International Journal of Hematology

https://doi.org/10.1007/s12185-017-2373-3

PROGRESS IN HEMATOLOGY

Iron metabolism and the related diseases

Modern iron replacement therapy: clinical and pathophysiological

insights
Domenico Girelli1 · Sara Ugolini1 · Fabiana Busti1 · Giacomo Marchi1 · Annalisa Castagna1

Received: 15 November 2017 / Accepted: 24 November 2017

© The Japanese Society of Hematology 2017

Abstract
Iron deficiency, with or without anemia, is extremely frequent worldwide, representing a major public health problem. Iron
replacement therapy dates back to the seventeenth century, and has progressed relatively slowly until recently. Both oral and
intravenous traditional iron formulations are known to be far from ideal, mainly because of tolerability and safety issues,
respectively. At the beginning of this century, the discovery of hepcidin/ferroportin axis has represented a turning point in
the knowledge of the pathophysiology of iron metabolism disorders, ushering a new era. In the meantime, advances in the
pharmaceutical technologies are producing newer iron formulations aimed at minimizing the problems inherent with tradi-
tional approaches. The pharmacokinetic of oral and parenteral iron is substantially different, and diversities have become
even clearer in light of the hepcidin master role in regulating systemic iron homeostasis. Here we review how iron therapy
is changing because of such important advances in both pathophysiology and pharmacology.

Keywords Iron deficiency · Hepcidin · Iron therapy · Anemia · Heart failure

Background 2], mainly because of poverty and malnutrition in develop-

ing countries. Individuals with increased requirement of the
Iron deficiency anemia: prevalence and etiology micronutrient, like preschool children, adolescents during
the growth spurt, and women of childbearing age, are at the
Iron deficiency (ID), with or without anemia (iron defi- highest risk [3]. Nonetheless, IDA is also frequent in western
ciency anemia or IDA), represents a major global health countries, with a prevalence ranging from 4.5 to 18% of the
problem affecting more than 2 billions people worldwide [1, population, where elderly with multimorbidity and polyphar-
macy represent an adjunctive subcategory at high risk [4].
IDA can be due to a wide range of different causes (sum-
* Domenico Girelli marized in Table 1), which can roughly grouped into three
[email protected]
http://www.gimferverona.org
major categories: imbalance between iron intake and iron
needs, blood losses (either occult or overt), and malabsorp-
Sara Ugolini
http://www.gimferverona.org
tion. The coexistence of multiple causes or predisposing
factors is not uncommon in certain patients, particularly
Fabiana Busti
http://www.gimferverona.org
those with severe and/or recurring IDA [1, 5], and in the
elderly [4]. Complex overlap of different mechanisms can
Giacomo Marchi
http://www.gimferverona.org
occur in the individual patient. Just as an example, gastroin-
testinal angiodysplasia represent a relatively frequent cause
Annalisa Castagna
http://www.gimferverona.org
of occult bleeding in the elderly [6], which can be difficult
to diagnose when localized in the small bowel unless wire-
1
Department of Medicine, Section of Internal Medicine, less capsule endoscopy is performed. Angiodysplasia often
Veneto Region Referral Center for Iron Metabolism associate (in 20–25% of cases) with calcific aortic stenosis,
Disorders, Center of Excellence for Rare Hematological
Diseases “EuroBloodNet”, University of Verona, Policlinico
giving rise to the so-called Heyde’s syndrome [7]. Such syn-
G.B. Rossi, 37134 Verona, Italy drome includes an acquired coagulopathy further favoring

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Table 1  Main causes of IDA
Condition/mechanism Principal examples Notes

Physiological Growth spurt in adolescents, pregnancy No need for complete etiologic work-up, unless there is no response to iron
(↑Requirement) replacement therapy or relapses
Reduced intake Vegetarian/vegan diets, malnutrition, poverty –
Gastrointestinal blood losses Malignancies, peptic ulcer, erosive esophagitis/gastritis, hiatal hernia, diver- Bleeding is frequently occult. Diagnostic work-up (endoscopy) needed in all
ticula, Hemorrhoids, inflammatory bowel diseases (Crohn’s disease, ulcera- categories at risk of malignancy (adult males, postmenopausal women)
tive colitis), angiodysplasia, hereditary hemorrhagic telangiectasia (HHT,
where frequent/massive epistaxis can also occur)
Genitourinary blood losses Heavy menstrual bleeding (uterine fibromatosis, menorrhagia in women tak- –
ing anticoagulants)
Intravascular hemolytic anemias Paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemias, Rare conditions, associated with hemoglobinuria
microangiopathic hemolytic anemia, malfunctioning prosthetic heart valves
Malabsorption Celiac disease, chronic gastritis (atrophic autoimmune or related to helicobac- “Acquired IRIDA” (see below)
ter pylori infection), gastrectomy, bariatric surgery Helicobacter pylori infection can cause malabsorption regardless of the pres-
ence of atrophic gastritis (by host competition for iron)
Developing countries, migrants Parasitic infections (hookworm, schistosomiasis) Schistosomiasis contributes through both occult blood loss and inflammation
Genetic IRIDA (iron refractory iron deficiency anemia) Rare autosomal recessive disease in children/young adults with TMPRSS6
mutations (see text)
Drugs Non-steroidal anti-inflammatory drugs, antithrombotic drugs, proton pump Antithrombotic drugs often worsen occult losses. PPI can contribute to iron
inhibitors (PPI) malabsorption
Coagulopathies Von Willebrand disease, other forms Sometimes under recognized, may aggravate physiological losses (e.g. menor-
rhagia)
Miscellaneous Munchausen or Lasthènje de Feriol Syndrome (factitious anemia), frequent –
blood donors, endurance athletes (march hemoglobinuria)
D. Girelli et al.
Modern iron replacement therapy: clinical and pathophysiological insights

