The patient’s diet has to be integrated with heme-rich food whenever possible. However, due to the low percentage of dietary iron absorbed (5% to 15% in normal subjects and about 25% to 30% in iron deficiency), the diet alone is insufficient to overcome iron deficiency and pharmacological iron has to be supplemented. Iron preparations are available for either oral or intravenous therapy.

Oral Iron Therapy

 Oral iron is the first-line therapy in stable patients with isolated iron deficiency or mild-moderate anemia. A plethora of compounds are available: the most effective and inexpensive are iron salts, such as ferrous gluconate, sulfate, and fumarate (containing from 36 to 100 mg elemental iron/tablet). Traditionally, the recommended therapy was 100 to 200 mg elemental iron daily supplemented as iron salts in divided doses at fast and between meals. However, a modified sched ule may increase the efficacy and reduce the side effects of oral iron treatment. Several requirements have to be met for oral iron to be efficacious. Patients must be compliant to the treatment schedule, gastric chloride production should be adequate, duodenal mucosa should be intact, and hepcidin levels should be suppressed to allow iron export by ferroportin into plasma. Unfortunately compliance to oral iron treatment is low, because of gastrointestinal side effects and because of the treatment duration. To correct anemia and replete the exhausted stores—that means reaching a target ferritin of 50 to 100 μg/L—may require 3 to 6 months of treatment and few patients com ply with such a long schedule. Nausea, epigastric discomfort, vomiting, constipation, dark stools, and metallic taste occur in 30% to 70% of the cases according to different studies, often leading to premature therapy discontinuation.13 Side effects are ascribed to the toxicity of non-absorbed iron on intestinal mucosa through generation of reactive oxygen species (ROS). Dose reduction or iron administration at meals may induce a better tolerance, although prolonging treatment. A further problem of non-absorbed iron concerns the modification of the intestinal microbiota, with reduction of Lactobacillae and Bifidobacteria and enhanced growth of pathogens such as enterobacteria, causing dysbiosis.

Slow-release iron formulations are better tolerated than iron salts, but less effective since beyond the duodenum iron absorption is negligible. Ferric iron is insoluble and compounds such as ferric saccharide complexes are less efficacious than iron salts. Ferric citrate, an intestinal phosphate binder, is useful in chronic kidney disease patients to correct both anemia and hyperphosphatemia. Preparations of iron plus multivitamins are useless, the exception being ascorbic acid that increases iron salts absorption.

Recent studies suggest a modified schedule of iron salts administration to increase the therapeutic efficacy and decrease adverse effects. Short-term trials with stable iron isotopes administered as iron sulfate at variable doses (from 60 to 240 mg) to iron-deficient non-anemic women showed that each dose acutely increases serum hepcidin levels, thus decreasing the fractional iron absorption of the consecutive doses up to 48 hours. The conclusion is that in iron In severe anemia or when oral iron treatment is inconvenient for whatever reason, the alternative option is parenteral, intravenous, iron administration.

Intravenous Iron Therapy

Indications to intravenous iron therapy have been limited in the past by the risk of severe hypersensitivity reactions with old iron compounds, especially high-molecular-weight iron dextran that is no longer available. True refractoriness, poor intestinal iron absorption due to medical or surgical pathological conditions, excessive needs not met by oral therapy (e.g., chronic bleeding not compensated by oral iron therapy), severe anemia, and need of quick recovery are established indications. The increased safety of currently available formulations has broadened the indications to parenteral iron therapy (Table 1). Intravenous iron is more effective than oral iron in conditions of mixed anemia (iron deficiency and inflammation), such as in inflammatory bowel disease, chronic heart failure, and chronic kidney disease (CKD). In acute flares of inflammatory bowel disease iron deficiency should be exclusively treated by intravenous iron, considering the high hepcidin levels, and to avoid further mucosal dam age and microbiota alteration. Patients in remission phase may respond to oral iron. Intravenous iron improves symptoms and physical performance, such as the 6-minute walk distance test, and quality of life in patients with iron deficiency and chronic heart failure with reduced ejection fraction. This occurs even independently from correction of anemia suggesting a direct effect of iron on cardiomyocyte function. Parenteral iron is more effective than oral iron in combination with erythropoiesis stimulating agents in CKD and has blood transfusions and ESA dose sparing properties that are relevant considering the negative ESA induced cardiovascular side effects.

Table1. Indications to Parenteral Iron Therapy

The use of intravenous preparation is increasing because of the increased safety profile of available preparations. The contemporary generations of compound have a structure (Table 2) based on a carbohydrate shell surrounding the iron core, which confers increased stability, preventing premature iron release. On one hand this reduces the acute adverse effects ascribed to labile free iron released in the circulation and on the other it allows high-dose infusion in a single injection.

Table2. Iron Preparations for Parenteral Intravenous Use

The currently available preparations have equivalent efficacy. The most important difference is between low-dose compounds that require repeated infusions and high-dose compounds. The latter have gained popularity because the total iron amount needed is replaced in one/ two infusion(s) with a good safety profile (see Table 2). The dose of iron to be replaced with multiple infusions is calculated based on body weight, the Hb deficit plus the amount (calculated in 500 mg) needed to restore iron stores. For the high-dose compounds a simplified formula is used based on Hb levels and body weight. Since Hb increase and stores reconstitution occur more promptly with high-dose preparations these compounds are convenient when a rapid recovery is necessary or in patients with limited hospital access; the main disadvantage is the high cost, which is nevertheless balanced by reduced hospital accesses. In practice the choice of the drug, besides what is approved/available at different centers, often depends on the clinical status such as age, sex, longstanding vs recent onset or recurrent anemia, the reversibility of the underlying cause, cost evaluation, and ultimately also patient’s preference.

In general, intravenous iron supplementation is safe. Minor/moderate infusion reactions (nausea, pruritus, urticaria, flushing, back or thoracic pain) often self-limited with infusion interruption are reported in 1:200 infusions with different preparations. Delayed reactions (headache, myalgia, arthralgia) may occur up to 48 hours after the infusion. Severe reactions (hypotension, dyspnea) are infrequent, estimated around 1:200,000. Guidelines to minimize the infusion risk are available and training of the personnel is important.

Contraindications to intravenous iron are limited. Immediate discontinuation is required in acute infections since microorganisms may use iron as a growth factor. Intravenous iron should not be used in the first trimester of pregnancy because of the lack of safety data and in patients with previous severe hypersensitivity reactions. Of some concern is the incidence of hypophosphatemia in patients treated with ferric carboxymaltose, an incidence significantly higher than with other preparations. Hypophosphatemia alteration is usually mild, transient, and asymptomatic. Occasionally, after repeated doses, it persists and causes osteomalacia with bone pain and risk of fractures. Phosphate control is recommended in the rare patients receiving multiple injections of high-dose ferricarboxymaltose.

Concerns exist about overcorrecting iron depletion with intra venous iron in subjects with heart failure, CKD, or inflammatory conditions. Possible late complications of excess iron in terms of increased risk of oxidative stress and atherosclerosis are not assessed in available trials. Increased susceptibility to infections in CKD patients who receive chronic iron therapy is controversial; a recent large trial of prolonged iron treatment in hemodialysis patients showed that the infection rate was similar irrespective of the high or low iron dose used. In the choice of oral vs intravenous treatment, risks and benefits should be evaluated on an individual basis.

Red blood cell transfusions should not be used to treat iron deficiency anemia unless anemia is life threatening or patients are at risk of cardiac or cerebral ischemia.

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