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IRON DEFICIENCY WITHOUT ANÆMIA
9
compared with a similar series of 40 patients treated with a conventional low protein diet. Patients taking the very low protein Giovannetti diet showed signs of agitation and a bleeding tendency, but had no gastrointestinal symptoms. When this symptomcomplex appears death can be expected within a fortnight unless chronic hxmodialysis is undertaken. The lower blood-urea levels may be responsible for the absence of gastrointestinal symptoms. were
..
to thank
Prof. D. A. K. Black for fruitful discussion and We wish advice; and the physicians of Manchester Royal Infirmary who allowed us to treat their patients. REFERENCES
Berlyne, G. M. (1964) Trans. Eur. Dialysis Transplantn Ass. 1, 173. Shaw, A. B. (1965) Nephron (in the press). Black, D. A. K. (1965) Personal communication. Giordano, C. (1963) J. Lab. clin. Med. 62, 231. Giovannetti, S., Maggiore, Q. (1964) Lancet, i, 1000. Shaw, A. B., Bazzard, F., Booth, E. M., Nilwarangkur, S., Berlyne, G. M. (1965) Q. Jl Med. 34, 237. Walser, M., Bodenlos, L. J. (1959) J. clin. Invest. 38, 1617. Williams, J. L., Dick, G. F. (1933) J. Am. med. Ass. 100, 484. —
IRON DEFICIENCY WITHOUT ANÆMIA
J. FIELDING M.R.C.P., F.C.Path., D.P.H. CONSULTANT HÆMATOLOGIST
M. C. O’SHAUGHNESSY M.B. N.U.I. RESEARCH REGISTRAR
GILLIAN M. BRUNSTROM F.I.M.L.T. RESEARCH ASSISTANT
PADDINGTON GENERAL
HOSPITAL, LONDON, W.9
possibility that lack of iron contributes to the production of clinical syndromes other than iron-deficiency anaemia has been reviewed by Beutler et al. (1963). They quoted earlier physicians who had observed that THE
symptoms of chlorosis occurred in the absence of anxmia and who had claimed that these symptoms yielded specifically to iron therapy. These observations are open to question, since hxmoglobinometry and precise hxmatological diagnosis were then in their infancy, nor could the effects of therapy on symptoms such as fatigue, anorexia, depression, palpitation, and vertigo be ignored in assessing the results. Waldenstrom (1938) showed that dysphagia, a concomitant of iron-deficiency anaemia, could occur without anaemia and was equally susceptible to iron therapy; Jacobs and Kilpatrick (1964) suggested that dysphagia might not be due to iron deficiency as such. Stafford (1961) found evidence of iron deficiency without anaemia in the form of low serum-iron, in cases of excessive postextraction dental bleeding, angular stomatitis, spontaneous bruising, and buccal ulceration. Since the introduction of parenteral iron preparations, Jennison and Ellis (1954), among others, have noted the rapid resolution of symptoms such as fatigue and anorexia within a few days of starting therapy, before haemoglobin levels have altered, and considered that this may have been due to the restoration of tissue-iron. Beutler et al. (1963) found, in experimental iron deficiency in animals, that catalase, cytochrome, succinic dehydrogenase, and aconitase-enzymes which either contain iron or require iron compounds as cofactors-may be deficient. Beutler et al. (1960) carried out a double-blind trial of irbn therapy in women with symptoms similar to those observed in iron-deficiency anaemia, with haemoglobin in
the normal range yet with no hasmosiderin demonstrable by sternal marrow-puncture. The relief of symptoms among those given iron was higher than among those given placebo. Beutler et al. (1963) state that iron deficiency without anaemia belongs to a class of disease which we cannot yet diagnose with certainty because of the limitations of diagnostic methods. The significance of iron depletion without anaemia will remain unknown until its presence can be recognised without a therapeutic trial of iron. Fielding (1965) described the differential ferrioxamine test for measuring the amount of body iron chelated by desferrioxamine. The two main sources of iron chelated in this way are iron stores as ferritin-hsemosiderin and iron newly released from hasm in some hxmolytic states. When the rate of destruction of red cells is normal, ferritinhaemosiderin stores can be measured by the amount of iron chelated in vivo by desferrioxamine. We have found a number of people with normal hxmoglobin in whom iron deficiency has been recognised by this method. Finch et al. (1950) showed that after phlebotomy haematocrits did not recover in the absence of available iron. We confirmed the validity of the differential ferrioxamine-test in defining iron-store depletion by venesection in volunteers using the criterion of failure to restore hsematocrits within 2 weeks. Methods and Materials The differential ferrioxamine-test is based on the iron chelation of desferrioxamine. Briefly it consists of an intravenous injection of a body-weight dose of desferrioxamine methanesulphonate (’ Desferal, ’ Ciba) together with a bodyweight dose of ferrioxamine labelled with 2 flC 59Fe. A single 6-hour specimen of urine is collected. The amount of injected ferrioxamine excrgted (Fex) is estimated as 59Fe by standard methods, and the total amount of ferrioxamine excreted (FJ, is estimated chemically (Fielding and Brunstrom 1964). The estimations are simple and take only a few minutes. The amount of ferrioxamine formed from body-iron (Fy) is calculated from the difference (Ft-Fex) which in iron deficiency approaches zero. Because of the variability of any single observation, the difference is sometimes negative but it is here recorded as zero chelation. Much of the isotope is excreted within 3 days of injection, and the test may therefore be repeated many times without significant exposure to radiation. Clinical Material studied.
