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Iron salts


See also Iron oxide

General information

Iron is a metallic element (symbol Fe; atomic no. 26). The symbol is derived from the Latin word for iron, ferrum.

Iron is found widespread in nature in ores such as almandine hercynite (iron aluminate); scorodite (iron arsenate); pyrites (iron disulfide); laterite (iron hydroxide); columbite (iron niobate); chromite, hematite, ilmenite, limonite, magnetite, mugearite, stilpnosiderite, and umber (iron oxides); lazulite (iron phosphate); babingtonite, crocidolite, cummingtonite, epidote, eudialyte, fayalite, gadolinite, glauconite, hornblende, hypersthene, olivine, pennine, piedmontite, and riebeckite (iron silicates); coquimbite, inkstone, and jarosite (iron sulfates); ankerite, arsenopyrites, bornite, chalcopyrite, pentlandite, and pyrrhotite (iron sulfides); marcasite (iron sulfite); and wolframite (iron tungstate).

Iron salts are commonly used medicinally to treat or prevent iron deficiency anemia. Ultrasmall superparamagnetic particles of iron oxide (USPIOs) of median diameter no less than 50 nm have been given intravenously to enhance liver imaging in patients with cirrhosis and to visualize lymph nodes (see separate monograph, Iron oxide ). Various iron oxides and hydroxides are also used as pigments in cosmetics.

The body has no physiological route for the excretion of excess iron, and iron overload is a constant risk of therapy. Long-term use of iron by any route in large amounts can lead to hemosiderosis, simulating hemochromatosis; the danger is greatest when the mucosal barrier is bypassed by parenteral injection. Even the safety of iron-fortified food is uncertain [ ]. As with other metals there is environmental exposure to iron in many forms. The use of iron cooking utensils is often considered a useful source of supplementary iron in the diet.

The molecular basis of iron overload and toxicity has been reviewed [ , ]. Much attention has been paid to mechanisms of hemochromatosis [ , ]. There have been reviews of the comparative tolerance and safety of iron salts [ ] and their use in specific conditions, such as renal insufficiency [ ].

In the following sections, adverse reactions are considered in connection with the types of iron therapy with which they have most commonly been associated, but any adverse reaction can in principle occur with any formulation or as a result of mixed medical and non-medical exposure.

The molecular and clinical aspects of iron hemostasis have been reviewed [ , ].

Oral iron

Despite the use of recombinant erythropoietin, anemia remains a significant problem for patients with end-stage renal disease [ ]. Because oral iron formulations are relatively ineffective and poorly tolerated, intravenous iron dextran has been widely used, despite the risk of adverse reactions.

Formulations of iron chelates, with improved intestinal iron absorption, have been studied [ ].

Parenteral iron

Like oral iron, parenteral iron is used too widely. When iron is truly needed, oral administration is generally preferable [ ]. Intractable gastrointestinal intolerance to oral formulations, hyperemesis in pregnancy, very severe blood loss, and possibly ulcerative colitis are some of the few valid indications for parenteral iron. A low iron-binding capacity (for example due to prior saturating iron therapy or malnutrition), folic acid deficiency, and an allergic constitution predispose the patient to adverse reactions to parenteral iron. Iron injections have been reported to provoke hemolytic anemia in cases of paroxysmal nocturnal hemoglobinuria.

Most parenteral iron is administered intramuscularly, but intravenous injections have enjoyed waves of popularity for no very good medical reason; it seems particularly likely to precipitate acute allergic or anaphylactic reactions in sensitive individuals, sometimes involving cardiac dysrhythmias, hypotension, circulatory collapse, and pulmonary edema.

Adverse reactions to iron formulations have resulted in trials to optimize dose regimens. A large database of clinical variance reports from Fresenius Medical Care North America (FMCNA) has been analysed to determine the incidence of suspected adverse drug reactions of iron dextran and the associated patient characteristics, dialysis practice patterns, and outcomes [ ]. A case-cohort design was used, comparing individuals who had suspected adverse drug reactions with the overall population. Out of 841 252 intravenous iron dextran administrations over 6 months, there were 165 reported suspected adverse drug reactions, corresponding to an overall rate of about 20 per 100 000 doses. Hospital evaluation was required in 43 patients (26%), 18 (11%) required hospitalization, and one (0.6%) died. Dyspnea (43%), nausea (34%), vomiting (23%), flushing (27%), pruritus (25%), hypotension (23%), and neurological symptoms (23%) were the most common adverse reactions. Serious adverse reactions to intravenous iron dextran are rare and difficult to predict; the risk appears to depend on the specific formulation of intravenous iron dextran.