bleeding from angiodysplasia, because of consumption of and “ecologic” (Fig. 1). Under physiological conditions,
high molecular weight von Willebrand factor multimers dur- RBCs contain the largest proportion of body iron (i.e. near
ing flux through the stenotic valve [7]. 2 g), and the 20–25 mg of iron needed for daily production
Treatment of IDA is based on two cornerstones. Recogni- of new RBCs derive almost totally from continuous recy-
tion and management of the underlying cause(s) is manda- cling of the element through the phagocytosis of senescent
tory, whenever possible. In the meantime, iron has to be erythrocytes. Only a minimum amount of iron (i.e. 1–2 mg,
reintegrated by selecting the most appropriate compound less than 0.05% of total body iron) is lost every day through
and route of administration in each individual patient. skin and mucosal exfoliation, plus menses in fertile women.
Such losses are obligated and there is no physiological way
Pathophysiological advances in iron metabolism to regulate iron excretion. Hence, homeostasis of total body
iron amount is maintained by regulating intestinal absorp-
Iron, a micronutrient essential for life, is particularly impor- tion in order to precisely match the losses, i.e. by absorbing
tant for an adequate production of red blood cells (RBCs), just 1–2 mg/day of iron out of the 10–15 mg contained in an
which deliver oxygen to all body’s tissues. RBCs represent average western diet.
by far the most numerous cells of the human body. An adult The hepcidin/ferroportin axis is finely tuned to ensure
man is made of near 30 trillions (3 × 1013) cells, exclud- the balance between erythropoiesis need and iron absorp-
ing the microbiome [8]. RBCs account for near 84% (24.9 tion. The regulation of hepcidin and ferroportin expression
trillions) of total cells, and are produced with a rate of near at molecular level is quite complex, and its description is
200 billions per day, i.e. near 2.4 millions per second. Such beyond the scope of this article (for comprehensive reviews
an impressive activity requires a daily supply of 20–25 mg see [22–24]). From a clinical standpoint, hepcidin produc-
of iron to erythroid precursors in the bone marrow [9]. The tion is modulated by a number of physiological and patho-
body iron content (~ 4 g in the adult male, ~ 3 g in the logical conditions that can exert opposite influences [25].
female) must be kept constant, to avoid either deficiency The three major determinants are body iron stores, eryth-
or overload, which can also be detrimental by facilitating ropoietic activity, and inflammation [24] (Fig. 1). Hepcidin
the production of toxic reactive oxygen species [10]. In synthesis by hepatocytes is stimulated when body iron stores
the recent years, enormous progresses have been made in are replete, mainly through a paracrine release of Bone Mor-
understanding of the mechanisms regulating iron homeo- phogenetic Protein 6 (BMP6) [26, 27]. Indeed, BMP6 is pro-
stasis at both cellular and systemic levels, so that our era duced by liver sinusoidal cells [28] in response to increased
has been defined “the golden age of iron” [11]. The turning transferrin saturation [22], and stimulates the BMP/Small
points have been the discoveries of hepcidin [12–14], fer- Mother Against Decapentaplegic (SMAD) signaling path-
roportin [15–17], and their interaction [18], at the beginning way critically involved in transcriptional regulation of hepci-
of this century (history reviewed in detail elsewhere [19]). din [26]. On the other hand, hepcidin is markedly suppressed
Hepcidin is a small cysteine-rich cationic peptide made of in iron deficiency [29, 30] to ensure maximal absorption of
only 25 amino acids [20]. It is synthesized primarily by the iron from the gut. Hepcidin is also negatively regulated by
hepatocytes, which accounts for the first part its name (“hep- erythropoietic activity in the bone marrow. For example,
”). The rest (“-cidin”) lies on the fact that it was originally after an acute blood loss hepcidin is suppressed in order to
discovered, partly by chance [19], during research focusing match the increased iron need of erythroid precursors for
on defensins, i.e. naturally occurring peptides with antimi- rapid production of new RBCs. In murine models, a hor-
crobial activity [21]. Indeed, hepcidin retains some degree mone named erythroferrone (ERFE) has been identified as
of antimicrobial activity, but this is exerted only indirectly, the hepcidin suppressing agent produced by erythroblasts
i.e. by subtracting iron to invading pathogens (see below). [9, 31]. In humans, the ERFE ortologue encoded by the
Hepcidin critically regulates systemic iron homeostasis by gene FAM132B seems also involved in hepcidin suppres-
binding to its receptor ferroportin, the only known channel sion under conditions of increased erythropoiesis [32, 33],
for exporting iron out of cells. Ferroportin, a multidomain although in combination with other factors still poorly char-
transmembrane protein, is highly expressed in cells critical acterized [23]. Finally, inflammation strongly stimulates
for iron handling like: (1) duodenal enterocytes, involved in hepcidin synthesis through several interleukins (IL), mainly
absorption of dietary iron; (2) splenic red pulp macrophages, IL-6 [34] and IL-1β [35]. In acute inflammatory conditions
involved in iron recycling from senescent erythrocytes; and hepcidin release from hepatocytes increases rapidly (within
(3) hepatocytes, involved in iron storage. Hepcidin bind- few hours) and exponentially (by more than 10–40-folds)
ing determines ferroportin internalization and degrada- [36, 37]. The ensuing rapid hypoferremia represents a pro-
tion [18], thereby decreasing iron fluxes into the plasma tective factor in several acute infections, by subtracting iron
through inhibition of both iron absorption and recycling. to invading microbial agents avidly requiring the element for
Of note, systemic iron homeostasis is highly conservative their growth [38–40]. On the other hand, hepcidin-induced

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 D. Girelli et al.

