideropenic effect. Prinzie and Lederer*” demonstrated a 64 per cent decrease in serum iron 16 days after cortisone administration to rats. A similar effect was found by Lederer?’ in patients treated with 10 mg. of prednisone per day for 3 to 5 months. Increase of plasma cortisol has been demonstrated in patients with AMI. Logan and Murdoch” reported a threefold increase of plasma cortisol in the majority of their 46 patients with AM1 during the first 10 hours following the event. The values had fallen to normal 90 hours later. Patients with AM1 in the present series showed an increase in ll-OHCS which occurred mainly in the evening hours. Although this increase was not as pronounced as the cases quoted in other reports, Z2it is possible that it caused a decrease in the serum iron, Patients in the present study receiving steroids or with diseasesacting as stress factors did not show sideropenia, but these conditions differ in many aspects from the stress accompanying AMI.
We are indebted to Dr. Lubin. from the Radioisotope Institute, for his helpful advice: to the heads of medical departments of Beilinson Hospital, Petah-Tiqva, for the opportunity to study some of t,heir patients; and to Drs. J. Ben-Bassat and A. Hershko for their helpful sl[ggestions.
REFERENCES I.
2.
3. 4.
5.
6.
7.
8.
American
Heart
Journal
infarction
ferrokinetics were within the normal Eirnits at, all times. Since in AM1 patients the ll-OHCS values were found to be significantly higher on the day following the infarction than on day i5 after the event, it is suggested that the decrease in iron concentration in these patients may braconnected with changes in plasma ll..OHC”S Irv+;l~.
Summary
Serum iron levels were determined in 16 patients with AM1 at different days following the event and in five patients either treated with steroids or suffering from diseasesacting as stress factors. Patients with AM1 showed a marked decrease in serum iron concentrations, the lowest value being recorded at day 3 after the event; serum iron returned to normal level at day 12. These alterations in iron concentration were not accompanied by changes in the 24 hour urine excretion of iron. On the other hand, a significant shortening of the half-time 59Feplasma clearance and an early increase in 5”Fe incorporation into the red blood cells were found immediately after the event. These values returned to normal in all but one patient, who had in addition polycythemia. In the five patients comprising the control group, serum iron, iron excretion in urine, and
.studies rn acute mv~c~~rdi~ri
9.
10.
11. 12.
13. 14. 15.
16. 17
Feldthusen, LJ., and Lassen, N. A.. Serum iron after coronary occlusion and traumatic inlurks. Acta Med. &and. 150:53, 1954. Myhrman, G., and Wilander, 0.: Inflammatory anemia and serum iron changes in myocardial infarction, Acta Med. Stand. 151:407, 1955. Brucknerova, O., and Pojer. J.: Serum iron levels in congestive heart failure, Cor Vasa 5:177. 1963. Handjani, A. M., Banihashemi, A., Rafiee. f-t., and Tolou, H.: Serum iron in acute myocardial infarction. Blut 23:363, 1971. Bass, D., and Shapira, J.: The values of serum iron levels as a diagnostic aid in acute myocardial infarction, M.D. Thesis, Hadassah Medical School &The Hebrew IJniversity, Jerusalem, 1965. Gibson, I. I.. Kelly, A. M., and Wang, 1. Serum iron values following acute myocardial inf’arcti~m. Scot. Med. ,J. 14:1X, 1969. Nitter-Hauge, S.: Serum iron, total iron binding capacity and transferrin following acute tnyocardial infarction, Arta Med. Stand. 190:337, 1971. Syrkis. I., and Machtey, I.: Hypoferremin in acute myocardial infarction, Am. Geriatr. Sot. 21:2&X, 197:I. CrispelI, K. R., Porter, B., and Neiset. R. ‘I’.: Studies of plasma volume using human serum albumm tagged with radioactive iodine-131. J. Clin. Invest. 29:51X 1950. Babson, A. L., Shapiro, P. 0.. Williams, P. A.. and Philips, G. E.: The use of diazonium salt for the determination of glutamic oxaloacetic t,ransaminasr in seruln. (Yin. Chim. Acta 71199, 1962. King, J., and Morris, M. B.: Serum enzyme act.lvity in the normal newborn infant,, Arch. Dis. Child. 36:604, 1961. de Moor, P.. Steeno, 0.. Raskin, M., and Hendrix. A.: Fiuorometric determination of free plasma 11 -hydroxycorticosteroids in man, Acta Endocrinol. 33:297, 1960. Trinder, I’.: The improved determinatic~n :)I’ iron in serum, ,J. Clin. Pathol. 9:170, 1956. Ressler, N., and Zak, B.: Serum unsaturalcd non binding capacity, J. Clin. Pathol. 30:RT, 195X. Fisher, D. S., and Price, D. C.: A simple serum iron method using the new sensitive chromogen tripyridyl-sthiazine, Clin. Chem. 10:21, 1964. Lajtha, I,. G.: The use of isotol:+ iti hematology. Toronto, 1961, Ryerson Press, p. 49. Beierwaltes, W. H., Johnson, P. C’.. and Solari. A. J.: Clinical use of radioisotopes, Philadelphi:1, 1957, W.B. Saunde1-s Company. p. 288.
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18.
19.
20.
164
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Quastel, M. R., and Ross, J. F.: The effect of acute inflammation on the utilization and distribution of transfer-r-in bound and erythrocyte radioiron, Blood 28:738, 1966. Kampschmidt, R F., and Upchurch, H. F.: Lowering of plasma iron concentration in the rat with leukocytic extracts, Am. J. Physiol. 216:1287, 1969. Prinzie, A., and Lederer, J.: Endocrine control of iron metabolism. VIII. Influence of cortisone on the plasma
21.
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level of iron male and female rabbits, Ann. Endocrinol. 21:158,1969. Lederer, J.: Endocrine control of iron metabolism. XV. Endocrine origin of the difference in the composition of blood in men and women, Ann. Endocrinol. 2:249, 1962. Logan, R. W., and Murdoch, W. R.: Blood levels of hydrocortisone, transaminases, and cholesterol after myocardial infarction, Lancet 2521, 1966.
August,
1975, Vol. 90, No. 2