BritishJournal ofhlaematology, 1979, 41, 145-150.
Annotation BIOCHEMICAL AND BEHAVIOURAL ASPECTS OF SIDEROPENIA Iron is the most abundant trace element in the human body (7.4 mg/roo g of fat-free tissue) (Widdowson, 1969). It is a transition element and, as such, forms strong complexes with the protein ligands of various enzymes. These metallo-proteins, in turn, regulate a host oE critical oxidative, hydrolytic and transfer processes (Frieden, 1974). Thus, iron is involved in tissue respiration, oxidative phosphorylation, porphyrin metabolism, collagen synthesis, lymphocyte and granulocyte function, somatic and neural tissue growth, and neurotransmitter synthesis and catabolism (Pollitt & Leibel, 1976; Leibel et al, 1978). S t d i e s of iron deficiency in animals and man have shown that iron deficiency may be present in the absence of anaemia (Cook et al, 1976) and that tissue (enzyme) iron may be affected early (Dallman, 1974). Behaviour or affective derangements which occur in iron deficiency are not primarily due to reduced tissue oxygen delivery except perhaps in the most severely anaemic patients (Hb t 8 g/dl). Cardiovascular mechanisms compensate for diminished Hb mass (Varat et al, 1972), and various ligands (H+, DPG) are able to adjust the molecular respiration of haemoglobin by reducing its oxygen affinity (Adamson & Finch, 197S), thus protecting the sufficiency of peripheral oxygen delivery. Although a ‘lesion’in almost any of the iron-dependent metabolic pathways could provide a basis for the behaviour changes attributed to iron deficiency, recent animal and human research has focussed on oxidative and neurotransmitter metabolism. The rate-limiting enzymes in the pathways of catecholamine (Tyrosine hydroxylase) and serotonin (tryptophan hydroxylase) synthesis are iron-dependent; monoamine oxidase,which catabolizes both compounds and aldehyde oxidase (final oxidation of 5-hydroxyindoleacetaldehyde to 5-hydroxyindoleacetic acid) are also apparently iron-dependent. Studies have recently appeared (see below) describing the in vitra function of these enzymes in brain tissue of iron-deplete animals and suggesting a correlative of behaviour changes with changes in brain chemistry.
Behaviour Studies in Humans Affective disturbances and pica. A large number of clinical symptoms have been associated with iron-deficiency anaemia. However, severely anaemic patients are sometimes asymptomatic, and the number and severity of symptoms does not appear to correlate with the degree of anaemia (Berry & Nash, 1954; Wood & Elwood, 1966; McFarlane et al, 1967; Elwood et al, 1969; Fairbanks et al, 1971). Furthermore, with some exceptions (Beutler et al, 1960), iron therapy and increased haemoglobin levels among previously anaemic subjects have not ameliorated the symptoms (Morrow et al, 1968). Pica, a perversion of appetite characterized by the compulsive ingestion of non-food substances, has been associated with iron-deficiency anaemia (Roselle, 1970; Crosby, 1976). Anaemia and pica are not well correlated and subjects whose pica is characterized by the eating of clay or starch may have induced their own anaemia, as these substances interfere with the Correspondence: Dr Ernesto Pollitt, Human Nutrition Center, University of Texas School of Public Health, P.O. Box 20186, Houston, Texas 77025, U.S.A. 0007-1048/79/020~0145$02.000 1 9 7 9 Blackwell Scientific Publications
14s
144
Annotation
absorption of dietary iron. However, disappearance of pica after iron therapy in subjects with very low haemoglobin values suggests that in some cases there is a causal connection between them (McDonald & Marshall, 1964). Pagophagia, or compulsive eating of ice, is a form of pica specifically associated with iron deficiency (Reynolds et al, 1968;Coltman, 1969).Cytochrome oxidase levels in buccal mucosa begin to rise within one day of the institution of iron therapy in iron-deficient individuals. Pagophagia and its rapid response to iron treatment might be related to levels of iron-dependent enzymes in the buccal mucosa (Coltman, 1969). Mental development and function. Several clinical studies of the relationship between iron deficiency and behaviour should be considered. ( I ) Thirty-two 6-7-year-old children who experienced iron-lack anaemia (Hb 6.19.5 g/dl) when they were 6-18 months old had a higher incidence of ‘soft’ neurological signs, i.e. inattentiveness and hyperactivity, than 29 children who had been given an intramuscular iron supplement a t age 6 months and who had remained nonanaemic (Cantwell, 1974). Since no statistical information was reported and the definition and measurement of attention and hyperactivity were not given, these differences may not be real and are difficult to interpret. (ii) Twenty-four 9-26-month-old infants with haemoglobin values equal to or less than 10.5 g/dl were randomly assigned to one of two groups (Oski & Honig, 1977). One group received an iron dextran complex intramuscularly, and the other received a placebo. Eight days later the treated children showed a significant increase (13 points) on the Bayley Mental Scale score as compared to a nonsignificant increase (6 points) in the control children. The low correlation between test and retest scores 011 infant scales suggests that significant developmental transformations occur with time in the functions assessed. The large age range of infants in this study suggests that different functions were tested in different subjects. It is similarly affected by iron treatment. (iii) Eighty-three black preschool children (3-5 years old) from low-income families, with haemoglobin values less than 10.5 g/dl, were randomly divided into two groups (Howell, 1971).One group received iron intramuscularly; the other group received the same volume of saline. Behaviour test results indicated no between-group differences in IQ. Anaemic girls, however, were characterized as having a shorter attention span and displaying more aimless manipulations than nonanaemic girls. Anaemic