Fig. 1  Essentials of systemic iron metabolism. Systemic iron metab- hepcidin, which neutralize ferroportin (black dotted arrows), i.e. the
olism is highly conservative of total body iron content (3–4 g), only known cell membrane iron exporter mainly expressed by mac-
through the continuous recycling of iron from the senescent eryth- rophages and on the basolateral membrane of absorbing intestinal
rocytes by splenic macrophages, which supplies the 20–25 mg/day cells. Hepcidin production is stimulated by high iron concentration in
of iron needed for bone marrow hematopoiesis (thick red arrows). tissues (via BMP6) and in the circulation (via saturated transferrin),
Both iron deficiency and iron overload are detrimental and have to as well as by pro-inflammatory cytokines. On the other hand, it is
be avoided. Total body iron homeostasis is maintained by accurately suppressed by iron deficiency, hypoxia, and increased erythropoiesis
matching unavoidable daily losses with intestinal absorption of die- (see also the text)
tary iron, (1–2 mg/day) (thin blue arrows). The master regulator is

iron sequestration into macrophages leads to iron-restricted [44]. Unfortunately, both oral and IV traditional iron for-
erythropoiesis, a major driver of the “anemia of inflamma- mulations are known to be far from ideal, mainly because
tion”, and, in the long term, of the “anemia of chronic dis- of tolerability and safety issues, respectively. From a phar-
eases” [41, 42]. It is now increasingly clear that the hepcidin/ macological point of view, iron replacement therapy has
ferroportin axis also critically influence the response to iron progressed relatively slowly until recently. At the beginning
treatments. of this century, concomitantly with the pathophysiological
advances mentioned above, improvements in the pharma-
Historical considerations ceutical technologies have allowed the production of newer
iron formulations, particularly for IV administration, aimed
Iron therapy dates back to the seventeenth century, when at minimizing the problems inherent with traditional com-
Thomas Sydenham (1624–1689) first proposed the use of pounds. Noteworthy, the pharmacokinetic of oral iron is
oral iron salts for the treatment of “chlorosis”, although completely different from that of IV iron (Fig. 2). Oral iron
the disorder was initially believed as an hysterical problem is incorporated into plasma transferrin after release from
rather than due to IDA [43]. The first iron compound to be the basolateral membrane of intestinal cells, providing that
used for intravenous (IV) route (iron saccharide) entered the no condition leading to malabsorption (i.e. celiac disease,
clinical scenario near to the second half of the past century autoimmune or HP-related chronic gastritis) is present [5].

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Modern iron replacement therapy: clinical and pathophysiological insights

Fig. 2  Different pharmacokinetic between oral and IV iron, revisited the circulation through ferroportin. Both oral and IV iron requires fer-
in the hepcidin era. Pharmacokinetic of oral iron requires the integrity roportin to be released in the plasma. Hepcidin production is typically
of the mucosa of the stomach (acidity is needed to solubilize iron) suppressed in uncomplicated IDA, allowing maximal iron absorption.
and duodenum/proximal jejunum (where most of iron is absorbed). However, slightly elevated (or even inappropriately normal) hepcidin
This integrity can be compromised by several conditions leading to levels appear sufficient to inhibit intestinal ferroportin. This can be
malabsorption (see Table 1). The maximum absorption capacity due to a genetic disorder (IRIDA), to concomitant low-grade inflam-
during oral iron treatment is estimated to be near 25–30 mg/die, i.e. mation (i.e. in chronic heart failure), or even to transient stimulation
near ten to twenty-fold the typical daily absorption of dietary iron in after a first dose of oral iron. This constitutes the basis for current rec-
steady-state condition (1–2 mg). Unabsorbed iron is mainly responsi- ommendation of using oral iron on an alternate day schedule instead
ble of gastrointestinal adverse effects (AEs). IV iron has a completely of the classical daily schedule (see the text for details). On the other
different pharmacokinetic that circumvents these problems. The iron- hand macrophage ferroportin, whose expression is much higher than
carbohydrate complexes (see Fig. 3 for details) are rapidly taken up at the intestinal level, requires much more elevated hepcidin levels
by macrophages, then iron atoms of the core are slowly released in (i.e. like during acute inflammation) to be substantially suppressed

By contrast, IV iron compounds are first taken up by mac- symptomatic, e.g. those with hemodynamic instability
rophages and then released into the bloodstream. As the two or signs of myocardial ischemia, need RBC transfusion,
treatments cannot be considered merely interchangeable and although such clinical presentation is uncommon in IDA.
have different indications, we will examine them separately.
A complex market scenario

