1. Absorption and Metabolism of Iron

Background

Iron is an essential trace element. Its rare property to oscillate between the divalent and trivalent state is utilized in proteins and enzymes to transport oxygen and electrons, both of which is pivotal for energy metabolism and to degrade xenobiotics. However, these properties are also the basis for detrimental effects, such as catalysis of oxidative stress. Moreover, iron is essential for bacteria and parasites. Ample.iron-supply supports the expansion of pathogen populations which is, again, detrimental for the host organism. In order to supply enough iron to maintain the essential functions during periods of scarce supply on the one hand, and to avoid excess during situations of over-supply on the other, a complex system of mechanisms has evolved to maintain iron homoeostasis. This system encompasses adaptation of intestinal iron absorption to the demand as well as the regulation of intracellular iron stores to provide for situations of scarcity and, at the same time, to avoid damage by unbound iron. In the circulation, iron is bound to transferrin which is taken up by the cells via transferrin receptors according to their demand. This complex system can become dysfunctional in a number of hereditary diseases (e.g. hemochromatosis): it can be overwhelmed by oversupply and may not be able to cope with grave states of undersupply. Moreover, it may interact with inflammation of different origin, or with toxic trace metals such as lead or cadmium.

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2. Iron and Inflammation

Iron Absorption in Mice

Genetically modified mice permit to investigate absorptive and metabolic pathways in vivo. Intestinal ⁵⁹Fe-absorption can be determined in vivo in ligated intestinal loops and after gavage. HGF investigated the mechanisms of intestinal iron absorption and body iron distribution by the methods described under 1. in a number of genetically modified murine models in cooperation with those working groups who developed the models or had them at hand. These studies contribute to the understanding of the molecular and physiological bases of interactions between iron metabolism and inflammation (I33, I36, I37, I41, I47, I48, I49, I51), to testing the extent to which lead went piggyback on the iron absorption system (I36), and to what extent ferritin-bound iron enters the body by pathways that differ from those of Fe(II) (I41).

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Iron and Malaria

The interaction between iron and malaria moved into focus of public health interests when a large intervention trial on Pemba Island, where malaria is hyper-endemic, was stopped at midterm. Evidence for more severe courses and higher mortality rates of malaria had become obvious in children without iron deficiency, who nevertheless received low-dose iron supplements. In consequence, the WHO stopped most iron supplementation programs in malaria endemic areas, leaving iron-deficiency in these areas untreated until date. This puts people living in malaria-endemic areas on the horns of a dilemma: either iron-deficient individuals receive no iron-supplements and suffer from deficiency symptoms (e.g. from impaired physical and intellectual capacity, cellular immune deficiency, increase rates of stillbirth and “small for gestational age” babies, or the population consumes iron-supplements which increases their risk for more severe courses of malaria and increased death rates (R23). Several ways to solve this dilemma were proposed: 1.) To target iron-supplements to iron-deficient individuals. 2.) To supplement iron-compounds that do not form non-transferrin-bound iron (= NTBI, a form of iron that is suspected to aggravate clinical malaria courses). 3.) To supply antimalarial drugs along with iron-supplements. HGF supported studies along the first two of these lanes.

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Iron Homeostasis and Obesity

Obesity goes along with inflammation. This increases circulating hepcidin concentrations which in turn reduces intestinal iron-absorption and promotes iron-sequestration into the stores. This disturbs hepcidin-medicated iron homoeostasis (R25, R26). Due to worldwide increases in obesity prevalence, particularly in developing countries, such interference between obesity and iron homoeostasis has considerable consequences. The same increments in body mass index (BMI), however, seem to affect iron homoeostasis to a different extent in different regions of the world. HGF plans to investigate this relationship in Guatemala.

According to current concepts hepcidin is a tissue hormone of largely hepatic origin. It regulates whole body iron availability by initiating ferroportin degradation which inhibits cellular iron export. Correspondingly, hepcidin expression increases in iron overload. This reduces intestinal iron absorption and sequesters iron in the reticuloendothelial system by blocking ferroportin-mediated iron export across the enterocytes’ basolateral membrane and out of leukocytes. Both reduces free iron concentration in the plasma. Hepcidin synthesis is also increased in inflammation in order to reduce iron availability to pathogens and to reduce oxidative stress as mediated by Fenton reaction.
However, in this respect literature reports are contradictory. Thus, reduced hepcidin concentrations were reported after injection of the pro-inflammatory cytokine TNF-α. Our foundation supported research on this issue in TNF^ΔARE/+- and IL10^-/--mice, two murine models of inflammation. In contrast to expectation, hepcidin concentration was, indeed, reduced in inflammation which, again in contrast to expectation, was not accompanied by increased intestinal iron absorption (I53). Both models showed anemia and stimulated erythropoiesis to compensate for this, though compensation was more marked in TNF^ΔARE/+-mice. These results indicate interactions between competing regulatory mechanisms – such as inflammation and anemia, the first tending to reduce intestinal iron absorption, the second tending to increase it. The integrated effects of such mechanisms determine the impact on hepcidin synthesis and intestinal iron absorption (I53).

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3. Non-transferrin-bound Iron (NTBI)

Background

Iron-deficient diets reduce the intensity of inflammation in a mouse model for colitis ulcerosa (I28). Intestinal iflammation remains low when the missing iron amounts were supplemented by parenteral injection (I37). These results help to understand the molecular mechanisms of inflammation and their contribution to oxidative stress and protein folding, as well as the effect of local inflammation on iron distribution (I29, I37). This opens perspectives for future therapeutic interventions.
Oxidative stress in the intestinal gut content participates in the pathogenesis of inflammatory bowel diseases and of colonic tumors. HGF supported the development of a method to determine the extent of oxidative stress in stool samples (I30). Oral iron supplementation at dosages recommended by WHO increases oxidative stress in the gut lumen significantly. This can be balanced by simultaneous consumption of antioxidative food components, such as palm oil (I30).

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4. Non-invasive Hemoglobin Measurement

Background

Iron supplements aggravate the clinical course of Plasmodium falciparum-induced malaria tropica, if they are not explicitly targeted to iron-deficient individuals. On the one hand, these findings point out the problem of untargeted iron-supplementation in malaria-endemic areas, as they lead to more severe clinical courses and increased death rates. Without iron intervention programs, on the other hand, iron-deficiency leading to impaired physical and mental development and increased numbers of still births and abortions are the consequence (R10). HGF analyzed this dilemma (R23) and supports the quest for its solution. A possible way-out is to develop or adapt inexpensive and robust methods for the determination of the hematological status, inflammatory- and iron-status. These methods should preferably be non-invasive to prevent dissemination of AIDS and hepatitis through blood sampling. HGF supported field-testing of devices for non-invasive, transcutaneous hemoglobin determination (I44, I32). To differ between anemia of iron-deficiency and anemia of inflammation, and to help with the decision whether to administer iron or not, we tested non-invasive parameters, e.g. the use of urinary 25-hepcidin (I35).

Results

In spite of some initially promising results, a breakthrough has not been reached and a reliable method for non-invasive hemoglobin determination could not be picked. The correlation with invasive standard methods remained poor for all tested methods of transcutaneous photometry.

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