boys were described as being more passive and less able to respond to nondominant features of the environment than nonanaemic boys. No information on statistical analyses, methods of testing, or study design was provided in the report. Furthermore, one study (Garn et al, 1975) has shown that blacks generally have haemoglobin values about I .o g/dl lower than iron-replete whites when socioeconomic status is controlled. In view of this finding and the apparent failure of iron therapy to raise the Hb level of many of these children, it is likely that a portion of the sample was not in fact ‘anaemic’. (iv) A study of 4-5-year-old black children enrolled in a ‘Head-Start’ programme was conducted in New Orleans (Sulzer et al, 1973). Two behaviour test batteries were used, one measured cognitive ability, and the other assessed endurance, memory, attention, reaction time, learning, and transfer of training. A haemoglobin value of less than 10.5 g/dl defined anaemia. Analysis of the results indicated a reliable statistical difference between normal and anaemic children on two IQ tests as well as on a reaction-time task involving associative learning. The
Annotution
I47
difference on the latter test may have resulted from inattention, poor motivation, or fatigue among the anaemic children, rather than from differences in learning ability. The retrospective nature of this study design makes it impossible to determine whether the index and control groups were equivalent except haematologically. Indeed, some evidence suggests that the nutritional history of the children interacted with their iron level in determining performance of the behaviour tests. Children of short stature who had anaemia obtained the lowest I Q scores. (v) Junior high school students (12-14 years old) living in an economically deprived, predominantly black community in Philadelphia have also been studied (Webb 8: Oski, 1973a, b, 1974). Ninety-two students were classified as anaemic (Hb levels ranging between 10.1and 11.4 g/dl). The remaining I O I students served as a normal control group (Hb ranging from 14.0 to 14.9 g/dl). Anaemic students did not perform as well as the control group on the achievement tests (Iowa Tests of Basic Skills). In addition, the index children took significantly longer (4.08 s) than controls (1.81 s) to respond on a visual after-image task. Finally, teacher evaluations indicated that anaemic males displayed significantly more conduct problems than nonanaemic males. Conclusions cannot be drawn from this retrospective study. (vi) Forty-seven Welsh women (20 years and older) whose Hb levels were below 10.5g/dl were randomly divided into treatment ( I 50 mg of iron as ferrods carbonate daily) and placebo groups (Elwood ,& Hughes, 1970). Haematological and psychological tests of psychomotor function were administered before and 8 weeks after treatment began. Analysis of the results yielded no between-group differences. A lack of effect of treatment was also noted when data were analysed according to increments in Hb with iron treatment. Possible explanations for these results include: ( I ) the behaviour areas tested are not affected by iron deficiency; ( 2 ) subjects were not sufficiently iron deficient for an effect to occur; (3) the tests were not sensitive enough. The available data are insufficient to exclude any of thesc alternative explanations. Brain Biochemistry The concentration of iron in the human brain increases during the first 20 years of life, achieving its highest levels in the phylogenetically oldest portions of the brain. The concentration ofiron in the globus pallidus (21.3 mg/Ioo g of fresh-weight brain), for instance, exceeds that in the iron-replete liver (13-14 mg/Ioo g) (Hallgren & Sourander, 1958). A small portion of this iron undoubtedly participates in brain oxidative metabolism, but much of it exists in a nonhaem form, possibly as ferritin (Hallgren 8: Sourander, 1958). In both rats and dogs, the majority (about 5 5 % ) of this nonhaem iron is in the mitochondria while a smaller amount (35%) is in the microsomal fraction; the remainder appears in the nucleus. Iron deficiency produces equivalent reductions in all subcellular fractions, and thus the relative distribution of nonhaem iron is unchanged. Brain ferritin presumably protects this organ from the vicissitudes of systemic iron status, and in the adult human (Hallgren & Sourander, 1958) these brain iron stores seem resistant to significant depletion even in the face of severe systemic iron deficiency. The timing of the insult seems critical, for permanent deficits in nonhaem iron (e.g. certain enzymes, ferritin) are demonstrable in the brains of rats deprived of iron from day 10 to day 28 of life and subsequently returned to an adequate iron intake (Dallman et a f , 1975). This failure to ameliorate iron deficiency in the brain is apparently the result of a very slow turnover rate
148
Annotation
for brain iron compounds rather than of a developmental decrease in the permeability of the blood-brain barrier to iron (Dallman & Spirito, 1977). Early studies in rats (Beutler, 1959; Dallman & Schwartz, 1965) reported a failure of systemic iron deficiency to result in decrements in brain iron compounds (aconitase;cytochrome C) despite reductions of these and other (succinate dehydrogenase, catalase) iron-containing enzymes in other tissues (muscle, intestine, kidney). More recent studies (Quik & Sourkes, 1977; Youdim & Green, 1977; Mackler et al, 1978) have confirmed the general impression of CNS enzyme resistance to iron deficiency by demonstrating undiminished activities of monoamine oxidase, tyrosine hydroxylase, succinate dehydrogenase, the cytochromes, and catalase in brains of irondeficient, anaemic rats. Mackler et a1 (1978), however, reported a 3 5 % reduction in brain aldehyde oxidase activity with an attendant I 5 % rise in the brain concentration of 5-hydroxyindole compounds in iron deficient rats. This reverted to normal I week after 5 mg of intraperitoneal