Oral iron therapy Iron-containing oral preparations currently available in the

market are innumerous, with a variety of pharmaceutical
Easy, cheap and often effective (not always) forms including pills, effervescent tablets, elixir, and so on.
Their chemistry is also heterogeneous, including either tri-
Oral iron represents the mainstay of IDA treatment, being valent ­(Fe3+, or ferric) or divalent (­ Fe2+, or ferrous) iron, in
easy, cheap, and effective in the majority of mild to mod- form of iron salts or iron polysaccharide complexes [46].
erate cases, i.e. when hemoglobin is ≥ 11 g/dl, or ≤ 10.9 Many preparations are over the counter and often aggres-
but ≥ 8.0 g/dl, respectively, according to the WHO (http:// sively advertised as “ideal”, or the “most natural” way to
www.who.int/vmnis/indicators/haemoglobin/en). Indeed, in reintegrate ID. Pharmacological iron is absorbed through
severe IDA (hemoglobin < 8.0 g/dl), whatever the cause, the same pathway of non-heme dietary iron found in plant
there is an increasing agreement on the use of new IV iron foods, which is exceedingly less efficient than absorption of
compounds (see below) as first-line therapy, because of heme–iron found in meat [47, 48]. Non-heme dietary iron is
their superior efficacy and rapidity [45]. Patients severely largely ferric, and, as such, highly insoluble. To be absorbed,

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 D. Girelli et al.

it needs to be reduced by a brush-border ferrireductase (duo- As absorption of ferrous salts is favored by a mildly acidic
denal cytochrome b or DCYTB), allowing the resulting diva- medium, ascorbic acid 250–500 mg/day is often concomi-
lent iron to enter the luminal surface of enterocytes through tantly prescribed, although formal demonstration of a meas-
a specialized transporter (Divalent Metal Transporter 1, or urable advantage is lacking [55]. On the other hand, ant-
DMT1). By contrast, the absorption of heme–iron is less acids, including proton pump inhibitors (PPI), are likely a
well understood [48], and attempts to produce heme–iron cofactor of insufficient response to oral iron, particularly in
polypeptides has resulted in greater costs and insufficient certain populations like elderly patients assuming polyphar-
clinical evaluation [49]. Thus, for the moment divalent iron macy [4]. Optimal response to oral iron is generally defined
salts appear the most appropriate form of oral iron replace- as an hemoglobin increase of 2 g/dl after 3 weeks. However,
ment therapy, the most used being ferrous gluconate, ferrous the final goal of the treatment has to be not only the nor-
fumarate, and ferrous sulfate (FS) (Table 2). In particular, FS malization of hemoglobin, but also repletion of iron stores,
represents the universally available compound considered by with an ideal target of ferritin > 100 μg/l [49, 51]. This
all guidelines [50, 51]. often requires a prolonged treatment for at least 3 months
[50], if not more. Stopping the treatment too early is a com-
The traditional prescription. Be aware of elemental mon error in clinical practice. In our experience at a refer-
iron. Replace stores, not only hemoglobin ral center for iron disorders, this is particularly frequent in
young premenopausal women, resulting in significant mor-
What really matter in different divalent oral iron preparations bidity and risk of recurrence. By contrast, an hemoglobin
is the content of elemental iron. As a general rule, oral iron increase less than 1 g/dl after 3 weeks notwithstanding
preparations do not contain more than 30% of elemental adequate compliance defines “refractoriness” to oral iron.
iron, but a source of confusion is represented by the fact This should prompt appropriate investigations to exclude
that such proportion can vary by manufacturer, as well as malabsorption, i.e. due to celiac disease, helicobacter pilory
in different countries. For example, typical FS tablets of infection, or autoimmune gastritis [5].
nominal 325 mg salt, contain 65 mg of elemental iron in the
US, and 105 mg in Europe. Other iron salt tablets, i.e. fer- A far from ideal treatment
rous gluconate usually contain less elemental iron by weight
(for example 28 mg/256 mg, 38–48 mg/325 mg) (Table 2). Unfortunately, oral iron is frequently associated to adverse
As the classically recommended daily dose for IDA treat- effects (AEs), mainly represented by gastrointestinal dis-
ment is 100–200 mg of elemental iron, physicians should turbs including metallic taste, nausea, vomiting, heartburn,
always check this content before prescribing any prepara- epigastric pain, constipation, and diarrhea. They are likely
tion, including liquid ones like syrup, elixir, and drops. The due to direct toxicity of unabsorbed iron on the intestinal
most popular prescription for IDA is 2–3 tablets per day mucosa. Two recent meta-analyses including several thou-
of FS, which should be assumed preferably on an empty sands of patients receiving ferrous iron salts have reported
stomach to maximize absorption [52]. Such relatively high gastrointestinal AEs in proportion variables from 30 to 70%
doses are mainly based on traditional practice, and recent of cases [56, 57]. The ensuing reduction of adherence, in
recalculations suggest they are likely excessive (see below). combination with the need of prolonged treatment (see
Noteworthy, only a minor fraction (no more than 10–20%) above), results in undertreatment of a significant proportion
of a high dose of oral iron is effectively absorbed [52–54]. of IDA patients in daily clinical practice. In recent years,

Table 2  Traditional oral iron preparations (ferrous iron salts)

Drug Content in elementary iron Recommended dose (elementary iron)

Ferrous sulphate (FS) Can vary by manufacturer in different countries, generally 20–30% of total 100–200 mg/die
mg of mineral salt. Classical schemes: 100 mg b.i.d.;
Examples: 105 mg in 330 mg FS tablets (Europe); 65 mg in 325 mg FS 60 mg t.i.d.
tablets (US) Maximal absorption when assumed
15 mg/ml pediatric drops (US) on an empty stomach (see text)
60 mg/5 ml syrup (US)
Ferrous glycine sulphate 100 mg in 567 mg tablets Idem
Ferrous gluconate (FG) Generally less than FS (10–14% of total mg of mineral salt) Idem
80 mg in 695 effervescent tablets (EU); 27 mg in 240 mg FG tablets (US);
Ferrous fumarate (FF) Generally 33% of total mg of mineral salt Idem
Examples: 29.5 mg in 90 mg FF tablets; 106 mg in 325 mg FF tablets