Four groups were Group A.-31 healthy men (medical students and hospital employees). As far as could be ascertained from medical history, they were in good health, had no source of bloodloss, and no recent illness. In only 1 was haemoglobin as low as 12-3 g. per 100 ml., the range for the others was 13 116-0 g. per 100 ml. Group B.-37 patients (33 female, 4 male) with unequivocal iron-deficiency anaemia, haemoglobin less than 11-5 g. per 100 ml., serum-iron-binding capacity less than 20% saturated. All of these patients subsequently responded to iron therapy. Group C.-45 healthy women (medical students and hospital employees). Selection was based on absence of recent illness, and haemoglobin above 12-0 g. per 100 ml. No attempt was made before the test to assess menstrual history or the presence of subjective symptoms. Group D.-26 patients (25 female, 1 male) who had been treated for iron-deficiency anaemia with either oral iron or parenteral iron or both, and in whom iron therapy had recently been discontinued on the attainment of a satisfactory
haemoglobin. Serum-iron was determined by the method of Kok and Wild and total serum-iron-binding capacity (T.LB.C.) by
(1960),
10
Group C Of 45 healthy women with Hb greater than 12-0 g. per 100 ml., 30 had iron chelation in the range for healthy men. 15 (33%) had values below those for men and in the range for patients with iron-deficiency anaemia. Details of these patients are shown in table I: in only 3 patients (cases 48, 145, and 194) latent iron deficiency might have been suspected from serum-iron and T.I.B.C.
Group
D
Of 26 patients treated for established iron-deficiency anaemia, until a satisfactory haemoglobin had been achieved, 8 had Fv’s below the normal range for men, i.e., in the range of untreated iron-deficiency anaemia. In this group only 4 (cases 10, 16, 20, and 99) might have been suspected of latent iron deficiency from serum-iron and T.I.B.C. (table II). Response to Venesection 15 subjects with Fv’s ranging from 0 to 360 g. per kg. were phlebotomised. Of 6 with Fv’s higher than 150 fLg. per kg., 5 regained their prephlebotomy haematocrits TABLE II-TREATED IRON DEFICIENCY ANEMIA WITH
110 .g. per
Fig. 1-Scattergram of Fv’s for four
absorption of excess (Ramsay 1957).
ferric chloride with
Fv
LESS THAN
kg.
groups.
magnesium carbonate
Soon after their Fy values had been determined, 15 volunteers from groups A and C were venesected to the extent of 350-750 ml. of blood. Hsematocrits were determined at the time of venesection and 1, 2, 7, and 14 days later. For women the programme was arranged to begin and end between two menstrual periods. A tolerance of dz 1 % was permitted in defining a change of haematocrit.
TABLE III-RESPONSE TO PHLEBOTOMY IN HIEMOGLOBIN
15 SUBJECTS
WITH NORMAL
Results
Group A In 31 healthy men the Fv-the amount of ferrioxamine formed in vivo by chelation of iron after a standard dose of desferrioxamine-ranged from 109 to 498 flg. per kg. The distribution (fig. 1) is a little suggestive of the presence of two sub-groups, one with values less than 200 g. per kg. and a second group with values between 250 and 500 flg. per kg.
Group B In 29 of 37 patients (78%) with iron-deficiency anaemia the F was less than 110 flg. per kg. and thus below the range for healthy men; in 2 patients the F was low normal, 120-150 flg. per kg.; in 6 cases the F, was in the normal range. TABLE I-NORMAL WOMEN WITH
Fv
LESS THAN
110 jjtg. per
kg.
days; only 1 (case 147) did not regain prephlebotomy level (table ill). Of 9 subjects with Fy’s of 120 g. per kg. or less, 8 did not regain their prephlebotomy hxmatocrit; only 1 (case 146) regained the prephlebotomy level in 14 days. 4 typical responses are shown in fig. 2. within 14
Heemoglibin and F The mean haemoglobin among healthy women with Fv less than 110 g. per kg. was marginally but not significantly lower than for those with Fy above this level (table iv). The mean haemoglobin for healthy women is lower than that for men, but the interpretation of this finding has always been obscured by the possible inclusion of women with slight iron-deficiency anxmia. Our results permit a comparison of 31 healthy men with 30 healthy women, both groups having iron stores in the same range as measured by the differential ferrioxamine-
11 test ; the mean value and standard deviation for men was Hb 14-7 ±0-90 g. per 100 ml., and for women 13-7 ±0-85 g. per 100 ml.