iron dextran. The authors point out the similarity between behaviours (diminished responsivity and learning ability) reported in individuals with elevated brain tryptophan levels and those with iron deficiency. Youdim & Green (1977)~on the other hand, found reduced brain tryptophan levels in iron-deficient rats but no apparent functional deficit in enzymes concerned with catecholamine and indoleamine synthesis and catabolism. They attributed the diminished serotonin levels to reduced serotonin binding protein in synaptosomes. Youdim & Green (1977) also demonstrated a reduced physical activity after administration of catecholamine and serotonin precursors in iron-deficient rats. This reduction disappeared after 8 d of oral iron therapy. Because syntheticlcatabolic rates for these compounds were apparently normal (in conflict with Mackler et al, 1978) and because there was also a diminished response to serotonin and dopamine agonists, the authors concluded that the apparent defect in neurotransmission in iron deficiency is located somewhere in the post-synaptic response. However, a study by Finch et al (1976) in which muscle dysfunction was correlated with reduced muscle alphaglycerophosphate dehydrogenase activity and behaviour and biochemical normality were achieved within 4 d of iron therapy, implies that Youdim & Green may have been observing a peripheral (i.e. muscle tissue) rather than a central nervous effect of iron deficiency. Likewise, Dallman’s studies of iron turnover rates in brain make suspect the finding of Mackler et a1 (1978) of short-term recovery of a CNS iron-related biochemical lesion. Finally, although reversible deficits in platelet monoamine oxidase activity (Woods et af, 1977) and elevations in urinary norepinephrine excretion (Voorhess et al, 1975) have been demonstrated in iron-deficient humans, no CNS functional significance can be proven for these findings. And, in view of the points raised above, it is unlikely that these peripheral manifestations of iron deficiency reflect parallel alterations in CNS chemistry.
Developmental Considerations Important aspects of human brain development (glial proliferation, myelinization, dendrite arborization) occur during a period characterized by falling iron stores in the infant (Dallman, 1974). Because of the non-division of differentiated neurons, one would anticipate that, if iron deficiency affects central nervous system processes, growth during infancy would be especially vulnerable to abnormalities that might not be remediable by subsequent restoration of adequate iron intake. As noted previously, permanent deficits in non-haem iron are demonstrable in the brains of rats only transiently deprived of iron early in life.
Annotation
I49
If iron status does influence metabolism on the brain, it is likely that the impact of iron deficiency would vary with the developmental status of the brain. Thus, in the older child o r adult whose brain growth is complete, one might expect to see neLzrologica1 or psychological signs consistent with altered neurotransmitter function of oxidative metabolism, whereas in the infant (or older patient who was iron-deficient as an infant) one might expect to see, in addition, signs related to subtle structural alterations in the brain.
ACKNOWLEDGMENTS
Supported in part by Grant No HDo9228-03 from the National Institute of Child Health and Human Development, Department of Health, Education and Welfare, United States Public Health Service and by the Ford Foundation.
R. LEIBEL D. GREENFIELD
Department of Nutrition and Food Science, Massachusetts Institute of Technology, and Department of Pediatrics, Harvard University School of Medicine
E. POLLITT
REFERENCES ADAMSON, J.W. & FINCH,C.A. (1975) Hemoglobin function, oxygen affinity, and erythropoietin. Annual Review ofPhysiology, 37, 3 51-369. BERRY, W.T.C. & NASH,F.A. (1954) Symptoms as a guide to anaemia. British Medical journal, i, 918. BEUTLER, E. (1958) Iron enzymes in iron deficiency. VI. Aconitase activity and citrate metabolism.Journal of Clinical Investigation, 38, 1605-1616. BEUTLER, E., LARSH, S.E. & GURNEY, C.W. (1960)Iron therapy in chronically fatigued, nonanemic women: a double blind study. Annals of Internal Medicine, 52, 378-394. CANTWELL, R.J. (1974) The long term neurological sequelae of anemia in infancy. (Abstract). Pediatric Research, 8, 342. COLTMAN, C.A. (1969) Pagophagia and iron lack. Journal of the American Medical Association, 207, 513-516. COOK, J.D., FINCH,C.A. &SMITH,N.J. (1976) Evaluation of the iron status of a population. Blood, 48, 449-45 5. CROSBY, W.H. (1976) Pica. Journal of the American Medical Association, 235, 2765. DALLMAN, P.R. (1974) Tissue effects of iron deficiency. Iron in Biochemistry and Medicine (ed. by A. Jacobs and M. Worwood), pp. 437-475. Academic Press, New York. DALLMAN, P.R. & SCHWARTZ, H.C. (1965) Myoglobin and cyto-chrome response during repair of iron deficiency in the rat.Journal of Clinical Investigation, 44, 1631-1638.
DALLMAN, P.R., SIIMES, M.A. & MANIES, E.C. (1975) Brain iron: persistent deficiency following shortterm iron deprivation in the young rat. BritishJournal ofHaematology, 31, 209-215. DALLMAN, P.R. & SPIRITO, R.A. (1977) Brain iron in the rat: extremely slow turnover in normal rats may explain long-lasting effects of early iron deficiency. Journal ofNutrition, 107, 1075-1081. ELWOOD, P.C. & HUGHES, D. (1970) Clinical trial of iron therapy on psychomotor function in anaemic women. British Medicaljournal, iii, 254-255. ELWOOD,P.C., WATERS,W.E., GREENE,W.J.W., SWEFTNAM, P. & WOOD,M.M. (1969) Symptoms and circulating haemoglobin level. Journal of Chronic Diseases, 21. 615628. FAIRBANKS, V.F., FAHEY, J.L. & BEUTLER, E. (1971) Clinical Disorders oflron Metabolism. Grune & Stratton, New York. FINCH,C.A., MILLER, L.R., INAMDAR, A.R., PERSON, R., SEILER, K. & MACKLER, B. (1976) Iron deficiency in the rat. Physiological and biochemical studies of muscle dysfunction. Journal of Clinical Investigation, 589 447-453.
