On both sides of the ocean

Remarkably, in the Western world, there are enormous differences in the front-line standards for treatment of iron deficiency anaemia (IDA) associated with inflammatory bowel disease (IBD) on different sides of the Atlantic. In the United States, oral iron is considered the standard¹, in spite of up to 70% with gastrointestinal perturbation among otherwise normal individuals. In Europe, over the last 20 years, intravenous iron has become the front-line standard².

Apart from iron deficiency secondary to blood loss, iron absorption through the intestinal epithelium and release from macrophages into the circulation is decreased in IBD patients due to the induction of hepcidin expression by inflammatory cytokines. Hepcidin initiates destruction of the cellular iron export protein ferroportin. Thus, elevated hepcidin levels greatly diminish the efficacy of oral iron. Increasing the dose of oral iron is futile, as only a limited amount of iron can be absorbed from the gut daily, and excess luminal iron will exacerbate gastrointestinal side effects. Furthermore, a recent publication by Moretti et al.³ reports that frequent daily iron dosing in normal young women increases hepcidin and decreases absorption, supporting alternate day dosing. This constellation of factors makes correction of iron deficiency in IBD patients primarily using oral iron an onerous task.

In contrast, there is abundant published evidence of the convenience, safety, and efficacy of intravenous (i.v.) iron to correct IDA in IBD. Supporting this recommendation is a meta-analysis by Avni et al., which found i.v. iron was associated with a higher rate of haemoglobin response in comparison to oral iron, decreased adverse events requiring discontinuation of therapy, with no increase in serious adverse events⁴. Given the safety and efficacy of modern i.v. iron formulations, it is of some concern that gastroenterologists in the United States continue to favour oral iron. We believe this is fuelled, at least in part, by misinterpretation and misinformation about the incidence and clinical nature of the adverse events associated with administration of i.v. iron⁵. Infusion reactions consisting of myalgias of the chest or back or flushing occur infrequently; these abate without therapy within minutes. Avoidance of pressors and anti-histamines, which may exacerbate symptoms and mistakenly lead practitioners to believe a serious adverse event secondary to i.v. iron has occurred, will eliminate the overwhelming majority of adverse events ostensibly due to i.v. iron. When these tenets are followed, serious adverse events are rare, occurring in less than 1:200,000 administrations⁶. Clearly, a more critical view of the information available about the safety and efficacy of i.v. iron is needed.

There are distinct advantages for i.v. iron, particularly in the setting of IBD, as this route bypasses the hepcidin intestinal block. This facilitates faster iron restitution, especially with newer i.v. formulations in which iron is more tightly bound to a carbohydrate core (ferric carboxymaltose [FCM], low molecular weight iron dextran, ferumoxytol, and iron isomaltoside)⁷, which allow administration of full replacement doses in one or two sessions. This compares favourably to months of therapy with oral iron during which patients’ quality of life (QoL) is continuously impaired by both iron deficiency and gastrointestinal side effects. Furthermore, there is growing concern about the negative impact of oral iron on microbiota, colonic inflammation, and carcinogenesis¹.

In this issue of Blood Transfusion, García-López et al.⁸ demonstrate significant improvements in haemoglobin, iron parameters, and QoL in IBD patients upon administration of FCM at doses up to 20 mg/kg. As early as two weeks after therapy, significant improvements in clinical end points were clearly observed with complete correction of anaemia seen in nearly half the study subjects. Twelve weeks after therapy, over 80% had a complete response in haemoglobin. Of the 88 patients, only one experienced an infusion reaction, no serious adverse events were observed, and there was no worsening of IBD symptoms. This is in agreement with a recent comprehensive meta-analysis that combines data across a wide range of indications for iron therapy including, but not restricted to, IBD. Avni et al. reported that while i.v. iron therapy is associated with infusion reactions, it is not associated with an increased risk of serious adverse events or infections⁴.

García-López et al.⁸ commented that, as in previous studies, Ganzoni’s formula may under-estimate iron requirements in IBD. Our simple dosing regimen has been shown to be more effective than Ganzoni-calculated dosing while still maintaining a similar safety profile⁹. Patients are stratified according to haemoglobin and body weight; those with haemoglobin 7–10 g/dL and body weight below 70 kg receive a total dose of 1,500 mg, while those over 70 kg receive 2,000 mg. Haemoglobin levels between 10 and normal receive a total dose of 1,000 mg (<70 kg) or 1,500 mg (>70 kg). The maximum amount that may be administered in one session is 500 mg (<70 kg) or 1,000 mg (>70 kg).

Besides correcting anaemia, IBD patients are prone to recurrence and maintenance of iron stores is required. I.V. iron effectively restores iron levels and prevents recurrence of anaemia when used appropriately¹⁰. Iron deficiency is also associated with fatigue, restless legs syndrome, and impaired cognitive function, which contribute to diminished QoL, and may resolve with i.v. iron^11,12. In addition to its benefit in IBD, i.v. iron has been shown to reduce peri-operative transfusions and post-operative infections, as well as length of hospital stay¹³. Iron deficiency is also associated with reactive thrombocytosis and activation of platelet aggregation¹⁴. In IBD, where thromboembolic events are an important cause of morbidity and mortality, i.v. iron has been shown to reduce both platelet count and activity without altering disease activity¹⁴. Similarly, the incidence of venous thrombotic events that occur with administration of iron-consuming erythropoiesis-stimulating agents diminishes with concomitant administration of i.v. iron^15,16. Combined therapy also leads to increased haemoglobin responses, shorter duration of the much more expensive ESA therapy, higher energy levels, a more active lifestyle and improved QoL.

The results of the study by García-López et al.⁸ contribute to a considerable body of evidence supporting a larger and earlier role for i.v. iron in the treatment paradigm of IDA associated with IBD. One could surely ask if improved and less expensive clinical outcomes could be achieved were oral iron dismissed from the treatment paradigm. It is time for common sense to prevail on both sides of the Atlantic.