Iron requirements in pregnancy and strategies to meet them.

Iron requirements are greater in pregnancy than in the nonpregnant state. Although iron requirements are reduced in the first trimester because of the absence of menstruation, they rise steadily thereafter; the total requirement of a 55-kg woman is approximately 1000 mg. Translated into daily needs, the requirement is approximately 0.8 mg Fe in the first trimester, between 4 and 5 mg in the second trimester, and >6 mg in the third trimester. Absorptive behavior changes accordingly: a reduction in iron absorption in the first trimester is followed by a progressive rise in absorption throughout the remainder of pregnancy. The amounts that can be absorbed from even an optimal diet, however, are less than the iron requirements in later pregnancy and a woman must enter pregnancy with iron stores of >/=300 mg if she is to meet her requirements fully. This is more than most women possess, especially in developing countries. Results of controlled studies indicate that the deficit can be met by supplementation, but inadequacies in health care delivery systems have limited the effectiveness of larger-scale interventions. Attempts to improve compliance include the use of a supplement of ferrous sulfate in a hydrocolloid matrix (gastric delivery system, or GDS) and the use of intermittent supplementation. Another approach is intermittent, preventive supplementation aimed at improving the iron status of all women of childbearing age. Like all supplementation strategies, however, this approach has the drawback of depending on delivery systems and good compliance. On a long-term basis, iron fortification offers the most cost-effective option for the future.

Iron fortification with special reference to the role of iron EDTA

La fortificación con hierro ha sido ampliamente utilizada por varías décadas en muchos países industrializados para combatir la deficiencia de hierro y parece haber jugado un papel significativo en su reducción, particularmente en niños y mujeres. La estrategia general ha sido la fortificación con hierro de alimentos básicos como la harina de trigo. Aunque los efectos parecen ser positivos, aún persisten problemas por resolver. En este contexto, la selección del fortificante siempre representa un compromiso entre compuestos químicamente reactivos de alta biodisponibilidad como el sulfato ferroso y los compuestos inertes, de muy poca absorción. El sulfato ferroso es muy efectivo cuando es agregado durante la preparación del pan y productos de panificación y de fórmulas infantiles, pero no puede usarse en harinas de reserva por los problemas organolépticos, por lo que compuestos inertes de hierro elemental en polvo tienen que usarse. La búsqueda por compuestos de alta biodisponibilidad que no causen cambios organolépticos en los vehículos al que son agregados continua. Los problemas asociados a la efectividad de los programas de fortificación en países en desarrollo están influenciados por una variedad de factores. La mayoría de los vehículos potenciales no son procesados centralmente, existen ligandos inhibidores en las dietas básicas que deprimen la absorción tanto del hierro intrínseco como el hierro agregado. La anemia es de etiología multifactorial, los recursos financieros son limitados y el apoyo gubernamental está a veces ausente. A pesar de todas las dificultades, hay signos de progreso prometedores en varios países, utilizando una variedad de fortificantes y vehículos. En la presente revisión se ha dado particular atención al papel potencial del hierro EDTA como fortificante en países en vías de desarrollo. Este compuesto está afectado por los inhibidores de la absorción de hierro presentr en las dietas bajo biodisponibilidad, puede agregarse a varios vehículos sin provocar cambios organolepticos y su eficacia ha sido afirmada en tres estudios de intervención

Iron fortification with special reference to the role of iron EDTA.

Iron fortification has been used for decades in a number of industrialized countries to combat iron deficiency and seems to have played a significant role in reducing its prevalence, especially in infants and women. The overall strategy has been one in which staples such as wheat, flour, have been fortified with iron. While the effects appear to have been positive, there are still problems not yet completely resolved. In this context, the selection of the fortificant always represents a compromise between a choice of chemically reactive compounds of high bioavailability, such as ferrous sulfate, and inert compounds, which are poorly absorbed. Ferrous sulfate is very effective when added during the preparation of bread and bakery products and infant formulas, but cannot be used in stores flour because of organoleptic problems and inert compounds, such as elemental iron powders, have to be used. The search, therefore, continues for compounds of high bioavailability which do not cause organoleptic changes in the vehicles to which they are added. Problems associated with effective iron fortification programmes are compounded in a number of developing countries by a variety of factors. Most potential vehicles are not centrally processed, inhibitory ligands in staple cereal diets depress the absorption of both intrinsic and fortification iron, anemia is often of multifactorial in etiology, financial resources are scanty and governmental support sometimes lacking. Despite such difficulties there are encouraging signs of progress in a number of countries, using a variety of fortificants and vehicles. In the present review particular attention is paid to the potential role of NaFeEDTA as a fortificant in developing countries. It is much less affected by the inhibitors of iron absorption present in diets of low bioavailability, it can be added to a number of vehicles without causing organoleptic problems and its efficacy has been underlined in three intervention studies.

Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects.

The human leukocyte antigen (HLA)-linked iron-loading gene (HFE) associated with the autosomal recessive disorder known as hereditary hemochromatosis occurs in about 10% of subjects of European descent, most of whom are unaffected heterozygotes. In contrast, the 3 to 5 per 1,000 who are homozygotes are at risk of developing severe and potentially lethal iron overload, with damage to a number of organs, including the liver, pancreas, heart, joints, and the endocrine glands. Although the removal of the excess iron by repeated venesections is simple, effective, and safe therapy, much of the organ damage, once it has occurred, is irreversible. Because symptoms are often nonspecific, it is important for physicians in the relevant specialties to develop a high index of suspicion and to apply widely the appropriate screening tests, including transferrin saturation and serum ferritin concentration. Equally important is the detection of affected family members, who are usually siblings, before they have developed significant iron overload. In addition, screening of populations in which the prevalence of hereditary hemochromatosis is high has become an attractive and cost-effective option, especially now that the molecular structure of the HFE gene has been defined. Using this approach it is now possible to detect individuals homozygous or heterozygous for the gene using a simple polymerase chain reaction-based test. The application of this exciting new tool promises to provide fresh insights into the range of phenotypic expression in hereditary hemochromatosis. A challenge for the future will be to define the genetic or environmental factors responsible for iron overload in up to 20% of patients with clinical hemochromatosis who do not have the HFE gene.

Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited.

We analyzed data from the first study of iron overload in Africans, conducted between 1925 and 1928, to determine whether this common condition is associated with death from hepatocellular carcinoma and/or tuberculosis. In the original study, necropsies were performed on 714 adult blacks from southern Africa. Hepatic and splenic iron levels were measured semiquantitatively in 604 subjects and one of five iron grades was assigned. We examined death from hepatocellular carcinoma or from tuberculosis and the variables of age, sex, the presence of cirrhosis or other diagnoses that might be influenced by iron status, and tissue iron grades. Nineteen percent of men and 16% of women had the highest grade of hepatic iron. After adjustment for the presence of cirrhosis, hepatic iron grade was the variable most significantly associated with death from hepatocellular carcinoma (P = .021). The odds of death from hepatocellular carcinoma in subjects with the highest grade of hepatic iron was 23.5 (95% confidence interval, 2.1 to 225) times the odds in subjects with the three lowest grades. Splenic iron was the variable most significantly associated with death from tuberculosis (P <.0001). The odds of death from tuberculosis with the highest grade of splenic iron was 16.9 (4.8 to 59.9) times the odds with the two lowest grades. These findings suggest that iron overload in black Africans may be a risk factor for death from hepatocellular carcinoma and for death from tuberculosis.

Overview and mechanisms of iron regulation.

There are two major disturbances of iron balance: iron deficiency and iron overload. Iron-deficiency anemia is a major problem in developing countries and affects between 500 million and 600 million people worldwide. While iron overload is much less prevalent, it has a number of major pathologic sequelae and there have been recent suggestions that even modest increases in the body's iron stores may have pathologic associations. To understand the ways in which iron balance can be disturbed, it is necessary to have an understanding of how losses from the body are matched by the absorption of iron in different dietary settings as well as the limits of this regulatory control.

Serum transferrin receptor in hereditary hemochromatosis and African siderosis.

The present investigation evaluated the serum transferrin receptor concentration in subjects with nontransfusional iron overload who were identified in two separate studies on the basis of a serum ferritin level above 400 micrograms/L. Subjects with preclinical hereditary hemochromatosis were evaluated in the first study and those with the African form of iron overload in the second. In the first study, hereditary hemochromatosis was identified in 14 white men on the basis of a persistent elevation in transferrin saturation above 55%. The serum receptor concentration was elevated above the upper cut-off of 8.5 mg/L in two of the subjects, but the mean receptor of 6.1 +/- 1.4 mg/L (mean +/- 2 SE) did not differ significantly from the normal mean for this assay of 5.6 +/- 0.3 mg/L. In the same study, 60 control subjects with secondary iron overload were identified on the basis of a serum ferritin persistently above 400 micrograms/L, with a normal serum C-reactive protein concentration but with a transferrin saturation < 55%. Three of these subjects had an elevated serum receptor concentration but the mean value of 5.5 +/- 0.4 mg/L did not differ from normals nor from subjects with hemochromatosis. In the second study, 49 black Africans with iron overload were divided into those with or without an elevated transferrin saturation. The mean serum receptor concentration of 5.0 +/- 0.8 mg/L and 4.5 +/- 0.4 mg/L, respectively, did not differ statistically. It was concluded that there is no evidence of generalized dysregulation of the transferrin receptor in hemochromatosis or African siderosis.