FRIEDEN, E. (1974) The evolution of metals as essential elements (with special reference to iron and copper). Advances in Experimental Medicine and Biology, 48, 1-31. GARN,S.M., SMITH,N.J. & CLARK, D.C. (1975) The magnitude and implications of apparent race differences in hemoglobin values. American Journal of Clinical Nutrition, 28, 563-565.
150
Annotation
HALLGREN, B. & SOURANDER, P. (1958) The effect of age on the non-haemin iron in the human brain. Journal ofNeurochemistry, 3, 41-5 I. HOWELL, D. (1971) Significance of iron deficiencies. Consequences of mild deficiency in children. In: Extent and Meanings of Iron Deficiency in the U.S., Summary Proceedings of a Workshop of the Food and Nutrition Board. National Academy of Sciences, Washington, D.C. LEIBEL, R.L., GREENFIELD, D. & POLL^, E. Iron deficiency: behavior and brain biochemistry. In: Nutrition: Pre- and Post-Natal Development (ed. by M. Winick). Plenum Press, New York. MACKLER, B., PERSON, R., MILLER, L.R., INAMDAR, A.R. & FINCH,C.A. (1978) Iron deficiency in the rat: Biochemical studies of brain metabolism. Pediatric Research, 12, 2 I 7-220. MCDONALD, R. & MARSHALL, S.R. (1964) The value of iron therapy in pica. Pediatrics, 34, 558-562. MCFARLANE, D.B., PINKERTON, P.H., DAGG, J.H. & GOLDBERG, A. (1967) Incidence of iron deficiency, with and without anaemia in women in general practice. BritishJournal offfaematology,13,790-796. MORROW, J.J., DAGG, J.H. & GOLDBERG, A. (1968) A controlled trial of iron therapy in sideropenia. Scottish MedicalJournal, 13, 78-83. OSKI, F.A. & HONIG,A.M. (1977) The effects of therapy on the developmental scores or iron deficient infants. (Abstract). Pediatric Research, 11, 380. POLLIIT,E. & LEIBEL, R.L. (1976) Iron deficiency and behavior. Journal of Pediatrics, 88, 3 72-3 8 I . QUIK,M. & SOURKES, T.L. (1977) The effect of chronic iron deficiency on adrenal tyrosine hydroxylase activity. CanadianJournal of Biochemistry, 5 ~ ~ 6 ~ 5 . REYNOLDS, R.D., BINDER,H.J., MILLER,M.B., CHANG, W.Y. & HORAN, S. (1968)Pagophagia and iron deficiency anemia. Annals of Internal Medicine, 693 435-440. ROSELLE, H.A. (1970) Association of laundry starch and clay ingestion with anemia in New York City. Archives ofInternal Medicine, 125, 57-61.
SULZER, J.L., WESLEY,H.H. & LEONIG,F. (1973) Nutrition and behaviour in Head Start children: results from the Tulane study. In: Nutrition, Development and Social Behaviour (ed. by D. J. Kallen). Department of Health, Education and Welfare, Publication No. (NIH) 73-242, Washington, D.C. VARAT, M.A., ADOLPH, R.J. & FOWLER, N.O. (1972) Cardiovascular effects of anemia. American Heart Journal, 83,415-426. VOORHESS, M.L., STUART, M.J., STOCKMAN, J.A. & OSKI,F.A. (1975) Iron deficiency anemia and increased urinary norepinephrine excretion.Journal of Pediatrics, 86, 542-547. WEBB,T.E. & OSKI,F.A. (1973a) Iron deficiency anemia and scholasticachievement in young adolescents.Journal of Pediatrics, 82, 827-830. WEBB,T.E. & OSKI,F.A. (1973b) The effect of iron deficiency anemia on scholastic achievement, behavioral stability and perceptual sensitivity of adolescents. (Abstract). Pediatric Research, 7, 294. WEBB,T.E. & OSKI,F.A. (1974) Behavioral status of young adolescents with iron deficiency anemia. Journal ofspecial Education, 8, 153-156. WIDDOWSON, E.M. (1969) Trace elements in human development. Mineral Metabolism in Paediatrics (ed. by D. Barltrop and W.L. Burland), p. 87. Adlard 8: Son, Dorking. P.C. (1966) Symptoms of WOOD,M.M. & ELWOOD, iron deficiency anaemia: a community survey. British Journal of Preventive and Social Medicine, 20, 117-121. WOODS,H.F., YOUDIM,M.B.H., BOULLIN, D. & CALLENDER, S. (1977) Monarnine metabolism and platelet function in iron-deficiency anemia. Iron Metabolism: Ciba Foundation Symposium 5 1 , p. 227. Elsevier, Amsterdam. YOUDIM,M.B.H. & GREEN,A.R. (1977) Biogenic amine metabolism and functional activity in irondeficient rats: behavioral correlates. Iron Metabolism, Ciba Foundation Symposium 5 1 , p. 201. Elsevier, Amsterdam.