TABLE
IV—HÆMOGLOBIN,
SERUM-IRON
T.I.B.C., AND Fv
FOR
FOUR
GROUPS
Serum-iron, T.I.B.C., and Fv For 31
healthy
men, the
serum-iron and T.I.B.C. were 116±23 and 333±60 g. per 100 ml. respectively. The mean values for 30 women with normal haemoglobin and with Fy above 110 g. per kg. were 103±30 and 348 ±67 i.g. per 100 ml. respectively. Among women with normal haemoglobin there was no difference in serum-iron between those with Fy below 110 µg. per kg. (considered iron depleted) and those with iron stores in the normal range. However, the T.I.B.C. of the iron-depleted group was significantly higher at 381 70 µg. per 100 ml. Both these findings agree with Weinfeld (1964) who used chemical analysis of biopsy material to assess stored iron, and suggested that T.I.B.C. always has an inverse relationship to iron stores, whereas serum-iron does not directly reflect the level of stored iron. The overlap in the two groups is very considerable and T.I.B.C. cannot be used as an index of iron-store depletion in isolated cases. Haemoglobin, serum-iron, T.I.B.c., and their relation to Fv are summarised in table iv. mean
Discussion
The differential ferrioxamine-test measures the amount of body-iron as ferrioxamine (Fv) chelated by an intravenous dose of desferrioxamine. In healthy men this varies
*
1 male excluded from original group. t Figures in parentheses indicate numbers in
group if different from main
group.
from 110 to 500 µg. per kg. body-weight (ferrioxamine contains approximately a tenth its weight-of iron). 29 out of 37 patients with established iron-deficiency anxmia had Fv’s below 110 µg. per kg., 2 cases gave results in the low normal range, and 6 were in the range for healthy men. The significance of normal Fv’s in some iron-deficiency anaemias has been discussed elsewhere (Fielding 1965). The Fv’s in healthy men and in established irondeficiency anaemias form a continuous series, which suggests that even among healthy men the range of iron stores extends from little or nothing to higher values. In 15 out of 45 healthy women with haemoglobins abovee 12-0 g. per 100 ml. Fy’s were below the range for men and in the range of patients with well defined iron-deficiency anxmia (table I). Of these 15 volunteers, only 3 might have been suspected of having latent iron-deficiency from values of their serum-iron and T.l.B.c. Among the remaining 30 women, 4 might have been suspected of latent iron-deficiency by similar criteria, and their Fv’s were in the low normal range, 129, 120, 119, and 117 µg. per kg. Thus if an Fv of 120 µg. per kg. is taken as the lower level of significant iron stores, then 18 of 45 healthy women would be assessed as iron-deficient. These would include 6 of 7 women who might be similarly assessed from their serum-iron and iron-binding capacities. Similar results were obtained among 25 women recently treated for irondeficiency anaemia until haemoglobin levels were satisfactory. 8 had depleted iron stores as measured by F’s of less than 120 µg. per kg.; of these, only 4 might be similarly assessed from serum-iron and iron-binding
capacity (table II).
Fig. 2-Response to venesection in 4 volunteers with normal hxmoglobin, 2 with normal Fo’s and 2 with low Fv’s (see table III).