In a retrospective analysis of the incidence of adverse effects associated with 250 mg of ferric gluconate infused over 1–4 hours in 40 patients with severe chronic renal insufficiency, who received 79 treatments, four treatments in two patients were associated with adverse effects, including diarrhea, vomiting, low back pain, hypotension, and a burning sensation in the feet. The duration of the infusion did not influence the adverse effects profile.

Intramuscular iron

Iron compounds for intramuscular administration are iron sorbitol-citric acid complex (iron sorbitex), iron dextran, iron glycerin-citric acid complex, and iron polyisomaltose. The work on these formulations is largely old and has been reviewed in previous volumes in this series.

Intramuscular iron injections are often painful, can produce topical discoloration of the skin, and some local inflammation with lymphadenopathy. Rarely, more severe local reactions follow [ ], such as transient lipomyodystrophy. An unpleasant metallic taste in the mouth is common and can persist for some hours or days. Some patients develop general symptoms, such as headache, flushing, sweating, nausea, vomiting, dizziness, generalized aches and pains, malaise, arthralgia, palpitation, and pericardial or abdominal pain. Although very rare, a severe anaphylactic reaction to intramuscular iron dextran can occur.

The safety and efficacy of iron dextran have been evaluated in patients on home renal replacement therapies, without adverse reactions [ ].

Intravenous iron

Iron dextran is the most commonly used iron compound for intravenous use, and most reported adverse reactions to intravenous iron relate to this formulation.

Local reactions to intravenous iron dextran include transient pain (in some 4% of cases) and phlebitis. The risk of the latter may be reduced by using saline instead of 5% dextrose as diluent. Nevertheless, deep vein thrombosis has been observed in a few patients infused with a dilution of iron dextran in normal saline [ ].

Systemic reactions to iron dextran given intravenously are more common than those to intramuscular iron; they include non-immunological and immunological, immediate and delayed reactions. Flushing, a sensation of warmth, and a metallic taste are often associated with excessively rapid injection, but usually subside within less than a minute after slowing or stopping the injection. In about 1% of cases, including patients with no known prior exposure to dextran, life-threatening anaphylactoid reactions occur rapidly, with hypotension, cardiovascular shock, syncope, cyanosis, bronchospasm, respiratory arrest, urticaria, and angioedema; deaths have ensued. Milder allergic reactions comprise mild and transient hypotension, malaise, itching, and urticaria. Desensitization under an umbrella of glucocorticoids, antihistamines, and ephedrine has been carried out successfully [ ].

Delayed systemic reactions to intravenous iron dextran appear to be more common, the reported incidence ranging from 5% to 15%. They start within 4–48 hours of injection and can last for 3–7 days. Characteristic symptoms are fever, arthralgia, myalgia, headache, and lymphadenopathy, singly or in combination, and a classic serum sickness has been seen [ ]. Chills may also occur and individual patients may experience dizziness, tinnitus, paresthesia, a feeling of stiffness in the arms and neck, pruritus, urticarial or other cutaneous eruptions, pallor, nausea, vomiting, and nasal irritation. There may be hepatosplenomegaly. These delayed reactions are more frequent in children and, for some reason, in patients of Chinese origin. They tend to be more severe in patients with low body weight given higher doses, and in patients with rheumatoid arthritis or other types of inflammatory disease.

Large doses of intravenous iron dextran and iron saccharate have been compared in a retrospective study of 379 patients who had attended peritoneal dialysis clinics in the past 5 years [ ]. Of these, 62 were selected to receive intravenous iron based on ferrokinetic markers of iron deficiency, non-adherence to oral iron, ineffectiveness of oral iron, or increased erythropoietin requirements. Intravenous iron was given as two injections of 500 mg each 1 week apart in 61 patients, 33 of whom received iron dextran, 23 iron saccharate, and five both iron dextran and iron saccharate. One patient developed anaphylaxis to a test dose of iron dextran and was excluded from further therapy. Blood samples were collected before and 3 and 6 months after iron infusions. Five of the 34 patients who received iron dextran developed minor adverse effects and one had an anaphylactic reaction to the test dose. Of the 23 patients who received iron saccharate, one had an anaphylactic reaction and two had transient chest pain, which subsided without therapy. There were more adverse effects with iron dextran (7.4% of injections) compared with iron saccharate (4.3% of injections), but this difference was not statistically significant. The number of episodes of peritonitis also increased during the 6 months after intravenous iron infusion, especially with iron dextran, compared with the number of episodes during the 6 months before iron infusions, although the difference was not statistically significant.