Annotation BIOCHEMICAL AND BEHAVIOURAL ASPECTS OF SIDEROPENIA Iron is the most abundant trace element in the human body (7.4 mg/roo g of fat-free tissue) (Widdowson, 1969). It is a transition element and, as such, forms strong complexes with the protein ligands of various enzymes. These metallo-proteins, in turn, regulate a host oE critical oxidative, hydrolytic and transfer processes (Frieden, 1974). Thus, iron is involved in tissue respiration, oxidative phosphorylation, porphyrin metabolism, collagen synthesis, lymphocyte and granulocyte function, somatic and neural tissue growth, and neurotransmitter synthesis and catabolism (Pollitt & Leibel, 1976; Leibel et al, 1978). S t d i e s of iron deficiency in animals and man have shown that iron deficiency may be present in the absence of anaemia (Cook et al, 1976) and that tissue (enzyme) iron may be affected early (Dallman, 1974). Behaviour or affective derangements which occur in iron deficiency are not primarily due to reduced tissue oxygen delivery except perhaps in the most severely anaemic patients (Hb t 8 g/dl). Cardiovascular mechanisms compensate for diminished Hb mass (Varat et al, 1972), and various ligands (H+, DPG) are able to adjust the molecular respiration of haemoglobin by reducing its oxygen affinity (Adamson & Finch, 197S), thus protecting the sufficiency of peripheral oxygen delivery. Although a ‘lesion’in almost any of the iron-dependent metabolic pathways could provide a basis for the behaviour changes attributed to iron deficiency, recent animal and human research has focussed on oxidative and neurotransmitter metabolism. The rate-limiting enzymes in the pathways of catecholamine (Tyrosine hydroxylase) and serotonin (tryptophan hydroxylase) synthesis are iron-dependent; monoamine oxidase,which catabolizes both compounds and aldehyde oxidase (final oxidation of 5-hydroxyindoleacetaldehyde to 5-hydroxyindoleacetic acid) are also apparently iron-dependent. Studies have recently appeared (see below) describing the in vitra function of these enzymes in brain tissue of iron-deplete animals and suggesting a correlative of behaviour changes with changes in brain chemistry.
Behaviour Studies in Humans Affective disturbances and pica. A large number of clinical symptoms have been associated with iron-deficiency anaemia. However, severely anaemic patients are sometimes asymptomatic, and the number and severity of symptoms does not appear to correlate with the degree of anaemia (Berry & Nash, 1954; Wood & Elwood, 1966; McFarlane et al, 1967; Elwood et al, 1969; Fairbanks et al, 1971). Furthermore, with some exceptions (Beutler et al, 1960), iron therapy and increased haemoglobin levels among previously anaemic subjects have not ameliorated the symptoms (Morrow et al, 1968). Pica, a perversion of appetite characterized by the compulsive ingestion of non-food substances, has been associated with iron-deficiency anaemia (Roselle, 1970; Crosby, 1976). Anaemia and pica are not well correlated and subjects whose pica is characterized by the eating of clay or starch may have induced their own anaemia, as these substances interfere with the Correspondence: Dr Ernesto Pollitt, Human Nutrition Center, University of Texas School of Public Health, P.O. Box 20186, Houston, Texas 77025, U.S.A. 0007-1048/79/020~0145$02.000 1 9 7 9 Blackwell Scientific Publications
14s
144
Annotation
absorption of dietary iron. However, disappearance of pica after iron therapy in subjects with very low haemoglobin values suggests that in some cases there is a causal connection between them (McDonald & Marshall, 1964). Pagophagia, or compulsive eating of ice, is a form of pica specifically associated with iron deficiency (Reynolds et al, 1968;Coltman, 1969).Cytochrome oxidase levels in buccal mucosa begin to rise within one day of the institution of iron therapy in iron-deficient individuals. Pagophagia and its rapid response to iron treatment might be related to levels of iron-dependent enzymes in the buccal mucosa (Coltman, 1969). Mental development and function. Several clinical studies of the relationship between iron deficiency and behaviour should be considered. ( I ) Thirty-two 6-7-year-old children who experienced iron-lack anaemia (Hb 6.19.5 g/dl) when they were 6-18 months old had a higher incidence of ‘soft’ neurological signs, i.e. inattentiveness and hyperactivity, than 29 children who had been given an intramuscular iron supplement a t age 6 months and who had remained nonanaemic (Cantwell, 1974). Since no statistical information was reported and the definition and measurement of attention and hyperactivity were not given, these differences may not be real and are difficult to interpret. (ii) Twenty-four 9-26-month-old infants with haemoglobin values equal to or less than 10.5 g/dl were randomly assigned to one of two groups (Oski & Honig, 1977). One group received an iron dextran complex intramuscularly, and the other received a placebo. Eight days later the treated children showed a significant increase (13 points) on the Bayley Mental Scale score as compared to a nonsignificant increase (6 points) in the control children. The low correlation between test and retest scores 011 infant scales suggests that significant developmental transformations occur with time in the functions assessed. The large age range of infants in this study suggests that different functions were tested in different subjects. It is similarly affected by iron treatment. (iii) Eighty-three black preschool children (3-5 years old) from low-income families, with haemoglobin values less than 10.5 g/dl, were randomly divided into two groups (Howell, 1971).One group received iron intramuscularly; the other group received the same volume of saline. Behaviour test results indicated no between-group differences in IQ. Anaemic girls, however, were characterized as having a shorter attention span and displaying more aimless manipulations than nonanaemic girls. Anaemic boys were described as being more