Dosing and Treatment

Successful management of iron deficiency should replenish iron stores, improve symptoms and limit the negative clinical consequences associated with insufficient iron. These include increased morbidity, reduced quality of life and, in some cases, mortality1.

A number of therapeutic options are available; however, all have limitations that restrict their use. Care must be taken to choose the appropriate treatment strategy for the individual patient and this will depend on the underlying cause of the iron deficiency, as well as the overarching clinical picture.

Oral iron

Treatment with oral iron – such as ferrous sulphate, gluconate or fumerate – offers a relatively simple and cost-effective option for iron replacement. Daily supplementation with oral iron is often recommended as a preventative measure during pregnancy, where normal dietary iron intake is insufficient2.

There are instances where the efficacy of oral iron is limited. This is because oral iron has low bioavailability, with an approximate intestinal absorption of only 10%. This is due, in part, to free iron forming complexes with certain foods and medicines in the gut, and to inhibition by proteins such as the liver hormone, hepcidin​3,4. The secretion of hepcidin from the liver is increased by inflammation – a common consequence of many co-morbid diseases3,4. Oral iron is therefore unsuitable in some patient populations, such as for the treatment of iron deficiency in patients exhibiting signs of inflammation5.

Tolerance of oral treatments is generally low and the frequency and severity of side effects often leads to poor compliance.

Intravenous iron

Intravenous iron is delivered directly into the blood and is, therefore, often effective when oral iron is unsuccessful or inappropriate. The currently used formulations offer the benefits of a relatively quick correction of iron deficiency.

In intravenous preparations, the iron – usually iron (III)-oxyhydroxide – is contained within a shell of carbohydrates which vary from sucrose, dextran and gluconate, to the newer carboxymaltose and isomaltose. Preparations of carboxymethylated dextran complexes containing iron (III)-oxide are also available, however an increased risk of hypersensitivity with this formulation has been suggested6.

Despite the apparent similarities in components, the choice of carbohydrate shell determines the pharmacological and biological profiles of the different formulations, including efficacy and tolerability. This is because the carbohydrate is instrumental in determining the physicochemical properties of the iron complex, such as its pH, size and stability7–9.

Although offering rapid restoration of iron levels, intravenous preparations have potential risk associated with them and the risk can vary depending on the specific formulation used9. The high risk of anaphylatic reactions associated with high molecular weight iron-dextran formulations has resulted in their use being limited10,11. More labile, lower molecular weight compounds can lead to rapid release of larger amounts of iron into the circulation, saturating transferrin, and leading to non-transferrin bound iron12. It is this free iron that has the potential to lead to oxidative stress and associated tissue damage.

Dosing

The recommended dosing schedule varies depending on the specific iron preparation and the clinical profile of the individual patient. Factors including age and the underlying cause of iron deficiency must be considered when determining dose.

Recommendations for iron replacement can be found in guidelines specific to each therapeutic area (see ‘Clinical guidelines’), as well as in the dedicated therapy area sections of this website.

The Summary of Product Characteristics for each individual treatment should be consulted for specific dosing instructions, as administration varies between the different preparations.

The response to iron therapy should be determined by monitoring changes in clinical symptoms, and haematological and biochemical parameters, such as transferrin saturation, serum ferritin levels and haemoglobin concentration (see ‘Screening’).

Click below for further information on iron deficiency and therapy in different therapy areas:

Iron and infection

Pathogenic micro-organisms, including bacteria, fungi, viruses and protozoa, require iron for growth and proliferation. Bacteria species such as Salmonella, Listeriae, Mycobacteria and Chlamydiae depend on iron sources derived from their human host13–15, and their presence in the body can negatively impact upon the body iron status of the infected person13. Viruses such as human immunodeficiency virus (HIV) and hepatitis C also show an association with iron status and several pathways in their replicative process are iron dependent16,17.

Cytokines stimulate the release of the iron-regulatory liver hormone, hepcidin, which suppresses the absorption of dietary iron and reduces the transfer of iron from macrophages, where the iron is recycled from senescent erythrocytes13. Humans have thus developed numerous homeostatic defence mechanisms to reduce the availability of iron to invading pathogens18. Although effective in treating iron deficiency and the associated morbidity, there is also a concern that iron therapy could inhibit the body’s natural immune response to infection14,18.

Evidence of an association between infection and iron therapy is currently limited and most research in this area has been conducted with oral iron only13,19. To date, no prospective clinical trials have evaluated the clinical impact of iron therapy in patients with active infections and more data are needed to fully elucidate the complex interactions between iron, immunity and infection. The decision to prescribe iron therapy for infected patients should be made in the context of each specific clinical setting and with consideration of risk versus benefit14. It is worthwhile considering that many infections are short-lived and in this case a supplementation of iron may be postponed to the time after resolution of the infection. However, in certain chronic infection, iron therapy may be required to treat true iron deficiency (for example, as a consequence of chronic gastrointestinal or urogenital bleeding) to maintain adequate iron stores20.

Iron and the immune response to viral infection

Immune response to infection differs according to the specific pathogen involved. In HIV, replication of the virus takes place via a series of both iron-dependent and iron-regulated steps (see Figure 1). A link has also been found between available iron and disease progression to acquired immune deficiency syndrome (AIDS), although the mechanism is as yet unclear16.

Figure 1. Click to view larger image.