Other iron compounds for intravenous use

Saccharated iron oxide is strongly alkaline and hypertonic; if injected outside the vein it can cause marked local reactions. Significant serum hypophosphatemia has on occasion been observed during treatment, accompanied by reduced renal tubular reabsorption of phosphate. The mechanism of these changes, which were reversible after stopping the iron injections, has not been clarified [ ].

Topical iron

Iron chloride is sometimes used topically as a hemostyptic after minor surgery. It can result in persistent brown staining at the site of application. Use of Monsel’s solution (ferric subsulfate), another hemostyptic agent, can cause fibrovascular proliferation accompanied by strongly pigmented macrophages after an interval of up to 3–5 weeks; the condition may be mistaken for malignant melanoma.

Drug studies

Comparative studies

Adverse reactions to two intravenous iron formulations, iron dextran and iron sucrose, have been studied in 60 patients with end-stage renal disease, who were randomized to one of the two formulations [ ]. Standard test doses of 25 mg of low molecular weight iron dextran and iron sucrose were given over 15 minutes during the initial visit, monitoring very closely for adverse reactions. If this dose was well tolerated, 75 mg of iron diluted in 100 ml of isotonic saline was given over 30 minutes. The mean age of the patients was 52 (range 21–80) years. Of the 30 patients who received low molecular weight iron dextran, 11 had adverse reactions: pruritus, wheezing, chest pain, hypotension, swelling (n = 1 each), headache (n = 2), and nausea (n = 4). Of the 30 patients who received iron sucrose, 13 developed adverse effects: pruritus, wheezing, diarrhea, swelling (n = 1 each), hypotension (n = 2), headache (n = 3), and nausea (n = 4). Adverse events occurred with similar frequency in the two treatment groups. There were no serious reactions.

Adverse reactions to parenteral iron products have been reviewed [ ]. The authors concluded that iron sucrose and ferric gluconate are safer than iron dextran, but this may be a premature conclusion.

Organs and systems

Cardiovascular

Intramuscular iron

The major hazard of the intramuscular use of iron sorbitex consists of severe systemic reactions with cardiac involvement, which may be fatal. They occur in up to 1% of cases. They start 10–30 minutes after injection and a patient who has received an injection must be monitored for an hour. Nausea, chest pain, profuse sweating, cardiac dysrhythmias, and loss of consciousness can occur. Cardiac complications include complete atrioventricular block, ventricular tachycardia, and ventricular fibrillation.

Intravenous iron

Non-transferrin-bound iron, which increases after intravenous ferric saccharate, has been suggested to act as a catalytic agent in oxygen radical formation in vitro, and may therefore contribute to endothelial impairment in vivo [ ]. The effect of ferric saccharate infusion 10 mg has been investigated in 20 healthy volunteers. Ferric saccharate caused a greater than four-fold increase in non-transferrin-bound iron and transient significant reduction in flow-mediated dilatation 10 minutes after infusion of ferric saccharate. The generation of superoxide in whole blood increased significantly 10 and 240 minutes after infusion of ferric saccharate by 70% and 53% respectively. Thus, infusion of iron leads to increased oxygen radical stress and acute endothelial dysfunction.

Respiratory

Spontaneously regressing bronchial necrosis with granuloma formation has been associated after aspiration of a tablet of ferrous sulfate in a single case [ ].

Acute respiratory distress syndrome has been attributed to iron [ ].

  • A 3.5-year-old girl was admitted after accidental ingestion of 50–60 tablets of ferrous sulfate 200 mg. She was unresponsive and her serum iron concentration was 138 μmol/l. She required resuscitation and ventilation and an intravenous infusion of deferoxamine was started at a rate of 15 mg/kg/hour, reducing to 5 mg/kg/hour 20 hours later, when the iron concentration was 27 μmol/l. At that time, her liver function deteriorated, with raised alanine transaminase activity (57 IU/l), raised bilirubin (56 μmol/l), and a coagulopathy with an INR of 2.7. She was given an infusion of N-acetylcysteine 12.5 mg/kg/hour and her hepatic function stabilized. After about 40 hours she had acute respiratory deterioration with tachypnea and hypoxemia. A chest X-ray showed widespread bilateral infiltrates. A diagnosis of acute respiratory distress syndrome was made.

Aspiration of iron tablets can produce an acute reaction in the airways since they are highly irritative; immediate removal bronchoscopy is necessary to avoid permanent damage [ ]. Lung damage has been reported in a man who had inhaled an oral iron formulation containing 350 mg of elemental iron [ ].