26 of 70 women with haemoglobin within the normal range had chelatable iron below the range for men and in the range found in patients with established iron-deficiency anaemia. The interpretation of low chelatable iron as ironstore depletion is confirmed by the response to phlebotomy. Finch et al. (1950) showed that iron was a limiting factor in the hæmopoietic response to phlebotomy, without iron stores there was no recovery from blood-loss. This cannot be a sensitive procedure since to obtain a measurable change in hæmatocrit at least 200 mg. iron— about a quarter of the normal store-must be removed as haemoglobin. Nevertheless of 8 women and 1 man with Fv’s of 120 µg. per kg. or less, only 1 woman regained her prevenesection hæmatocrit in 14 days; whereas of 3 men and 3 women with Fv’s of 156-360 µg. per kg., all but 1 woman regained the prevenesection haematocrit. These
12
results confirm the
interpretation of Fv’s below 120
(.Lg. depletion of iron stores. per kg. The recognition of depletion of the iron stores in the presence of normal haemoglobin by the differential ferrioxamine-test in as many as 35% of women should prove useful in the investigation of clinical syndromes believed, but not yet proved, to be associated with lack of iron. Attention has been directed to excessive blood-loss as the principal cause of a negative iron-balance with consequent iron-deficiency anaemia. It is doubtful, however, whether many women with normal haemoglobin but iron-store depletion are in negative iron-balance, since this would imply that at any given moment this high proportion of women are in the process of developing anaemia. If this were so there would soon be few left with normal haemoglobin. It is more probable that when haemoglobin is in the normal range, there is insufficient absorption of iron from a modern diet to permit the accumulation of an adequate iron store. It might be useful to investigate once again the sources and adequacy of dietary iron: in such an investigation, absorption in people with normal haemoglobin yet depleted stores would be particularly relevant. A third of apparently healthy women with normal haemoglobin have no significant iron stores. In this large group any increased demand for iron as in pregnancy, or any increased blood-loss, must lead inevitably to irondeficiency anaemia. as
Summary The differential ferrioxamine-test measures the amount of body-iron as ferrioxamine (Fv) taken up by the chelating In the absence of increased agent, desferrioxamine. haemolysis, the source of this iron is mainly iron stored as
ferritin-hæmosiderin. The test was carried
out in healthy men, in untreated in healthy women, and in patients anæmia, iron-deficiency with treated iron-deficiency anxmia. About 35% of women with normal haemoglobin are found to have Fv less than 110 µg. per kg., i.e., below the range for healthy men and in the same range as patients
iron-deficiency anaemia. It is considered that such women have no significant iron stores. The interpretation of low F as depletion of iron stores was confirmed by the failure of subjects with low Fv with
to restore
PLACENTAL TRANSFUSION AN ATTEMPT AT PHYSIOLOGICAL DELIVERY
P. VÁRDI Budapest
M.D.
From the
Gynœcological Clinic No. 2 of the Medical University, Budapest
A NUMBER of investigations have made it clear that placental transfusion is beneficial to the newborn especially with regard to hasmodynamics immediately after birth (Bonham Carter et al. 1956, Mahaffey and Rossdale 1957, Brown 1959, Wallgren et al. 1960, Bound et al. 1962) and iron metabolism after the ninth month of extrauterine life (Fullerton 1937, Wilson et al. 1941, DeMarsh et al. 1942, Sturgeon 1956, Betke 1959). Nevertheless, few obstetricians have adopted the practice although it was not until the 17th century that cutting the umbilical cord before delivery of the placenta became the rule (Fasbender 1906). In addition, women were usually seated or squatting during labour (Ebers papyrus) and this position allowed a better use of the force of gravity and intra-abdominal pressure. Delivery still takes place in this way among many primitive peoples, and in anthropoid apes the connection between newborn and placenta is not interrupted before placental
delivery (Hooton 1942). Our technique has the object of transferring most of the placental blood to the newborn baby at’arate and in a quantity adjusted by a self-regulating mechanism. Care is taken not to impede the passage of blood from the placenta to the infant by any undue haste in delivery. Method
The method is based on the procedures of Guillemeau (1612), Luge (1879), and Secher and Karlberg (1962) and has been adapted to vaginal delivery. The newborn baby is placed between the abducted legs of the mother and kept there dry and warm. Suction, if necessary, is done without the cord being tugged. After antiseptic treatment of the eyes, the baby is covered up until the placenta is detached, meanwhile carefully protecting the cord from
being damaged. After its delivery,
the placenta is examined to see that its connection with the baby remains intact. The placenta
their hasmatocrits after venesection.
We wish to thank the many volunteers, Ciba Laboratories Ltd. for gifts of drugs and apparatus, and the North West Metropolitan Regional Hospital Board for research grants. REFERENCES
V. F., Fahey, J. L. (1963) Clinical Disorders of Iron Metabolism. New York. Larch, S., Guerney, C. W. (1960) Ann. int. Med. 52, 378. Fielding, J. (1965) J. clin. Path. 18, 88. Brunstrom, G. M. (1964) ibid. 17, 395. Finch, S. C., Haskins, D., Finch, C. A. (1950) J. clin. Invest. 29, 1078. Jacobs, A., Kilpatrick, G. S. (1964) Br. med. J. ii, 79. Jennison, R. F., Ellis, H. R. (1954) Lancet, ii, 1245. Kok, D’A., Wild, F. (1960) J. clin. Path. 13, 241. Ramsay, W. N. M. (1957) Clin, chim. Acta, 2, 221. Stafford, J. L. (1961) Proc. R. Soc. Med. 54, 1000. Waldenström, J. (1938) Acta med. scand. suppl. no. 90, p. 380. Weinfeld, A. (1964) ibid. suppl. no. 427, p. 95.
Beutler, E., Fairbanks, -
-
"
Much of the trouble came ... from the use of the word in human affairs. A problem implied a solution. It was a word borrowed from mathematics, or logic, which had no relevance to human entanglements.... no human problems, in this sense, existed-only situations, which could be dealt with, in some fashion, as they arose, but never finally disposed of."-ELSPETH HUXLEY. A Man from Nowhere. London, 1964; p. 221.