passive and less able to respond to nondominant features of the environment than nonanaemic boys. No information on statistical analyses, methods of testing, or study design was provided in the report. Furthermore, one study (Garn et al, 1975) has shown that blacks generally have haemoglobin values about I .o g/dl lower than iron-replete whites when socioeconomic status is controlled. In view of this finding and the apparent failure of iron therapy to raise the Hb level of many of these children, it is likely that a portion of the sample was not in fact ‘anaemic’. (iv) A study of 4-5-year-old black children enrolled in a ‘Head-Start’ programme was conducted in New Orleans (Sulzer et al, 1973). Two behaviour test batteries were used, one measured cognitive ability, and the other assessed endurance, memory, attention, reaction time, learning, and transfer of training. A haemoglobin value of less than 10.5 g/dl defined anaemia. Analysis of the results indicated a reliable statistical difference between normal and anaemic children on two IQ tests as well as on a reaction-time task involving associative learning. The
Annotution
I47
difference on the latter test may have resulted from inattention, poor motivation, or fatigue among the anaemic children, rather than from differences in learning ability. The retrospective nature of this study design makes it impossible to determine whether the index and control groups were equivalent except haematologically. Indeed, some evidence suggests that the nutritional history of the children interacted with their iron level in determining performance of the behaviour tests. Children of short stature who had anaemia obtained the lowest I Q scores. (v) Junior high school students (12-14 years old) living in an economically deprived, predominantly black community in Philadelphia have also been studied (Webb 8: Oski, 1973a, b, 1974). Ninety-two students were classified as anaemic (Hb levels ranging between 10.1and 11.4 g/dl). The remaining I O I students served as a normal control group (Hb ranging from 14.0 to 14.9 g/dl). Anaemic students did not perform as well as the control group on the achievement tests (Iowa Tests of Basic Skills). In addition, the index children took significantly longer (4.08 s) than controls (1.81 s) to respond on a visual after-image task. Finally, teacher evaluations indicated that anaemic males displayed significantly more conduct problems than nonanaemic males. Conclusions cannot be drawn from this retrospective study. (vi) Forty-seven Welsh women (20 years and older) whose Hb levels were below 10.5g/dl were randomly divided into treatment ( I 50 mg of iron as ferrods carbonate daily) and placebo groups (Elwood ,& Hughes, 1970). Haematological and psychological tests of psychomotor function were administered before and 8 weeks after treatment began. Analysis of the results yielded no between-group differences. A lack of effect of treatment was also noted when data were analysed according to increments in Hb with iron treatment. Possible explanations for these results include: ( I ) the behaviour areas tested are not affected by iron deficiency; ( 2 ) subjects were not sufficiently iron deficient for an effect to occur; (3) the tests were not sensitive enough. The available data are insufficient to exclude any of thesc alternative explanations. Brain Biochemistry The concentration of iron in the human brain increases during the first 20 years of life, achieving its highest levels in the phylogenetically oldest portions of the brain. The concentration ofiron in the globus pallidus (21.3 mg/Ioo g of fresh-weight brain), for instance, exceeds that in the iron-replete liver (13-14 mg/Ioo g) (Hallgren & Sourander, 1958). A small portion of this iron undoubtedly participates in brain oxidative metabolism, but much of it exists in a nonhaem form, possibly as ferritin (Hallgren 8: Sourander, 1958). In both rats and dogs, the majority (about 5 5 % ) of this nonhaem iron is in the mitochondria while a smaller amount (35%) is in the microsomal fraction; the remainder appears in the nucleus. Iron deficiency produces equivalent reductions in all subcellular fractions, and thus the relative distribution of nonhaem iron is unchanged. Brain ferritin presumably protects this organ from the vicissitudes of systemic iron status, and in the adult human (Hallgren & Sourander, 1958) these brain iron stores seem resistant to significant depletion even in the face of severe systemic iron deficiency. The timing of the insult seems critical, for permanent deficits in nonhaem iron (e.g. certain enzymes, ferritin) are demonstrable in the brains of rats deprived of iron from day 10 to day 28 of life and subsequently returned to an adequate iron intake (Dallman et a f , 1975). This failure to ameliorate iron deficiency in the brain is apparently the result of a very slow turnover rate
148
Annotation
for brain iron compounds rather than of a developmental decrease in the permeability of the blood-brain barrier to iron (Dallman & Spirito, 1977). Early studies in rats (Beutler, 1959; Dallman & Schwartz, 1965) reported a failure of systemic iron deficiency to result in decrements in brain iron compounds (aconitase;cytochrome C) despite reductions of these and other (succinate dehydrogenase, catalase) iron-containing enzymes in other tissues (muscle, intestine, kidney). More recent studies (Quik & Sourkes, 1977; Youdim & Green, 1977; Mackler et al, 1978) have confirmed the general impression of CNS enzyme resistance to iron deficiency by demonstrating undiminished activities of monoamine oxidase, tyrosine hydroxylase, succinate dehydrogenase, the cytochromes, and catalase in brains of irondeficient, anaemic rats. Mackler et a1 (1978), however, reported a 3 5 % reduction in brain aldehyde oxidase activity with an attendant I 5 % rise in the brain concentration of 5-hydroxyindole compounds in iron deficient rats. This reverted to normal I week after 5 mg of intraperitoneal iron