Changing patterns of dietary iron overload in black South Africans.

Over the last 17 years there has been a significant reduction in the prevalence and severity of dietary iron overload in urban blacks of Johannesburg. This is attributed to a decrease in the consumption of traditionally brewed beer of high iron content over this period. A 40% reduction was found in hepatic iron concentrations measured in necropsy specimens from 248 male patients who died in 1976 as compared with 220 who died in 1959 and 1960. While hepatic iron concentrations rose with age in both groups there was no evidence of iron accumulation during the period between the two studies. Hepatic iron concentrations measured in 345 female subjects were many fold less than those of males and the 1976 group did not differ significantly from the 1959 to 1960 group. A paradoxical increase in the prevalence of portal fibrosis and cirrhosis was seen and may be due to the effects of increased ingestion of spirits and fortified wine in recent years. Iron overload was significantly greater in males with carcinoma of the esophagus and in those with idiopathic heart failure when compared to subjects who died of other causes. This suggests excessive exposure of these subjects to traditionally brewed beverages and the adulterants present in them.

Storage iron in "muscle".

In Bantu subjects with iron overload iron is visible in skeletal muscle cells and in the tissue histiocytes which lie between these cells. In the present study the concentrations of ;muscle' iron were measured chemically in subjects with varying hepatic storage iron concentrations. The results indicate that the concentrations of storage iron in ;muscle' are much lower than those in the liver. However, the muscle mass is so large that the total amount of iron present is at least equal to that in the liver in subjects with normal body stores. The concentrations of iron in ;muscle' are raised in subjects with iron overload but the degree to which they rise is far less than occurs in the liver; a thirtyfold increase in hepatic iron concentrations is associated with only a sixfold increase in ;muscle' iron. Experiments in rats revealed that storage iron in ;muscle' represents a relatively non-miscible pool which responds very little to acute changes in the iron environment.

Iron absorption.

The rate of absorption of iron is adjusted according to body iron requirements, but the virtual absence of heme and the poor bioavailability of the nonheme iron in the diets of many people, especially in developing countries, means that the amount that can be absorbed is limited. Those whose requirements are increased by growth, menstruation, or pregnancy frequently cannot absorb enough. Sufficient is now known about the factors in food that increase or diminish the bioavailability of nonheme iron to permit the effective fortification of dietary staples, although the application of this information has proved difficult particularly in the Third World where nutritional iron deficiency is most prevalent. Effective fortification may lead to iron overload in those whose control of iron absorption is genetically defective, and recent evidence that the HLA-linked recessive gene for idiopathic hemochromatosis may occur much more commonly than hitherto suspected makes it imperative that an effective monitoring system should form a part of every fortification program.

The relationship between maternal and infant iron status.

Serum ferritin, iron and haemoglobin (Hb) concentrations were determined in 103 pregnant women and in the cord of their normal full-term offspring. In 50 of the cases the placental non-haem iron was also measured. The correlations between serum ferritin concentration and other measurements of iron status were similar in both maternal and cord blood suggesting that cord serum ferritin concentration may, as in adults, reflect neonatal iron stores. The inverse relationship found between cord serum ferritin and hb concentrations (r = -0.35, P less than 0.001) suggests that the amount of iron in foetal stores is influenced by that required for Hb. When Hb levels are elevated, as was demonstrated in babies of older mothers, significantly lower serum ferritin were found. Thus a low cord serum ferritin concentration does not necessarily indicate that less iron was transferred to the foetus. Maternal iron reserve, as reflected by serum ferritin concentration, was shown to be related to the amount of non-haem iron in the placenta (r = 0.41, P less than 0.005), but this iron does not seem to form part of foetal iron stores as it does not correlate with measurements of foetal iron status. A week correlation between cord and maternal serum ferritin concentrations was demonstrated (r = 0.21, P less than 0.05) but its biological significance is questionable.

Effects of iron overload on ascorbic acid metabolism.

Studies of the ascorbic acid status in two subjects with idiopathic haemochromatosis and in 12 with transfusional siderosis showed that all had decreased levels of white cell ascorbic acid. The urinary excretion of ascorbic acid was also diminished in those subjects in whom such measurements were made. The administration of ascorbic acid was followed by only a small rise in the urinary ascorbic acid output, while the oxalic acid levels (measured in two subjects) showed a significant rise. These findings resemble those described in siderotic Bantu, and support the thesis that increased iron stores lead to irreversible oxidation of some of the available ascorbic acid.

The mechanism of endotoxin-induced hypoferraemia.

The effect of endotoxin on the processing of erythrocyte iron by reticuloendothelial cells of the liver and spleen was studied in rats using heat damaged erythrocytes labelled with 59Fe. Endotoxin did not alter the uptake of the damaged cells but markedly inhibited the subsequent early phase of iron release from the reticuloendothelial cells. The inhibition seemed to be due to both a decreased rate of labelled haem destruction and an increased incorporation of radioiron into ferritin. Although early iron release was decreased 0--2 h after endotoxin administration, the diversion of iron into ferritin was more marked when endotoxin was given 18 h before. The block in iron release was partially overcome in animals that had been kept on an iron free diet or had been phlebotomised. In these animals the decreased rate of haem catabolism remained unaltered but less iron was diverted into ferritin.