, problem’
Placenta in
place above newborn baby
compared with a similar series of 40 patients treated with a conventional low protein diet. Patients taking the very low protein Giovannetti diet showed signs of agitation and a bleeding tendency, but had no gastrointestinal symptoms. When this symptomcomplex appears death can be expected within a fortnight unless chronic hxmodialysis is undertaken. The lower blood-urea levels may be responsible for the absence of gastrointestinal symptoms. were
..
to thank
Prof. D. A. K. Black for fruitful discussion and We wish advice; and the physicians of Manchester Royal Infirmary who allowed us to treat their patients. REFERENCES
Berlyne, G. M. (1964) Trans. Eur. Dialysis Transplantn Ass. 1, 173. Shaw, A. B. (1965) Nephron (in the press). Black, D. A. K. (1965) Personal communication. Giordano, C. (1963) J. Lab. clin. Med. 62, 231. Giovannetti, S., Maggiore, Q. (1964) Lancet, i, 1000. Shaw, A. B., Bazzard, F., Booth, E. M., Nilwarangkur, S., Berlyne, G. M. (1965) Q. Jl Med. 34, 237. Walser, M., Bodenlos, L. J. (1959) J. clin. Invest. 38, 1617. Williams, J. L., Dick, G. F. (1933) J. Am. med. Ass. 100, 484. —
IRON DEFICIENCY WITHOUT ANÆMIA
J. FIELDING M.R.C.P., F.C.Path., D.P.H. CONSULTANT HÆMATOLOGIST
M. C. O’SHAUGHNESSY M.B. N.U.I. RESEARCH REGISTRAR
GILLIAN M. BRUNSTROM F.I.M.L.T. RESEARCH ASSISTANT
PADDINGTON GENERAL
HOSPITAL, LONDON, W.9
possibility that lack of iron contributes to the production of clinical syndromes other than iron-deficiency anaemia has been reviewed by Beutler et al. (1963). They quoted earlier physicians who had observed that THE
symptoms of chlorosis occurred in the absence of anxmia and who had claimed that these symptoms yielded specifically to iron therapy. These observations are open to question, since hxmoglobinometry and precise hxmatological diagnosis were then in their infancy, nor could the effects of therapy on symptoms such as fatigue, anorexia, depression, palpitation, and vertigo be ignored in assessing the results. Waldenstrom (1938) showed that dysphagia, a concomitant of iron-deficiency anaemia, could occur without anaemia and was equally susceptible to iron therapy; Jacobs and Kilpatrick (1964) suggested that dysphagia might not be due to iron deficiency as such. Stafford (1961) found evidence of iron deficiency without anaemia in the form of low serum-iron, in cases of excessive postextraction dental bleeding, angular stomatitis, spontaneous bruising, and buccal ulceration. Since the introduction of parenteral iron preparations, Jennison and Ellis (1954), among others, have noted the rapid resolution of symptoms such as fatigue and anorexia within a few days of starting therapy, before haemoglobin levels have altered, and considered that this may have been due to the restoration of tissue-iron. Beutler et al. (1963) found, in experimental iron deficiency in animals, that catalase, cytochrome, succinic dehydrogenase, and aconitase-enzymes which either contain iron or require iron compounds as cofactors-may be deficient. Beutler et al. (1960) carried out a double-blind trial of irbn therapy in women with symptoms similar to those observed in iron-deficiency anaemia, with haemoglobin in
the normal range yet with no hasmosiderin demonstrable by sternal marrow-puncture. The relief of symptoms among those given iron was higher than among those given placebo. Beutler et al. (1963) state that iron deficiency without anaemia belongs to a class of disease which we cannot yet diagnose with certainty because of the limitations of diagnostic methods. The significance of iron depletion without anaemia will remain unknown until its presence can be recognised without a therapeutic trial of iron. Fielding (1965) described the differential ferrioxamine test for measuring the amount of body iron chelated by desferrioxamine. The two main sources of iron chelated in this way are iron stores as ferritin-hsemosiderin and iron newly released from hasm in some hxmolytic states. When the rate of destruction of red cells is normal, ferritinhaemosiderin stores can be measured by the amount of iron chelated in vivo by desferrioxamine. We have found a number of people with normal hxmoglobin in whom iron deficiency has been recognised by this method. Finch et al. (1950) showed that after phlebotomy haematocrits did not recover in the absence of available iron. We confirmed the validity of the differential ferrioxamine-test in defining iron-store depletion by venesection in volunteers using the criterion of failure to restore hsematocrits within 2 weeks. Methods and Materials The differential ferrioxamine-test is based on the iron chelation of desferrioxamine. Briefly it consists of an intravenous injection of a body-weight dose of desferrioxamine methanesulphonate (’ Desferal, ’ Ciba) together with a bodyweight dose of ferrioxamine labelled with 2 flC 59Fe. A single 6-hour specimen of urine is collected. The amount of injected ferrioxamine excrgted (Fex) is estimated as 59Fe by standard methods, and the total amount of ferrioxamine excreted (FJ, is estimated chemically (Fielding and Brunstrom 1964). The estimations are simple and take only a few minutes. The amount of ferrioxamine formed from body-iron (Fy) is calculated from the difference (Ft-Fex) which in iron deficiency approaches zero. Because of the variability of any single observation, the difference is sometimes negative but it is here recorded as zero chelation. Much of the isotope is excreted within 3 days of injection, and the test may therefore be repeated many times without significant exposure to radiation. Clinical Material studied.
