Iron

Mechanism of Action

Intravenous iron – Iron therapy in intravenous form consists of an iron-hydroxide core encased in a carbohydrate ligand. After administration, these complexes are taken up by macrophages via endocytosis. Once inside macrophages, they can either be expelled into the serum as ferrous iron (Fe2+) or incorporated into ferritin for storage. The iron expelled from the macrophage is quickly oxidized to ferric iron (Fe3+) and bound to transferrin for transport to target sites, including the bone marrow for production of hemoglobin and the liver for storage.[3]

Oral iron – Iron administered orally travels to the duodenum, where it is taken up into enterocyte cells along the brush border by the divalent metal-ion transporter 1 (DMT1). From there, it can either be incorporated into ferritin for storage or expelled into the serum by the ferroportin 1 transporter on the basolateral membrane. This transporter is bound to multicopper oxidases that oxidize ferrous iron (Fe2+) into ferric iron (Fe3+) that can bind to transferrin for transport to the bone marrow for hemoglobin synthesis or to the liver for storage.[4]

Of note, these processes of active absorption can only absorb a set amount of iron at a given time. Iron consumed exceeding these limits is absorbed passively into the blood via the paracellular route.[4][5]

Administration

The administration of iron supplementation can be both orally and parenterally. Oral iron therapy is the preferred route as it tends to be both affordable and effective in mild to moderate deficiency cases. In iron deficiency anemia, 100 to 200 mg elemental iron is given daily divided into two doses to adult patients. For severe iron deficiency or when oral treatment fails (or is intolerable), or in patients with impaired intestinal absorption, intravenous therapy can be the administration option. Both oral and intravenous iron is available in a variety of formulations.[6]

Adverse Effects

Oral iron – the most common side effects of oral iron administration are gastrointestinal upset, which can include nausea, diarrhea, cramping, and more commonly, constipation. More serious are gastrointestinal hemorrhage and ulceration, as well as hypersensitivity reactions.[7]

Intravenous iron – the most common side effect of intravenous iron administration is hypotension. Other side effects include minor infusion reactions, typically presenting as arthralgias/myalgias, headache, nausea, and flushing.[8]

Contraindications

Hypersensitivity and hemochromatosis are the main contraindications. Contraindications to intravenous iron infusion include the first trimester of pregnancy. Use caution in patients with peptic ulcer disease, inflammatory bowel disease, and patients receiving regular blood transfusions.[9]

Monitoring

The hemoglobin level should increase by 2 g/dL within 4 to 8 weeks of initiating therapy. Ferritin should be rechecked 8 to 12 weeks after completion of treatment as normalization of ferritin levels and transferrin saturation is the target goal. For patients suffering from severe deficiency, it may take up to 3 months for hemoglobin to return to the normal range.[10]

Toxicity

Both oral and intravenous forms of iron have the potential to cause oxidative stress and damage. Iron-induced coagulopathy, liver damage, kidney failure, and cardiomyopathy may occur upon reaching toxic levels. The toxicity correlates with the amount of elemental iron within iron products ingested. Ingestion/administration of 20 mg/kg or more of elemental iron can result in symptoms of toxicity. Serum levels peak between 4 and 6 hours and can be used to assess the potential for toxicity. If a patient is symptomatic and hemodynamically unstable, they should be treated with IV fluids and potentially with deferoxamine – a chelating agent that can bind to iron and be excreted renally, removing it from the body. Vitamin K or fresh frozen plasma are therapy options in cases of iron-induced coagulopathy. A toxicologist should be consulted for guidance when iron toxicity is suspected.[11]

Enhancing Healthcare Team Outcomes

Interprofessional healthcare teams are often made up of many members from different disciplines and can include, but are not limited to, a physician (MD, DO), nurse practitioner or physician assistant, pharmacist, and nurse.

The clinician (MD, DO, NP, PA) will evaluate and decide whether supplemental iron is needed. The pharmacist can consult with various dose formulations available and recommended doses and perform medication reconciliation. Nursing can counsel on proper administration (e.g., avoid taking calcium-rich foods within 2 hours of supplemental iron, etc.) and verify patient compliance. A dietitian or nutritionist can also educate the patient regarding improving their diet and iron-rich foods. All these providers on the interprofessional healthcare team must report back to the treating clinician should they encounter any concerns.

All such team members treating iron-deficient patients must be able to recognize indications for the administration of iron and be familiar with contraindications, adverse effects, monitoring, and toxicity, and practice interprofessional communication to ensure all healthcare team members are in synch. Increasing the knowledge of iron therapy for each team member will improve implementation and, by extension, improve patient outcomes. [Level 5]