Peter R. Dallman

Percentile curves for hemoglobin and red cellvolume in infnacy and childhood

Percentile curves were calculated for hemoglobin and mean corpuscular volume in children between 0.5 and 16 years of age. The curves were derived from several populations of non-indigent white children who lived near sea level. Subjects were excluded from the reference population if they had laboratory evidence of iron deficiency, thalassemia minor, and/or hemoglobinopathy. The final reference populations included 9,946 children for the derivation of the hemoglobin curves and 2,314 for the MCV curves. The percentile curves should be particularly applicable to the diagnosis and screening of iron deficiency and thalassemia minor.

Brain Iron: Persistent Deficiency following Short-term Iron Deprivation in the Young Rat

This study was designed to determine the content of non‐haem iron in the brain as iron deficiency develops in the rapidly growing rat. Rats were provided with either an iron‐deficient diet or an identical control diet with added ferrous sulphate starting at 10 d of age and continuing after weaning at 21 d. At 28 or 48 d of age the deficient animals received 5 mg of iron (iron dextran) i.m. and were placed on the control diet regimen. The deficient animals had a concentration of non‐haem iron in the brain that was 27% below the control value at 28 d and 22% below at 48 d. After 14–45 d of iron treatment, the non‐haem iron remained depressed, 19–29% below the control means (P<0.05 to 0.001). Ferritin iron in brain also remained depressed, 33–42% below the control means (P<0.01). In contrast, haematocrit, liver non‐haem iron, and liver ferritin iron, although they were more profoundly depressed in the iron‐deficient animals, promptly returned to control values after treatment with iron. Thus, a brief period of severe iron deficiency in the young rat resulted in a deficit of brain iron that persisted in the adult animal despite an adequate intake of iron.

At what age does iron supplementation become necessary in low-birth-weight infants?†

Prevention of iron deficiency in low-birth-weight infants requires iron supplementation before neonatal iron stores are exhausted. In order to accurately determine when this depletion occurs, we measured the hemoglobin, mean corpuscular volume, serum iron/iron-binding capacity, and serum ferritin in 117 low-birth-weight infants (1,000 to 2,000 gm) from 0.5 until 6 months of age. All infants received banked breast milk in the hospital and breast milk or cow milk formula later; those with odd birth dates received 2 mg iron as ferrous sulfate/kg/day starting at 0.5 months; those with even birth dates received no additional iron unless they developed anemia. The results indicate that low-birth-weight infants who receive no supplemental iron may develop iron deficiency by three months of age and that a dose of iron of 2 mg/kg/day started at two weeks of age prevents iron deficiency without providing excess.

Cardiac hypertrophy in rats with iron and copper deficiency: quantitative contribution of mitochondrial enlargement.

ExtractQuantitative studies of the ultrastructure of heart muscle in iron- and copper-depleted rats show an increased mitochondrial area that contributes to cardiac hypertrophy in both conditions. The mean ratios of mitochondrial/myofibrillar areas are 1.73 and 1.69, respectively, in the deficient groups compared with 0.70 in control animals. The markedly enlarged mitochondria appear to displace and distort the myofibrils. After iron-deficient rats are provided with iron, the reversal of the abnormal mitochondrial/myofibrillar ratio and of cardiac hypertrophy requires about 16 days or approximately twice as long as the complete repair of anemia.In heart muscle from iron-deficient animals, the mitochondrial cytochromes, which all contain iron, remain essentially normal in concentration. In the copper-deficient rats, in contrast, cytochrome a+a3, which contains copper, is depressed to less than one-half the normal concentration. Isolated mitochondria from heart and liver of all animals deficient in iron and copper function normally with respect to respiration and phosphorylation. Thus, a correlation between abnormality of mitochondrial structure, composition, and function is not as yet apparent.The mitochondrial contribution to the cardiac hypertrophy of iron and copper deficiency cannot be attributed entirely to increased work load secondary to anemia, particularly in copper-deficient rats whose cardiac enlargement precedes the development of anemia. The morphologic changes are distinct from those observed in experimental work hypertrophy and can represent a response to the lack of essential precursors required for the cytochromes or other mitochondrial constituents.Speculation: Cardiac hypertrophy in iron and copper deficiency is in part attributable to enlargement of the mitochondrial compartment. This results from the lack of trace metals required for the production of cytochromes or other mitochondrial constituents.

Postnatal changes in erythropoietin levels in untransfused premature infants

The purpose of this study was to determine whether an inappropriately low erythropoietin response in premature infants might be a basis for the anemia of prematurity. Erythropoietin was measured by radioimmunoassay in conjunction with hemoglobin and reticulocyte count in untransfused premature infants between birth and 60 days of age. The 27 infants had a mean gestational age of 31 weeks and a mean birth weight of 1378 gm. Between 2 and 30 days, mean erythropoietin concentration was 9.7 mU/ml, significantly and substantially lower than 15.2 mU/ml in 15 concurrently studied healthy adults (P less than 0.01). Subsequently, from 30 to 60 days, values rose gradually to a mean of 17.2 mU/ml, which did not differ significantly from the mean value in adults. Hemoglobin values fell from a mean of 12.9 gm/dl during the first month to 9.0 gm/dl between 30 and 60 days. Thus, during the second postnatal month, preterm infants had essentially the same erythropoietin values as in adults despite a mean hemoglobin concentration that averaged less than two thirds the adult value. This failure to mount a greater erythropoietin response may help to explain why hemoglobin declines to such low values at 2 months of age.

Long-term consequences of early iron deficiency in the rat.