Four groups were Group A.-31 healthy men (medical students and hospital employees). As far as could be ascertained from medical history, they were in good health, had no source of bloodloss, and no recent illness. In only 1 was haemoglobin as low as 12-3 g. per 100 ml., the range for the others was 13 116-0 g. per 100 ml. Group B.-37 patients (33 female, 4 male) with unequivocal iron-deficiency anaemia, haemoglobin less than 11-5 g. per 100 ml., serum-iron-binding capacity less than 20% saturated. All of these patients subsequently responded to iron therapy. Group C.-45 healthy women (medical students and hospital employees). Selection was based on absence of recent illness, and haemoglobin above 12-0 g. per 100 ml. No attempt was made before the test to assess menstrual history or the presence of subjective symptoms. Group D.-26 patients (25 female, 1 male) who had been treated for iron-deficiency anaemia with either oral iron or parenteral iron or both, and in whom iron therapy had recently been discontinued on the attainment of a satisfactory
haemoglobin. Serum-iron was determined by the method of Kok and Wild and total serum-iron-binding capacity (T.LB.C.) by
(1960),
10
Group C Of 45 healthy women with Hb greater than 12-0 g. per 100 ml., 30 had iron chelation in the range for healthy men. 15 (33%) had values below those for men and in the range for patients with iron-deficiency anaemia. Details of these patients are shown in table I: in only 3 patients (cases 48, 145, and 194) latent iron deficiency might have been suspected from serum-iron and T.I.B.C.
Group
D
Of 26 patients treated for established iron-deficiency anaemia, until a satisfactory haemoglobin had been achieved, 8 had Fv’s below the normal range for men, i.e., in the range of untreated iron-deficiency anaemia. In this group only 4 (cases 10, 16, 20, and 99) might have been suspected of latent iron deficiency from serum-iron and T.I.B.C. (table II). Response to Venesection 15 subjects with Fv’s ranging from 0 to 360 g. per kg. were phlebotomised. Of 6 with Fv’s higher than 150 fLg. per kg., 5 regained their prephlebotomy haematocrits TABLE II-TREATED IRON DEFICIENCY ANEMIA WITH
110 .g. per
Fig. 1-Scattergram of Fv’s for four
absorption of excess (Ramsay 1957).
ferric chloride with
Fv
LESS THAN
kg.
groups.
magnesium carbonate
Soon after their Fy values had been determined, 15 volunteers from groups A and C were venesected to the extent of 350-750 ml. of blood. Hsematocrits were determined at the time of venesection and 1, 2, 7, and 14 days later. For women the programme was arranged to begin and end between two menstrual periods. A tolerance of dz 1 % was permitted in defining a change of haematocrit.
TABLE III-RESPONSE TO PHLEBOTOMY IN HIEMOGLOBIN
15 SUBJECTS
WITH NORMAL
Results
Group A In 31 healthy men the Fv-the amount of ferrioxamine formed in vivo by chelation of iron after a standard dose of desferrioxamine-ranged from 109 to 498 flg. per kg. The distribution (fig. 1) is a little suggestive of the presence of two sub-groups, one with values less than 200 g. per kg. and a second group with values between 250 and 500 flg. per kg.
Group B In 29 of 37 patients (78%) with iron-deficiency anaemia the F was less than 110 flg. per kg. and thus below the range for healthy men; in 2 patients the F was low normal, 120-150 flg. per kg.; in 6 cases the F, was in the normal range. TABLE I-NORMAL WOMEN WITH
Fv
LESS THAN
110 jjtg. per
kg.
days; only 1 (case 147) did not regain prephlebotomy level (table ill). Of 9 subjects with Fy’s of 120 g. per kg. or less, 8 did not regain their prephlebotomy hxmatocrit; only 1 (case 146) regained the prephlebotomy level in 14 days. 4 typical responses are shown in fig. 2. within 14
Heemoglibin and F The mean haemoglobin among healthy women with Fv less than 110 g. per kg. was marginally but not significantly lower than for those with Fy above this level (table iv). The mean haemoglobin for healthy women is lower than that for men, but the interpretation of this finding has always been obscured by the possible inclusion of women with slight iron-deficiency anxmia. Our results permit a comparison of 31 healthy men with 30 healthy women, both groups having iron stores in the same range as measured by the differential ferrioxamine-
11 test ; the mean value and standard deviation for men was Hb 14-7 ±0-90 g. per 100 ml., and for women 13-7 ±0-85 g. per 100 ml.