In hepatitis C infection, iron accumulation in the liver becomes toxic, worsening the disease16. Figure 2 shows the key role of hepcidin in orchestrating hepatitis C virus interaction with iron homeostasis17. Hepatitis C virus increases reactive oxygen species’ production, which leads to an increase in histone deacetylase activity and induction of C/CBP homology protein, resulting in decreased binding of C/EBP and STAT-3 to the hepcidin promoter and decreased expression of the hepcidin gene. Hepcidin down-regulation leads to decreased ferroportin (see definition below) internalisation and degradation, and this eventually causes increased absorption of iron from the gut and elevated release of iron from macrophages (and other organs) into the plasma, leading to iron overload17. There are other mechanisms of regulation of hepcidin expression that need to be further elucidated in the hepatitis C virus infection.

Figure 2. Click to view larger image.

Definition of ferroportin

Ferroportin is a transmembrane iron exporter which transfers ferrous iron from duodenal enterocytes into the blood or from macrophages into the circulation20. Upon hepcidin binding to a cell, ferroportin is internalised and degraded, thereby resulting in iron retention within the cells21. Accordingly increased production of hepcidin, as a consequence of inflammation or iron loading, results in decreased duodenal iron absorption from the diet and reduced transfer of iron from macrophages. Accordingly, the availability of iron to the erythron is reduced when hepcidin levels are high, which can lead to iron deficiency and anaemia20.

Iron and the immune response to bacterial infection

Iron is also required for bacterial growth and proliferation13,14. Studies have shown that activation of macrophages by bacterial infection is associated with transcriptional up-regulation of ferroportin in several bacterial infections including Salmonella typhimurium or Myocbacteria. Investigations have concluded that changes in ferroportin expression or function can influence the growth of intracellular bacteria inside macrophages by altering iron availability. They also raise the possibility that variations in macrophage ferroportin levels may contribute to the altered susceptibility to infection.

In S. typhimurium infection, nitric oxide-mediated regulation of ferroportin controls macrophage iron homeostasis and immune function15. Macrophages display increased iron content due to reduced ferroportin expression and this allows for an enhanced iron acquisition by the intracellular bacterium S. typhimurium. This is paralleled by a reduced cytokine expression and impaired pathogen control15,22.

In Mycobacterium avium infection, there is also a high accumulation of iron inside the macrophages22,23. Interleukin-6-induced hepcidin production and the consequent decrease in iron release from macrophages and enterocytes, is presumed to contribute to host protection against infection by decreasing circulating iron levels. However, in the case of M. avium infection, these same iron alterations promote the growth of the pathogen22,23.

Click on the links below to watch video clips of leading expert Dr Günter Weiss, from the Medical University of Innsbruck, Austria, further describing the link between iron and the immune response to infection, and outlining the potential impact on clinical outcome.

Managing iron deficiency in infections

The management of iron deficiency in patients with infections is largely dependent on the cause of the iron deficiency and the type of infectious agent involved. General information on treating iron deficiency can be found in the section above on 'Dosing and Treatment'. Successful management of iron deficiency should replenish iron stores, improve symptoms and limit the negative clinical consequences associated with insufficient iron, whilst avoiding worsening the existing infection. Based on the roles of iron for pathogen growth, iron supplementation should be avoided in patients with active infection – however, data is currently lacking from prospective clinical studies providing useful information on the effects of iron supplementation on the course of a chronic underlying infection. On the other hand, absolute iron deficiency may cause detrimental effects not only on the patients’ quality of life but also on cardiovascular performance and tissue oxygenation or, in case of children, on growth and neurological development. The decision to prescribe iron therapy for infected patients should be made in the context of the individual clinical scenario and with careful consideration of risk versus benefit for the patient.

Treatment with oral iron offers a relatively simple and cost-effective option for iron replacement. However, oral iron is unsuitable in some patient populations, such as those exhibiting signs of inflammation24, which is likely to be the case in many types of infection. In Helicobacter pylori infection, iron absorption is impaired and thus it is recommended that H. pylori infection be eradicated before iron therapy is initiated25,26.

Intravenous iron is delivered directly into the blood and may therefore be effective when infection limits the absorption of oral iron. However, no clinical trials have evaluated the clinical impact of iron supplementation in patients with active or chronic infections. Nonetheless, it is important to consider the risk of infection in high-risk patient populations with iron deficiency, where routine dietary iron supplementation in children has been shown to result in increased mortality from infection27.

Serum iron markers have been associated with an increased risk for infectious complications in patients after liver transplantation and there may be an association between iron levels and bacteremia in haemodialysis patients28,29. However, further clinical research is needed to fully elucidate the complex interactions between iron, immunity, and infection. The decision to prescribe iron therapy for infected patients should be made in the context of the individual clinical scenario and with careful consideration of risk versus benefit14.

Iron-targeted treatment in infection

Recent research indicates that, using hepcidin, it might be possible to divert iron away from pathogens in a disease-specific manner, without subjecting the patient to iron deficiency16. Malaria pathogens, such as Plasmodium falciparum, invade hepatocytes and red blood cells, whereas tuberculosis pathogens (Mycobacterium tuberculosis) enter the body via alveolar macrophages. By controlling the flow of iron to these different tissues using hepcidin or iron modifying strategies, it might be possible to fight infections via the restriction of iron to each pathogens specific environment, without reducing the iron available to the patient. If iron is diverted precisely away from the invading pathogen, the immune system may have time to recognise and eliminate the infection30. This approach might be particularly useful in bacterial infections, where micro-organisms can develop antibiotic resistance, but most are unable to avoid the fundamental requirement for iron. Consequently, this approach to treating infection, which would avoid causing iron deficiency in the patient, might be of value in the future30

For further information on the relationship between iron therapy and infection please see the recent article 'Iron and infection'. Also available – video footage of Professor Guenter Weiss discussing iron and infection at BioIron 2013 can be viewed by clicking here. In addition, for up-to-date news on the treatment of iron deficiency from across the therapeutic spectrum please click here.

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