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Modern iron replacement therapy: clinical and pathophysiological insights

there has been an increasing awareness of a previously over- [76]. Thus, CHF represents a paradigmatic condition where
looked potentially negative effect of oral iron, i.e. the change recent pathophysiological insights on hepcidin appear to
in gut microbiome [58–60]. This is due to unabsorbed iron influence the choice on the most appropriate route of iron
reaching the colon, and appears particularly detrimental in administration. The same concept was previously suggested
low-income populations. Studies in Kenyan infants con- by two retrospective studies in cancer patients [77], and in
suming iron-fortified meals have documented a decrease unselected IDA patients [78], where baseline hepcidin lev-
of beneficial commensal bacteria (i.e. bifidobacteria and els predicted subsequent responsiveness to oral iron. After
lactobacilli, requiring little or no iron), and an increase of initial technical difficulties, hepcidin assays are continuously
enterobacteria, including iron-requiring enteropathogenic improving, and a number of them showing good accuracy
Escherichia coli strains [61]. Noteworthy, previous studies and reproducibility have been internationally validated
with iron fortification formulas in African children have [25]. However, lack of harmonization (i.e. comparability
raised serious concerns about the safety of indiscriminate between absolute values obtained in different laboratories)
iron supplementation in areas where either micronutrient has prevented until now the definition of universal ranges
deficiencies or infections are highly prevalent [62, 63]. for widespread clinical use [25, 79]. This problem is now
nearly solved through the use of a commutable reference
Oral iron therapy in the hepcidin era material, which will soon allow worldwide standardization
and results traceable to SI units (Swinkels D. W., personal
Optimal efficacy of oral iron requires not only the integ- communication). Thus, in a near future baseline hepcidin
rity of the gastrointestinal mucosa, but also an appropriate measurement in IDA could actually help in tailoring iron
suppression of hepcidin to allow full activity of ferroportin therapy, by selecting the optimal route of administration in
expressed on the basolateral surface of enterocytes (Fig. 2). a given individual [25]. This would be particularly useful in
As mentioned before, in typical IDA serum hepcidin levels certain “difficult” populations, such as the elderly [4] and
are extremely low, or even undetectable [29, 30]. Neverthe- children in developing countries [80].
less, serum hepcidin levels reflect the balance of multiple An already established major advance in oral iron therapy
opposing influence [25], and exception to this rule can be deriving from hepcidin discovery is related to the adminis-
due to genetic or acquired conditions. Subjects homozygous tration schedule. An elegant pilot-study by Moretti and col-
for mutations in TMPRSS6, encoding the hepcidin inhibitor leagues on non-anemic ID premenopausal women suggested
Matriptase-2, are affected by a rare genetic form of anemia that giving oral iron on an alternate day schedule might be
named Iron Refractory Iron Deficiency Anemia (IRIDA, as effective as the classical daily schedule based on divided
OMIM #206200) [64]. This condition should be suspected doses [81]. The classical schedule was associated to a rapid
in patients presenting with IDA early in life, and poor or response in hepcidin production that limited the absorption
no response to oral iron without apparent cause [65, 66]. of a second dose given too early. By contrast, the alternate
Indeed, the biochemical hallmark of IRIDA is the presence day regimen allowed a sufficient time for hepcidin return
of high (or inappropriately normal) serum hepcidin levels to baseline, hence maximizing fractional iron absorption.
[25], which are pathogenetically relevant. Relatively high Moreover, it minimized gastrointestinal AEs. Such results
or inappropriately normal hepcidin levels can be found also have been recently confirmed by two prospective rand-
in ID patients with a concomitant inflammatory disorder omized controlled trials with similar design, again showing
[67, 68]. The best studied condition in this sense is chronic better absorption in non-anemic young women taking iron
heart failure (CHF), where low-grade chronic inflammation on alternate day [82]. Whether or not these results also apply
is known to play an important role [69]. ID is quite common to anemic patients with ID remain formally unproven, but
in CHF, involving at least 30% of patients [70, 71]. Multiple it appears reasonable to assume that this will be the case.
factors concur to determine ID in CHF, including decreased Indeed, some Authorities now consider such results suffi-
iron intake because of anorexia, malabsorption due to cient to recommend the alternate day regimen as the prefer-
edema of the intestinal mucosa, and, possibly, occult bleed- able way for oral iron replacement therapy in IDA, although
ing favored by concomitant assumption of antithrombotic with prudence (grade 2 C) [83].
drugs. This results in decreased utilization of O ­ 2 by iron-
dependent mitochondrial enzymes in cardiomyocytes [72], New preparations
and an increased risk of hospitalization or even of death [70,
73]. Of note, IV iron therapy has been shown to be beneficial Another area of active work is the search for new oral prepa-
in CHF patients with ID (see also below) [71, 74, 75], while rations as effective as the standard FS, but better tolerated.
a recent trial with oral iron yielded negative results [76]. One of the most innovative preparation is “sucrosomial”
This refractoriness to oral iron was linked to relatively high iron (SI), that is a source of ferric pyrophosphate covered
(instead of suppressed) hepcidin levels in CHF ID patients by phospholipids plus sucrose esters of fatty acids matrix