  • A 75-year-old man developed chest discomfort and hemoptysis. A chest X-ray showed left lower lobe collapse and fiberoptic bronchoscopy showed that the left endobronchial mucosa was friable, edematous, and golden-yellow, with interspersed erythematous ulcerated areas with marked contact bleeding. There was heavy deposition of yellow-brown pigment on the basement membrane of the superficial bronchial epithelium, on the basement membrane of the bronchial glands, and on fibrillar material in the stroma. Pigment deposition was greatest in the necrotic fragments of mucosa, but was also seen in viable mucosa. This material stained strongly for ferric ion with Perls’ stain. Iron was withdrawn and the left lower lobe collapse improved.

Metabolism

In erythropoietic protoporphyria, iron can cause a relapse of symptoms [ ]. An involvement of iron overload in the pathogenesis of some cases of porphyria cutanea tarda has been suggested [ ].

Hematologic

Latent folic acid deficiency can become manifest during iron therapy due to additional demand for the vitamin secondary to increased erythropoietic activity [ ].

Severe intravascular hemolysis with acute renal failure have been attributed to iron dextran [ ].

  • A 40-year-old Arabic woman with microcytic anemia and severe iron deficiency was given oral iron supplementation repeatedly but always stopped because of adverse gastrointestinal effects. She was given intravenous low molecular weight iron dextran (Cosmofer®) at a slow infusion rate, but soon developed anxiety, chest discomfort, and a reduced blood pressure and heart rate. The infusion was stopped and she was given intravenous hydrocortisone and quickly recovered. Four weeks later she received two erythrocyte transfusions. The next day, another attempt was made to give her iron dextran. Again, she developed anxiety and chest pain without any change in blood pressure or signs of bronchospasm. She was given intravenous hydrocortisone, clemastine, and sublingual nitroglycerine. Within 5 minutes of withholding the infusion, all her symptoms disappeared. After 7 days, she was readmitted to hospital with back pain and almost black urine. Blood tests showed acute renal failure and hemolysis. The platelet count fell from 422 to 212 × 10 9 /l and then remained within the reference range. Within 24 hours after admission she developed anuria, and hemodialysis was begun. Over the next 18 days she received nine hemodialysis treatments, six plasma exchanges, and 14 erythrocyte transfusions. The hemolysis ceased and she regained kidney function. Two months later she had normal kidney function and no signs of hemolysis.

Intramuscular iron

Thrombocytopenia has been attributed to intramuscular iron [ ].

  • A 30-year-old woman had a hemoglobin concentration of 3.1 g/dl, a mean cell volume of 77 fl, a reticulocyte count of 2.13%, a platelet count of 426 × 10 9 /l, a serum iron concentration of 5 ng/ml, a transferrin saturation of 1%, and a ferritin concentration of 8 ng/ml. She was intolerant of oral iron and was given intramuscular iron dextran, 100 mg/day for 8 days, when she developed asymptomatic thrombocytopenia (platelet count 20 × 10 9 /l). Iron dextran was withdrawn and she took oral ferrous fumarate 200 mg/day plus ascorbic acid 120 mg/day. Within 2 days her platelet count improved.

Teeth

Most liquid ferrous products stain dental enamel, but this is usually reversible [ ].

Gastrointestinal

Severe gastrointestinal necrosis and strictures after iron overdose are well described. However, mucosal injury in patients taking therapeutic iron has received only scant recognition, despite its widespread use. In 36 upper gastrointestinal tract biopsies from 33 patients (24 gastric, nine esophageal, one gastro-esophageal junctional, and two duodenal) there was characteristic brown crystalline iron material [ ]. Most of the biopsies (32 of 36) contained luminal crystalline iron adjacent to the surface epithelium or admixed with luminal fibrinoinflammatory exudate. In 30 biopsies there was crystalline iron deposition in the lamina propria, either covered by an intact epithelium, subjacent to small superficial erosions, or admixed with granulation tissue. Three biopsies showed iron-containing thrombi in mucosal blood vessels. Erosive or ulcerative mucosal injury was present in 30 of 36 biopsies. The amount of iron accumulation in cases with mucosal injury was greater than in the cases without mucosal injury. About half of the patients (17 of 33) also had underlying infectious, mechanical, toxic, or systemic medical conditions that could have initiated or exacerbated tissue injury. Crystalline iron deposition was found in 0.9% of upper gastrointestinal endoscopic examinations (12 of 1300), and iron medication-associated erosive mucosal injury was present in 0.7% (nine of 1300). These results suggest that crystalline iron deposition in the upper gastrointestinal tract is not uncommon. It can cause or exacerbate a distinctive histological pattern of erosive mucosal injury, especially in patients with associated upper gastrointestinal disorders.

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