Studies on the fortification of cane sugar with iron and ascorbic acid.

1. The feasibility of improving iron nutrition by fortifying cane sugar with Fe and ascorbic acid was studied. 2. It was found to be possible to add a number of Fe salts together with ascorbic acid to sugar without affecting its appearance or storage properties. 3. The absorption of Fe from fortified sugar eaten with maize-meal porridge or made into jam or biscuits was measured in ninety-four volunteer multiparous Indian women using the 59-Fe erythrocyte utlization method. 4. The absorption of Fe from sugar fortified with ascorbic acid and ferrous sulphate and eaten with maize-meal porridge was increased about twofold in the ratio, ascorbic acid:Fe was 10:1 by weight. If the ratio was increased to 20:2, Fe absorption was increased a further threefold. 5. Sugar fortified with soluble Fe salts, including FeSO4.7H2O, discoloured both tea and coffee; sugar fortified with ferric orthophosphate did not have this effect. 6. Fe from FePO4.H2O was poorly absorbed when added with sugar to maize-meal porridge, and also when added with adequate quantities of ascorbic acid. This form of Fe was absorbed much less well than was the intrinsic Fe present in the maize. 7. When sugar fortified with FePO4.H2O and ascorbic acid was added to maize-meal porridge before cooling or was made into jam there was a several-fold increase in the amount of Fe absorbed.

The mechanism of the inhibition of iron absorption by tea.

Previous human studies have shown that drinking tea during meals significantly inhibits the absorption of both food iron and medicinal iron. This study provides evidence from experiments with rats that the tannins in the tea are responsible for the inhibition, probably by forming non-absorbable complexes with the iron within the intestinal lumen. The molar ratio of tannin: iron is dependent on the pH, being 1:1 at pH 2,0 2:1 at pH 5,5 and 3:1 at pH 8,0. Since tannins are present in many vegetable foods the formation of such complexes may be a factor in the poor availability for absorption of much food iron.

Equilibration of tracer radioiron with body iron.

1. The degree to which a tracer quantity of 55Fe bound to transferrin and introduced into the plasma 36 months previously had equilibrated with the body iron was studied in a subject who was phlebotomized repeatedly until iron-deficiency anaemia developed. 2. Analysis of the results with two mathematical models showed that equilibration with haemoglobin iron and storage iron was complete. 3. Estimates of the quantity of iron initially stored in the body by three different methods yielded values of 37.3, 33.1 and 34.8 mmol. 4. Since the previously determined mean initial plasma ferritin concentration was 185 micrograms/1 (462 pmol/1), there was 0.179-0.197 mmol of stored iron per 1 microgram of plasma ferritin/1. 5. The study suggests that the assumption on which currently accepted values for daily body iron loss were calculated is valid.

Effect of diet on the rate of iron accumulation in idiopathic haemochromatosis.

There is still controversy concerning the effects of increasing the dietary intake of iron on iron nutrition. This debate has not only centered on the question of efficacy but also on that of safety. At particular potential risk are those individuals with disorders such as idiopathic haemochromatosis, who absorb iron excessively from the diet. Data obtained in the present study and in several other investigations suggest that subjects homozygous for the mutant gene responsible for the disorder would develop clinical features of the disease at a younger age were the dietary iron intake to be increased. Iron stores in affected heterozygotes would increase but the size of the stores would probably equilibrate long before they had reached massive proportions. While these conclusions are drawn from a number of studies, there are enough unanswered questions to make it mandatory for any future fortification programmes, whether they be directed at the entire population or only at certain segments of it, to be carefully monitored. This can currently be achieved with serial plasma ferritin measurements, since the concentrations mirror the size of iron stores in the body.

Mobilisation of iron from peritoneal rat macrophages by desferrioxamine.

The amount of radioiron released from rat peritoneal macrophages after phagocytosis of 59Fe labelled erythrocytes can be enhanced by addition of desferrioxamine. The effect is dose dependent and the iron chelated by desferrioxamine appears to be at the expense of ferritin. However, desferrioxamine does not appear to chelate iron already incorporated into ferritin. It seems likely that the iron comes from a labile chelatable pool through which the iron from haemoglobin catabolism passes before being incorporated into ferritin. The desferrioxamine appears to enter the macrophage and chelate iron to form ferrioxamine which subsequently leaves the macrophage. In vivo it was not possible to show substantial iron chelaton by desferrioxamine in rats when 59Fe labelled non-viable red cells were injected intravenously. This suggests that in vivo mobilization of reticuloendothelial iron by desferrioxamine may be of limited significance.