13
 D. Girelli et al.

[84]. In vitro experiments on human intestinal Caco-2 A further active field of research, particularly to address
cells suggest that SI could be taken up through a DMT-1 IDA in developing countries, is the possibility of enriching
independent mechanism [84], possibly through endocyto- food with iron nanoformulations [91, 92]. Early attempts
sis and similarly to what happens with nanoparticles [85, using classical iron salts were disappointing, even because
86] (see below). Whether this occurs also in vivo, as well of changes in color and taste of food. Nanoparticles (NPs),
as whether SI utilizes unique mechanisms also to enter the including ferritin or ferritin-mimicking molecules [93],
bloodstream remain to be proven. Anyway, some prelimi- appear promising, and devoid of unwanted effects. Note-
nary clinical studies with SI look promising. For example, worthy, a very recent and elegant study has demonstrated
a small randomized, open-label trial in non-dialysis chronic that iron-containing NPs cross the cell membrane by
kidney disease (CKD) patients with IDA showed that low DMT1-independent mechanisms, like endocytosis, or even
dose (30 mg/day) oral SI for 3 months was non-inferior to by a non-endocytotic pathway allowing direct access to the
IV iron gluconate with regards to hemoglobin recovery cytoplasm [94].
[87]. On the other hand, IV iron remained superior with
respect to replenishment of iron stores, while IDA recurred
rapidly (after 1 months from suspension) in patients treated IV iron
with oral SI. This study had several limitations, including
the small sample size and the IV compound used as com- Historical considerations
parator (iron gluconate), which is now clearly surpassed by
the newer IV iron formulations (see below). Nevertheless, First attempts to administer iron through the parenteral route
the relatively good response obtained after 3 weeks with date back to the first half of the past century [95], but were
oral SI is intriguing, particularly considering the low dose unacceptably painful when administered intramuscularly,
(30 mg/day), as well as the peculiar IDA population stud- and caused serious hemodynamic toxicity attributed to rapid
ied (stage 3–5 CKD). Indeed, late stage CKD patients often release of labile-free iron. This led to the development of
have elevated hepcidin levels [88], so that some Authors carbohydrate shells surrounding an iron core, in order to
have recently claimed hepcidin as a sort of new “uremic limit the unwanted rapid release of the element [96]. The
toxin” [89]. To explain such result, one should assume that first preparation to be used was iron saccharide in 1947, fol-
absorption of oral SI is: (1) poorly affected by hepcidin inhi- lowed by High-Molecular Weight Dextran (HMWD) iron
bition; (2) nearly maximal, by contrast with traditional iron (Fig. 3a). Despite documented success in correcting IDA
compounds, as it is well known, for example, that no more [97, 98], rare cases of severe hypersensitivity reactions were
that 30 mg iron are absorbed when 100 mg elemental FS are reported, some of them being fatal. This led to extreme cau-
administered (see also above). Of note, tolerability of oral tion in prescribing IV iron, which was deemed to be reserved
SI was excellent. Such findings deserve further mechanistic only for conditions where oral iron could not be used [98].
studies on this novel compound, as well as confirmation by In facts, the medical community experienced a long lasting
larger clinical trials in other IDA populations. Nevertheless, generalized prejudice against IV iron, whatever the prepara-
they pose a key general question regarding the optimal dose tion used. Only relatively recently, it was realized that severe
of oral iron, whatever the compound. When hepcidin is sup- and potentially lethal reactions were almost exclusively due
pressed, as in common uncomplicated IDA, iron absorption to HMWD-iron [99], which, in the meantime, was no longer
is supposed to be maximal, but with a limit of 25–30 mg/ produced since 1992 [100] and replaced by other prepara-
day. Fractional absorption can vary substantially between tions (Fig. 3a). Indeed, a retrospective analysis of > 30 mil-
different compounds, but what is clear is that most AEs are lion doses of IV iron reported absolute rates of life-threaten-
related to the unabsorbed fraction. A small study in elderly ing AEs of 0.6, 0.9, and 11.8 per million with iron sucrose,
(> 80 years) with IDA conducted more than 10 years ago, ferric gluconate, and HMWD-iron, respectively [99].
showed that two low-dose schedules (15 or 50 mg/day of
elemental iron in form of liquid ferrous gluconate) were The chemistry of different IV iron preparations
equally effective as high “traditional” dose (150 mg/day of and its relation with adverse effects
elemental iron in form of ferrous calcium citrate tablets)
[90]. Low-doses also resulted in significantly lower AEs All IV iron preparations share a common structure, being
[90]. Overall, the new studies cited above, including those colloidal solutions of compounds made of a polynuclear
on alternate day regimen, suggest that it is time to reconsider core containing ­Fe3+ hydroxide particles surrounded by a
our traditional way of giving oral iron. Large-scale stud- carbohydrate shell (Fig. 3b). The most important differences
ies on patients with mild to moderate uncomplicated IDA between one preparation and another rely on the chemistry of
should definitively explore the efficacy and tolerability of the carbohydrate moiety forming the shell, as well as on the
alternate day low-dose oral iron. type and strength of its bonds with the iron core (Fig. 3b).