TABLE
IV—HÆMOGLOBIN,
SERUM-IRON
T.I.B.C., AND Fv
FOR
FOUR
GROUPS
Serum-iron, T.I.B.C., and Fv For 31
healthy
men, the
serum-iron and T.I.B.C. were 116±23 and 333±60 g. per 100 ml. respectively. The mean values for 30 women with normal haemoglobin and with Fy above 110 g. per kg. were 103±30 and 348 ±67 i.g. per 100 ml. respectively. Among women with normal haemoglobin there was no difference in serum-iron between those with Fy below 110 µg. per kg. (considered iron depleted) and those with iron stores in the normal range. However, the T.I.B.C. of the iron-depleted group was significantly higher at 381 70 µg. per 100 ml. Both these findings agree with Weinfeld (1964) who used chemical analysis of biopsy material to assess stored iron, and suggested that T.I.B.C. always has an inverse relationship to iron stores, whereas serum-iron does not directly reflect the level of stored iron. The overlap in the two groups is very considerable and T.I.B.C. cannot be used as an index of iron-store depletion in isolated cases. Haemoglobin, serum-iron, T.I.B.c., and their relation to Fv are summarised in table iv. mean
Discussion
The differential ferrioxamine-test measures the amount of body-iron as ferrioxamine (Fv) chelated by an intravenous dose of desferrioxamine. In healthy men this varies
*
1 male excluded from original group. t Figures in parentheses indicate numbers in
group if different from main
group.
from 110 to 500 µg. per kg. body-weight (ferrioxamine contains approximately a tenth its weight-of iron). 29 out of 37 patients with established iron-deficiency anxmia had Fv’s below 110 µg. per kg., 2 cases gave results in the low normal range, and 6 were in the range for healthy men. The significance of normal Fv’s in some iron-deficiency anaemias has been discussed elsewhere (Fielding 1965). The Fv’s in healthy men and in established irondeficiency anaemias form a continuous series, which suggests that even among healthy men the range of iron stores extends from little or nothing to higher values. In 15 out of 45 healthy women with haemoglobins abovee 12-0 g. per 100 ml. Fy’s were below the range for men and in the range of patients with well defined iron-deficiency anxmia (table I). Of these 15 volunteers, only 3 might have been suspected of having latent iron-deficiency from values of their serum-iron and T.l.B.c. Among the remaining 30 women, 4 might have been suspected of latent iron-deficiency by similar criteria, and their Fv’s were in the low normal range, 129, 120, 119, and 117 µg. per kg. Thus if an Fv of 120 µg. per kg. is taken as the lower level of significant iron stores, then 18 of 45 healthy women would be assessed as iron-deficient. These would include 6 of 7 women who might be similarly assessed from their serum-iron and iron-binding capacities. Similar results were obtained among 25 women recently treated for irondeficiency anaemia until haemoglobin levels were satisfactory. 8 had depleted iron stores as measured by F’s of less than 120 µg. per kg.; of these, only 4 might be similarly assessed from serum-iron and iron-binding
capacity (table II).
Fig. 2-Response to venesection in 4 volunteers with normal hxmoglobin, 2 with normal Fo’s and 2 with low Fv’s (see table III).