dextran. The authors point out the similarity between behaviours (diminished responsivity and learning ability) reported in individuals with elevated brain tryptophan levels and those with iron deficiency. Youdim & Green (1977)~on the other hand, found reduced brain tryptophan levels in iron-deficient rats but no apparent functional deficit in enzymes concerned with catecholamine and indoleamine synthesis and catabolism. They attributed the diminished serotonin levels to reduced serotonin binding protein in synaptosomes. Youdim & Green (1977) also demonstrated a reduced physical activity after administration of catecholamine and serotonin precursors in iron-deficient rats. This reduction disappeared after 8 d of oral iron therapy. Because syntheticlcatabolic rates for these compounds were apparently normal (in conflict with Mackler et al, 1978) and because there was also a diminished response to serotonin and dopamine agonists, the authors concluded that the apparent defect in neurotransmission in iron deficiency is located somewhere in the post-synaptic response. However, a study by Finch et al (1976) in which muscle dysfunction was correlated with reduced muscle alphaglycerophosphate dehydrogenase activity and behaviour and biochemical normality were achieved within 4 d of iron therapy, implies that Youdim & Green may have been observing a peripheral (i.e. muscle tissue) rather than a central nervous effect of iron deficiency. Likewise, Dallman’s studies of iron turnover rates in brain make suspect the finding of Mackler et a1 (1978) of short-term recovery of a CNS iron-related biochemical lesion. Finally, although reversible deficits in platelet monoamine oxidase activity (Woods et af, 1977) and elevations in urinary norepinephrine excretion (Voorhess et al, 1975) have been demonstrated in iron-deficient humans, no CNS functional significance can be proven for these findings. And, in view of the points raised above, it is unlikely that these peripheral manifestations of iron deficiency reflect parallel alterations in CNS chemistry.
Developmental Considerations Important aspects of human brain development (glial proliferation, myelinization, dendrite arborization) occur during a period characterized by falling iron stores in the infant (Dallman, 1974). Because of the non-division of differentiated neurons, one would anticipate that, if iron deficiency affects central nervous system processes, growth during infancy would be especially vulnerable to abnormalities that might not be remediable by subsequent restoration of adequate iron intake. As noted previously, permanent deficits in non-haem iron are demonstrable in the brains of rats only transiently deprived of iron early in life.
Annotation
I49
If iron status does influence metabolism on the brain, it is likely that the impact of iron deficiency would vary with the developmental status of the brain. Thus, in the older child o r adult whose brain growth is complete, one might expect to see neLzrologica1 or psychological signs consistent with altered neurotransmitter function of oxidative metabolism, whereas in the infant (or older patient who was iron-deficient as an infant) one might expect to see, in addition, signs related to subtle structural alterations in the brain.
ACKNOWLEDGMENTS
Supported in part by Grant No HDo9228-03 from the National Institute of Child Health and Human Development, Department of Health, Education and Welfare, United States Public Health Service and by the Ford Foundation.
R. LEIBEL D. GREENFIELD
Department of Nutrition and Food Science, Massachusetts Institute of Technology, and Department of Pediatrics, Harvard University School of Medicine
E. POLLITT
REFERENCES ADAMSON, J.W. & FINCH,C.A. (1975) Hemoglobin function, oxygen affinity, and erythropoietin. Annual Review ofPhysiology, 37, 3 51-369. BERRY, W.T.C. & NASH,F.A. (1954) Symptoms as a guide to anaemia. British Medical journal, i, 918. BEUTLER, E. (1958) Iron enzymes in iron deficiency. VI. Aconitase activity and citrate metabolism.Journal of Clinical Investigation, 38, 1605-1616. BEUTLER, E., LARSH, S.E. & GURNEY, C.W. (1960)Iron therapy in chronically fatigued, nonanemic women: a double blind study. Annals of Internal Medicine, 52, 378-394. CANTWELL, R.J. (1974) The long term neurological sequelae of anemia in infancy. (Abstract). Pediatric Research, 8, 342. COLTMAN, C.A. (1969) Pagophagia and iron lack. Journal of the American Medical Association, 207, 513-516. COOK, J.D., FINCH,C.A. &SMITH,N.J. (1976) Evaluation of the iron status of a population. Blood, 48, 449-45 5. CROSBY, W.H. (1976) Pica. Journal of the American Medical Association, 235, 2765. DALLMAN, P.R. (1974) Tissue effects of iron deficiency. Iron in Biochemistry and Medicine (ed. by A. Jacobs and M. Worwood), pp. 437-475. Academic Press, New York. DALLMAN, P.R. & SCHWARTZ, H.C. (1965) Myoglobin and cyto-chrome response during repair of iron deficiency in the rat.Journal of Clinical Investigation, 44, 1631-1638.
DALLMAN, P.R., SIIMES, M.A. & MANIES, E.C. (1975) Brain iron: persistent deficiency following shortterm iron deprivation in the young rat. BritishJournal ofHaematology, 31, 209-215. DALLMAN, P.R. & SPIRITO, R.A. (1977) Brain iron in the rat: extremely slow turnover in normal rats may explain long-lasting effects of early iron deficiency. Journal ofNutrition, 107, 1075-1081. ELWOOD, P.C. & HUGHES, D. (1970) Clinical trial of iron therapy on psychomotor function in anaemic women. British Medicaljournal, iii, 254-255. ELWOOD,P.C., WATERS,W.E., GREENE,W.J.W., SWEFTNAM, P. & WOOD,M.M. (1969) Symptoms and circulating haemoglobin level. Journal of Chronic Diseases, 21. 615628. FAIRBANKS, V.F., FAHEY, J.L. & BEUTLER, E. (1971) Clinical Disorders oflron Metabolism. Grune & Stratton, New York. FINCH,C.A., MILLER, L.R., INAMDAR, A.R., PERSON, R., SEILER, K. & MACKLER, B. (1976) Iron deficiency in the rat. Physiological and biochemical studies of muscle dysfunction. Journal of Clinical Investigation, 589 447-453.