13
Modern iron replacement therapy: clinical and pathophysiological insights

Fig. 3  IV iron preparations:

historical and chemical perspec-
tive. a A widespread use of
IV iron has been historically
hampered by unacceptable risks
with early preparations, particu-
larly anaphylactic reactions with
high molecular weight dextran
(HMWD) iron. b All IV iron
preparations consist of an iron
polynuclear core surrounded by
a carbohydrate shell that acts as
a stabilizer, preventing uncon-
trolled release of toxic free iron.
What is different in various
compounds is the identity of the
carbohydrate moiety, which is
unique for each compound and
influences both immunogenicity
and strength of stabilization (see
also the text)

These features are major determinants of the stability of the now increasingly attributed to complement activation-related
iron/carbohydrate complex, which in turn constitutes the fac- pseudo-allergy (CARPA) [106]. This mechanism is thought
tor limiting the maximum dose of iron administrable with a to be activated by iron nanoparticles [106], thus, again, the
single infusion. As depicted in Fig. 2, the pharmacokinetic stability of the carbohydrate shell and the different physico-
of IV iron is substantially different from that of oral iron. chemical properties of the various compounds are likely
Once injected in the bloodstream (hence circumventing critical. Anyway, a recent systematic meta-analysis of 103
problems in intestinal absorption), IV iron is mainly taken trials including more than 10,000 patients treated with vari-
up by macrophages, which subsequently release the element ous IV iron preparations and more than 7000 patients treated
through ferroportin [101]. However, less stable complexes with different comparators (oral iron, placebo) found serious
can release variable amount of ferric iron directly in the AEs with IV iron extremely rare (< 1,200,000 doses), and
circulation before macrophage uptake. This leads to the pres- no more frequent than comparators [107]. No fatal reac-
ence of toxic labile-free iron, once the binding capability of tion or true anaphylaxis was reported. Only minor infusion
transferrin is saturated. As a general rule, the more stable reactions were consistently reported, with a RR = 2.47 for
is the complex, the less will be the frequency of infusion any IV iron preparation [107]. These results are particularly
reactions, which are usually mild, consisting of rash, palpita- relevant if put in perspective with the frequency of AEs lead-
tions, dizziness, myalgias, and chest discomfort in variable ing to major morbidity occurring with RBC transfusions, the
combination but without hypotension or respiratory symp- only alternative to IV iron in certain circumstances. Indeed,
toms [49]. Such minor infusion reactions occur roughly in such frequency appears higher than that related to IV iron,
1:200 administrations [102], and resolve quickly by simply being estimated at a rate of near 1:21,000 [108].
stopping the infusion without the need of any other treat-
ment. Of note, there is increasing consensus on avoiding The newer IV iron preparations
anti-histaminic drugs in such conditions, with particular ref-
erence to diphenhydramine, as it could determine hypoten- In the last decade three new preparations have entered the
sion and other unwanted side effects, leading to paradoxical clinical scenario, which can be collectively grouped as “third
aggravation rather than amelioration of the clinical picture generation” IV iron compounds (Fig. 3). These preparations
[49, 103]. More serious “anaphylactoid” reactions, includ- share common features conferring superiority over the older
ing hemodynamic and respiratory changes, can also occur products, so that they are relevantly changing the way we
with virtually all IV iron preparations, including the newer manage IDA in clinical practice. Such favorable features,
ones (see below), but appear exceedingly rare (see below). as compared to traditional preparations, are illustrated in
At variance with serious AEs with old compound like iron- Table 3. The most important one is represented by the higher
HMWD, for whom in some cases a IgE-mediated mecha- stability of the carbohydrate shell, which in turn allows to
nisms could be demonstrated [104, 105], such reactions are give the total replacement dose (usually 1–1.5 g, depending

13
 D. Girelli et al.

Table 3  Currently used IV iron preparations

Drug Brand name Stability Maximum single dose Total replacement dose in Minimun admin-
single infusion (1–1.5 g) istration time
(min)

Fe-gluconate Ferlixit® Low 125 mg No 30–60

(repeated access needed)
Fe-sucrose Venofer® Low-moderate 200 mg No 30
(repeated access needed)
Fe-carboxymaltose Ferinject® High 1000 mg Yes 15
Fe-isomaltoside Monofer® High 20 mg Fe/Kg Yes 15
Ferumoxytol Feraheme® High 510 mg Yes/no 15