26 of 70 women with haemoglobin within the normal range had chelatable iron below the range for men and in the range found in patients with established iron-deficiency anaemia. The interpretation of low chelatable iron as ironstore depletion is confirmed by the response to phlebotomy. Finch et al. (1950) showed that iron was a limiting factor in the hæmopoietic response to phlebotomy, without iron stores there was no recovery from blood-loss. This cannot be a sensitive procedure since to obtain a measurable change in hæmatocrit at least 200 mg. iron— about a quarter of the normal store-must be removed as haemoglobin. Nevertheless of 8 women and 1 man with Fv’s of 120 µg. per kg. or less, only 1 woman regained her prevenesection hæmatocrit in 14 days; whereas of 3 men and 3 women with Fv’s of 156-360 µg. per kg., all but 1 woman regained the prevenesection haematocrit. These
12
results confirm the
interpretation of Fv’s below 120
(.Lg. depletion of iron stores. per kg. The recognition of depletion of the iron stores in the presence of normal haemoglobin by the differential ferrioxamine-test in as many as 35% of women should prove useful in the investigation of clinical syndromes believed, but not yet proved, to be associated with lack of iron. Attention has been directed to excessive blood-loss as the principal cause of a negative iron-balance with consequent iron-deficiency anaemia. It is doubtful, however, whether many women with normal haemoglobin but iron-store depletion are in negative iron-balance, since this would imply that at any given moment this high proportion of women are in the process of developing anaemia. If this were so there would soon be few left with normal haemoglobin. It is more probable that when haemoglobin is in the normal range, there is insufficient absorption of iron from a modern diet to permit the accumulation of an adequate iron store. It might be useful to investigate once again the sources and adequacy of dietary iron: in such an investigation, absorption in people with normal haemoglobin yet depleted stores would be particularly relevant. A third of apparently healthy women with normal haemoglobin have no significant iron stores. In this large group any increased demand for iron as in pregnancy, or any increased blood-loss, must lead inevitably to irondeficiency anaemia. as
Summary The differential ferrioxamine-test measures the amount of body-iron as ferrioxamine (Fv) taken up by the chelating In the absence of increased agent, desferrioxamine. haemolysis, the source of this iron is mainly iron stored as
ferritin-hæmosiderin. The test was carried
out in healthy men, in untreated in healthy women, and in patients anæmia, iron-deficiency with treated iron-deficiency anxmia. About 35% of women with normal haemoglobin are found to have Fv less than 110 µg. per kg., i.e., below the range for healthy men and in the same range as patients
iron-deficiency anaemia. It is considered that such women have no significant iron stores. The interpretation of low F as depletion of iron stores was confirmed by the failure of subjects with low Fv with
to restore
PLACENTAL TRANSFUSION AN ATTEMPT AT PHYSIOLOGICAL DELIVERY
P. VÁRDI Budapest
M.D.
From the
Gynœcological Clinic No. 2 of the Medical University, Budapest
A NUMBER of investigations have made it clear that placental transfusion is beneficial to the newborn especially with regard to hasmodynamics immediately after birth (Bonham Carter et al. 1956, Mahaffey and Rossdale 1957, Brown 1959, Wallgren et al. 1960, Bound et al. 1962) and iron metabolism after the ninth month of extrauterine life (Fullerton 1937, Wilson et al. 1941, DeMarsh et al. 1942, Sturgeon 1956, Betke 1959). Nevertheless, few obstetricians have adopted the practice although it was not until the 17th century that cutting the umbilical cord before delivery of the placenta became the rule (Fasbender 1906). In addition, women were usually seated or squatting during labour (Ebers papyrus) and this position allowed a better use of the force of gravity and intra-abdominal pressure. Delivery still takes place in this way among many primitive peoples, and in anthropoid apes the connection between newborn and placenta is not interrupted before placental
delivery (Hooton 1942). Our technique has the object of transferring most of the placental blood to the newborn baby at’arate and in a quantity adjusted by a self-regulating mechanism. Care is taken not to impede the passage of blood from the placenta to the infant by any undue haste in delivery. Method
The method is based on the procedures of Guillemeau (1612), Luge (1879), and Secher and Karlberg (1962) and has been adapted to vaginal delivery. The newborn baby is placed between the abducted legs of the mother and kept there dry and warm. Suction, if necessary, is done without the cord being tugged. After antiseptic treatment of the eyes, the baby is covered up until the placenta is detached, meanwhile carefully protecting the cord from
being damaged. After its delivery,
the placenta is examined to see that its connection with the baby remains intact. The placenta
their hasmatocrits after venesection.
We wish to thank the many volunteers, Ciba Laboratories Ltd. for gifts of drugs and apparatus, and the North West Metropolitan Regional Hospital Board for research grants. REFERENCES
V. F., Fahey, J. L. (1963) Clinical Disorders of Iron Metabolism. New York. Larch, S., Guerney, C. W. (1960) Ann. int. Med. 52, 378. Fielding, J. (1965) J. clin. Path. 18, 88. Brunstrom, G. M. (1964) ibid. 17, 395. Finch, S. C., Haskins, D., Finch, C. A. (1950) J. clin. Invest. 29, 1078. Jacobs, A., Kilpatrick, G. S. (1964) Br. med. J. ii, 79. Jennison, R. F., Ellis, H. R. (1954) Lancet, ii, 1245. Kok, D’A., Wild, F. (1960) J. clin. Path. 13, 241. Ramsay, W. N. M. (1957) Clin, chim. Acta, 2, 221. Stafford, J. L. (1961) Proc. R. Soc. Med. 54, 1000. Waldenström, J. (1938) Acta med. scand. suppl. no. 90, p. 380. Weinfeld, A. (1964) ibid. suppl. no. 427, p. 95.
Beutler, E., Fairbanks, -
-
"
Much of the trouble came ... from the use of the word in human affairs. A problem implied a solution. It was a word borrowed from mathematics, or logic, which had no relevance to human entanglements.... no human problems, in this sense, existed-only situations, which could be dealt with, in some fashion, as they arose, but never finally disposed of."-ELSPETH HUXLEY. A Man from Nowhere. London, 1964; p. 221.
, problem’
Placenta in
place above newborn baby