FRIEDEN, E. (1974) The evolution of metals as essential elements (with special reference to iron and copper). Advances in Experimental Medicine and Biology, 48, 1-31. GARN,S.M., SMITH,N.J. & CLARK, D.C. (1975) The magnitude and implications of apparent race differences in hemoglobin values. American Journal of Clinical Nutrition, 28, 563-565.
150
Annotation
HALLGREN, B. & SOURANDER, P. (1958) The effect of age on the non-haemin iron in the human brain. Journal ofNeurochemistry, 3, 41-5 I. HOWELL, D. (1971) Significance of iron deficiencies. Consequences of mild deficiency in children. In: Extent and Meanings of Iron Deficiency in the U.S., Summary Proceedings of a Workshop of the Food and Nutrition Board. National Academy of Sciences, Washington, D.C. LEIBEL, R.L., GREENFIELD, D. & POLL^, E. Iron deficiency: behavior and brain biochemistry. In: Nutrition: Pre- and Post-Natal Development (ed. by M. Winick). Plenum Press, New York. MACKLER, B., PERSON, R., MILLER, L.R., INAMDAR, A.R. & FINCH,C.A. (1978) Iron deficiency in the rat: Biochemical studies of brain metabolism. Pediatric Research, 12, 2 I 7-220. MCDONALD, R. & MARSHALL, S.R. (1964) The value of iron therapy in pica. Pediatrics, 34, 558-562. MCFARLANE, D.B., PINKERTON, P.H., DAGG, J.H. & GOLDBERG, A. (1967) Incidence of iron deficiency, with and without anaemia in women in general practice. BritishJournal offfaematology,13,790-796. MORROW, J.J., DAGG, J.H. & GOLDBERG, A. (1968) A controlled trial of iron therapy in sideropenia. Scottish MedicalJournal, 13, 78-83. OSKI, F.A. & HONIG,A.M. (1977) The effects of therapy on the developmental scores or iron deficient infants. (Abstract). Pediatric Research, 11, 380. POLLIIT,E. & LEIBEL, R.L. (1976) Iron deficiency and behavior. Journal of Pediatrics, 88, 3 72-3 8 I . QUIK,M. & SOURKES, T.L. (1977) The effect of chronic iron deficiency on adrenal tyrosine hydroxylase activity. CanadianJournal of Biochemistry, 5 ~ ~ 6 ~ 5 . REYNOLDS, R.D., BINDER,H.J., MILLER,M.B., CHANG, W.Y. & HORAN, S. (1968)Pagophagia and iron deficiency anemia. Annals of Internal Medicine, 693 435-440. ROSELLE, H.A. (1970) Association of laundry starch and clay ingestion with anemia in New York City. Archives ofInternal Medicine, 125, 57-61.
SULZER, J.L., WESLEY,H.H. & LEONIG,F. (1973) Nutrition and behaviour in Head Start children: results from the Tulane study. In: Nutrition, Development and Social Behaviour (ed. by D. J. Kallen). Department of Health, Education and Welfare, Publication No. (NIH) 73-242, Washington, D.C. VARAT, M.A., ADOLPH, R.J. & FOWLER, N.O. (1972) Cardiovascular effects of anemia. American Heart Journal, 83,415-426. VOORHESS, M.L., STUART, M.J., STOCKMAN, J.A. & OSKI,F.A. (1975) Iron deficiency anemia and increased urinary norepinephrine excretion.Journal of Pediatrics, 86, 542-547. WEBB,T.E. & OSKI,F.A. (1973a) Iron deficiency anemia and scholasticachievement in young adolescents.Journal of Pediatrics, 82, 827-830. WEBB,T.E. & OSKI,F.A. (1973b) The effect of iron deficiency anemia on scholastic achievement, behavioral stability and perceptual sensitivity of adolescents. (Abstract). Pediatric Research, 7, 294. WEBB,T.E. & OSKI,F.A. (1974) Behavioral status of young adolescents with iron deficiency anemia. Journal ofspecial Education, 8, 153-156. WIDDOWSON, E.M. (1969) Trace elements in human development. Mineral Metabolism in Paediatrics (ed. by D. Barltrop and W.L. Burland), p. 87. Adlard 8: Son, Dorking. P.C. (1966) Symptoms of WOOD,M.M. & ELWOOD, iron deficiency anaemia: a community survey. British Journal of Preventive and Social Medicine, 20, 117-121. WOODS,H.F., YOUDIM,M.B.H., BOULLIN, D. & CALLENDER, S. (1977) Monarnine metabolism and platelet function in iron-deficiency anemia. Iron Metabolism: Ciba Foundation Symposium 5 1 , p. 227. Elsevier, Amsterdam. YOUDIM,M.B.H. & GREEN,A.R. (1977) Biogenic amine metabolism and functional activity in irondeficient rats: behavioral correlates. Iron Metabolism, Ciba Foundation Symposium 5 1 , p. 201. Elsevier, Amsterdam.