A period of severe early iron deficiency (birth to 28 days of age) produced a persistent deficit (22%) in brain non-heme iron in adult rehabilitated animals. Long-term effects on behavior and physiological responsiveness were also observed. Although rehabilitated and control animals did not differ either in basal levels of plasma corticosterone or in the time course of the stress response following ether and cardiac puncture, possible differences in pituitary-adrenal responsiveness appeared to emerge following testing in an exploratory task. In addition, significant differences between rehabilitated and control animals were observed in both active and passive avoidance learning. Rehabilitated males made more intertrial responses than control males during active avoidance learning, and rehabilitated animals of both sexes performed better (i.e. showed longer reentry latencies) in a passive avoidance situation. It was suggested that shock may differentially affect motivation or arousal in rehabilitated and control animals.

Effects of iron deficiency exclusive of anaemia

EFFECTS O F IRON DEFICIENCY EXCLUSIVE OF ANAEMIA The symptoms of iron deficiency are partly due to the compromised delivery of oxygen to the tissues that results from a decrease in the concentration of hacmoglobin (Anderson & Barkve, 1970; Viteri & Torun, 1974; Gardner et a l , 1975). However, iron deficiency also results in depletion of iron-containing compounds in solid tissues (Beutlcr, I 964; Jacobs, I 969; Fairbanks et al, 1971; Dallman, I974), and it is reasonable to expect this to contribute to the clinical manifestations. While it is difficult to separate the physiological consequences of deficiencies in tissue iron compounds from those of anaemia, there has recently been some success in making this distinction by the demonstration of impaired exercise tolerance in the rat and of defects in the immune response in man, both of which occur indepcndcntly of anaemia. Such findings have stimulated renewed interest in delineating the links between disordered function and biochemical abnormalities in iron deficiency.

New Kinetic Role for Serum Ferritin in Iron Metabolism

Summary. The role of the iron in serum ferritin was investigated with regard to iron kinetics. Serum (or plasma) was fractionated on a sucrose gradient by ultra‐centrifugation to separate iron in ferritin from other iron‐containing components in serum. After injection of heat‐treated [59Fe]RBC in rats, detectable labelling of the serum ferritin fraction was brief, between 20 and 40 min. The labelling of other iron components in the serum was maximal between 1 and 2 hr. No labelling of the serum ferritin fraction was detected after intravenous administration of [59Fe]‐transferrin in man and in the rat, or after [59Fe]haemoglobin‐haptoglobin or oral [59Fe2+]citrate in the rat. These results indicate that iron in serum ferritin originates in part from the degradation of haemoglobin in senescent red cells and that this labelled ferritin is cleared from the serum rapidly.

Anemia in children with acute infections seen in a primary care pediatric outpatient clinic.

Anemia is a recognized feature of chronic disease and severe acute infection in hospitalized children. The purpose of this study was to determine the association of anemia with manifestations of infection in an unselected group of children seen as outpatients. The group consisted of 1347 children between the ages of 0.5 and 12 years that were seen over a 3-month period. Anemia was detected in 17% of the children ages 6 to 47 months (hemoglobin (Hgb) less than 11.0 g/dl) and in 5% of the children between 4 and 12 years of age (Hgb less than 11.5 g/dl). The prevalence of anemia was strongly associated with the degree of inflammation as indicated by the erythrocyte sedimentation rate (ESR). Of those children ages 6 to 47 months with an ESR greater than or equal to 50 mm/hour, 91% had Hgb less than 11.0 g/dl and 52% had Hgb less than 10.0 mg/dl. In contrast anemia (Hgb less than 11.0 g/dl) was rare (9%) in the group with ESRs of 0 to 19 mm. The corresponding prevalences of anemia in other ESR categories were 49% with ESR 40 to 49 mm/hour, 28% with ESR 30 to 39 mm/hour and 16% with ESR 20 to 29 mm/hour. There was also a significant association of anemia with the duration of fever in the children ages 6 to 47 months with ESR greater than or equal to 40 mm. The results show that anemia was commonly associated with the usually mild infections that are typically seen in a pediatric primary care setting. The anemia could be inferred to be reversible and unrelated to iron deficiency in most cases.

Diagnosis of iron deficiency: The limitations of laboratory tests in predicting response to iron treatment in 1-year-old infants

This study was designed to compare the effectiveness of laboratory tests for iron deficiency (mean corpuscular volume, erythrocyte protoporphyrin, transferrin saturation, and serum ferritin) in predicting hemoglobin response to iron therapy in infants found to have low Hgb concentrations. Screening for anemia was performed on capillary blood of 1,128 healthy 1-year-old infants of United States Air Force personnel. The 25% who had Hgb values less than 11.5 gm/dl were asked to return for tests on venous blood before therapy and again after three months of therapy. Of the 188 infants completing therapy, 66 (35%) had a rise in Hgb concentration greater than or equal to 1.0 gm/dl and were designated responders. None of the confirmatory tests on venous blood reliably distinguished responders from those who subsequently showed no response. By using any one of the tests in combination with a capillary Hgb value less than 11.5 gm/dl, more than half of the infants with an abnormal value responded. But well over half of the responders would have been missed if treatment had been restricted to infants with abnormal values. Neither changes in the criteria for normality nor combinations of tests substantially improved our ability to distinguish the two groups. Because of the difficulty in distinguishing responders from nonresponders with additional laboratory tests and because of the simplicity, low cost, and relative safety of iron therapy in infants, we favor an initial therapeutic trial of iron first for determining the cause of low Hgb values in similar high-risk populations. Further costly workup can then be reserved for the small number of infants who still have unexplained Hgb concentrations less than 11.0 gm/dl after a therapeutic trial.