on the degree of anemia and body weight, according to the with the only possible exception of patients with IDA in the
classical Ganzoni’s formula [109]) in just one or two infu- context of severe malnutrition, where baseline phosphate
sions. Such an easy schedule is clearly more comfortable for levels could be already reduced. On the other hand, FCM
patients than classical multiple infusion schemes, i.e. up to has been successfully and safely used in a number of clinical
7–10 infusions on consecutive days with ferric gluconate. settings, including CHF [74, 75], CKD [118], inflammatory
The increasing costs per vial appear counterbalanced by bowel disease [119, 120], heavy uterine bleeding [121], as
reduced costs in terms of personnel, and in-hospital organi- well as during pregnancy in the second and third trimester
zation [110]. Moreover, the higher stability also results in [122, 123].
a very good safety profile because of reduced probability
to release of free iron. An extensive review on the use of Expanding spectrum of clinical use of IV iron
single-dose IV iron is found elsewhere [111].
Iron isomaltoside is, for now, available only in few Euro- The availability of novel IV iron preparations safe and
pean nations, while Ferumoxytol and Ferric carboxymaltose easy to use is gradually abating prejudices and miscon-
(FCM) are becoming increasingly popular worldwide. ceptions regarding this therapeutic approach [45]. From
A peculiarity of Ferumoxytol consists on its core made historical restrictions considering IV iron as “an extreme
of superparamagnetic iron oxide NPs, surrounded by low solution for severe IDA when other options were imprac-
molecular weight semisynthetic carbohydrates. This com- ticable” [98], now there is a number of conditions where
pound was originally developed as enhancing agent for mag- its use is well-established or increasingly considered as
netic resonance imaging (MRI), and it is sometimes still first-option approach [111] (Table 4). At variance with
used for this purpose [112]. Thus, while its administration oral iron, compliance is assured and correction of IDA
for IDA does not definitively compromise the interpretation, is more rapid without need of prolonged administration.
should a patient undergo MRI within 3 months of adminis- From a pathophysiological point of view, the use of IV
tration, the radiologist should be notified [83]. iron in CHF is of particular interest. As noted above, CHF
Ferric carboxymaltose (FCM) is characterized by a tight patients are predisposed to develop ID or even IDA, but a
binding of elemental iron to the carbohydrate polymer shell. precise laboratory definition of ID in this setting is difficult
This is consistent with studies on labile-free iron release of because of the interference of subclinical inflammation.
different preparations, showing the lowest levels with FCM This tends to increase serum ferritin above the thresh-
[113]. Because of its high stability, FCM can be quickly old levels (< 15–30 μg/L) typical of uncomplicated IDA.
administered at high dose, up to 1000 mg of elemental iron Anker and colleagues first proposed wide and pragmatic
in 15 min [114]. Hypophosphatemia is not infrequent in the criteria for defining ID in CHF, i.e. serum ferritin lev-
following days after FCM infusion [115], with a mecha- els < 100 μg/L, or even < 300 μg/L if transferrin saturation
nism that appears peculiar to its unique carbohydrate moi- is concomitantly < 20% [74]. Notwithstanding skepticism
ety [116]. Indeed, FCM is able to induce the synthesis of in the hematological community about this “extensive”
fibroblast growth factor 23 (FGF-23), an osteocyte-derived definition, IV iron supplementation with FCM in CHF
hormone that regulates phosphate and vitamin D homeo- patients was effective in ameliorating either iron stores or
stasis [117], ultimately leading to increased renal excretion cardiac function [74]. Such results have been consistently
of phosphate [115]. However, FCM-induced hypophos- replicated [75, 124], so that most recent and authorita-
phatemia does not appear clinically meaningful, as it is tive guidelines suggest to systematically check for ID in
mild, transient, and without symptoms or sequelae. Serum CHF and IV iron treatment if ID is present [125–127].
phosphate levels do not need to be checked or monitored, Noteworthy, a sub-analysis of the seminal FAIR-HF trial

13
Modern iron replacement therapy: clinical and pathophysiological insights

Table 4  Indications for IV iron

Established Examples/comments

Failure of oral iron Non-adherence, AEs

Malabsorption Celiac disease, gastritis (atrophic, autoimmune, Hp +), bariatric
surgery, genetic IRIDA
Severe IDA Generally accepted threshold: Hb < 8 g/dl
End-stage chronic kidney disease (CKD) (+ Erythropoiesis Stimulating Agents-ESAs)
Inflammatory bowel diseases IDA in active disease
Pregnancy Severe IDA in II–III trimester
Heart failure (HF)a Systolic HF (­ LVEFb ≤ 45%)
Potential (extended) Examples/comments

ID/IDA in elderly If comorbidities/polypharmacy (including PPI) prevent adherence

to (or effectiveness of) long-term oral iron
Perioperative anemia Patient blood management strategies to prevent RBCs transfusions
IDA in cancer ± ESAs
Restless leg syndrome
Mountain sickness (Prevention)
Heavy uterine bleeding
a
Iron deficiency (even without anemia): serum ferritin < 100 or < 300 µg/L, if transferrin saturation ≤ 20%
b
Left Ventricular Ejection Fraction

[74] focusing on anemic CHF patients showed consistent inflammation sufficient to inhibit intestinal (but not mac-
Hb increase after IV iron, implicitly validating the above rophage) ferroportin.
mentioned “extensive” criteria for ID [128]. As mentioned Whether this applies to other chronic conditions where
above, the beneficial effect of iron in CHF is seen only inflammation and ID often coexist remains to be determined,
using IV preparation (for now FCM is the only compound and active clinical research is needed [131]. A further novel
tested in such condition), while a recent trial with oral example in this sense could be represented by chronic
iron was unsuccessful because of increased hepcidin lev- obstructive pulmonary disease (COPD), where a previously
els [76]. As depicted in Fig. 2, IV iron also needs a per- unrecognized detrimental role of ID would merit adequate
missive effect of ferroportin to be delivered to circulating addressing in the future [132].
transferrin and ultimately to erythroid precursors in the
bone marrow. However, it enters the circulation mainly
through macrophage ferroportin, at variance with oral iron Conclusions
that uses intestinal ferroportin (Fig. 2). According to most
recent basic studies [129, 130], it is increasingly recog- The recent advances in pathophysiology of IDA, along with
nized that there are substantial quantitative differences the availability of new iron preparations and the awareness
between overall expression of ferroportin at intestinal level of the implications of ID in a variety of clinical fields, is
(normally dealing with low amount of iron, ~ 1–2 mg/die), making iron replacement therapy more feasible and fasci-
as compared to the macrophage level (normally manag- nating than ever. We are hopefully approaching a new era
ing much more iron, ~ 20–25 mg/die). In other words, where we could eventually contrast more effectively the
the amount of hepcidin needed for blocking iron absorp- most important nutritional deficiency worldwide.
tion is likely much lower than that required for inhibiting
ferroportin expressed by the innumerous iron recycling Acknowledgements D. G. has received funding for research on iron
metabolism by Fondazione Cariverona (2014.0851), and the Veneto
macrophages. Hence, the clinically confirmed success of Region (PRIHTA no. 2014-00000451).
IV iron in CHF represents an interesting paradigm in mod-
ern iron replacement therapy. Indeed, CHF recapitulates
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