EDTA and the absorption of iron from food.

Iron EDTA is an effective fortificant in meals of low iron bioavailability. Na2EDTA, added to food to prevent oxidation, enhances iron bioavailability by chelating added iron. This study examines the optimal ratio of EDTA to iron causing enhanced iron absorption. Iron absorption from a rice-based meal of low iron bioavailability containing increasing molar ratios of EDTA to iron, was compared in 127 women volunteers by using standard double isotope techniques. Iron deficiency was present in 38% of the women. Mean standardized absorptions, at EDTA-iron ratios of 0.25, 0.5, and 1, were 11.3%, 13.5%, and 8.8%, respectively, compared with 3.8% when no Na2EDTA was present. In meals of high iron bioavailability, Na2EDTA (EDTA:Fe, 1.0) produced little enhancement (potato-based meal) nor inhibited iron absorption (apple-based meal). Na2EDTA added to meals with molar ratios of EDTA to iron between 1.0 and 0.25 significantly increases iron absorption provided the meal is of low iron bioavailability.

Anaemia, iron-related measurements and erythropoietin levels in untreated patients with active leprosy.

The mechanisms responsible for anaemia in leprosy were studied prior to the institution of therapy in 56 patients with active disease. Haematological indices, iron-related measurements, inflammatory markers and erythropoietin levels were assessed, with bone-marrow studies being performed on anaemic patients. Anaemia was more common in the patients with lepromatous leprosy (85.7%) than it was in the rest of the group (19%). The lepromatous group exhibited the disordered iron transport of the anaemia of chronic disorders in that they had a significantly lower mean serum iron level (P less than 0.05), and a mildly raised serum ferritin concentration. Anaemic lepromatous patients also showed a blunted erythropoietin response compared with controls with non-inflammatory anaemia. A subgroup of five anaemic subjects displayed apparently adequate transport of iron to the erythroid marrow (normal percentage transferrin saturations and appropriate sideroblast counts) and the blunted erythropoietin response appeared to be the dominant factor in the pathogenesis of their anaemia. Analysis of inflammatory markers revealed that while the erythrocyte sedimentation rate was very high in the lepromatous subjects, there was no concomitant rise in C-reactive protein concentration. This suggests the presence of a disordered cytokine-mediated acute phase response in the condition.

Ascorbic acid prevents the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption.

The effects of maize-bran phytate and of a polyphenol (tannic acid) on iron absorption from a white-bread meal were tested in 199 subjects. The phytate content was varied by adding different concentrations of phytate-free and ordinary maize bran. Iron absorption decreased progressively when maize bran containing increasing amounts of phytate phosphorous (phytate P) (from 10 to 58 mg) was given. The inhibitory effect was overcome by 30 mg ascorbic acid. The inhibitory effects of tannic acid (from 12 to 55 mg) were also dose dependent. Studies suggested that greater than or equal to 50 mg ascorbic acid would be required to overcome the inhibitory effects on iron absorption of any meal containing greater than 100 mg tannic acid. Our findings indicate that it may be possible to predict the bioavailability of iron in a diet if due account is taken of the relative content in the diet of the major promoters and inhibitors of iron absorption.

Maternal and fetal iron measurements in a hemochromatotic pregnancy.

The findings in the cord blood sample of an infant from a treated hemochromatotic mother of a raised transferrin saturation (88%) and a raised ferritin concentration (250.2 micrograms/L) together with elevated maternal values (66% and 91.6 micrograms/L, respectively) yet a normal total placental iron content (26.9 mg) suggested that in common with gastrointestinal mucosal cells and reticuloendothelial cells in hemochromatosis, the placental cell may exhibit an abnormality of iron storage and transport.

Effects of alpha-interferon on iron-related measurements in human subjects.

Subcutaneous administration of alpha-interferon to normal volunteers caused hypoferraemia and hyperferritinaemia. There was, however, no concomitant rise in other components of the acute-phase response, including the serum C-reactive protein value, the granulocyte count and the plasma lactoferrin concentration. In fact, the latter two dropped significantly. The hypoferraemic response could be prolonged when a second dose was given 48 hours after the initial one. This hypoferraemic response may play a role similar to that induced by interleukin-1, which limits the proliferation of invading micro-organisms or neoplastic cells. The present findings may therefore have relevance to the clinical mechanism of action of the interferons.