Iron is a mineral necessary for human life. It plays an important role in DNA synthesis and many other metabolic processes. It is also an essential component of heme, within hemoglobin, the protein responsible for transporting oxygen throughout the body. Hemoglobin is present within erythrocytes (red blood cells) which are produced by hematopoietic stem cells of the bone marrow. The stimulus for the production of red blood cells within the marrow is provided by the kidneys, via a hormone called erythropoietin. Erythropoietin travels from the kidneys to the bone marrow where it exerts its action. In addition to providing a basal amount of erythropoietin, the kidneys will increase synthesis and secretion in response to hypoxia.
Individuals who have a deficiency of iron have a decrease in their body’s ability to transport and subsequently utilize oxygen from the air they breathe. Symptoms may manifest in a variety of ways including but not limited to fatigue, pallor, tachycardia, and exercise intolerance. Though iron deficiency can occur with or without anemia, it is, in fact, the most common cause of anemia worldwide, representing a significant public health challenge. Those most at risk are patients with an increased physiologic demand for iron, e.g., young children, adolescents, and pregnant women; as well as those with impaired absorption, e.g. those with inflammatory bowel disease or who have undergone certain gastrointestinal surgical procedures.
Evaluation of iron status is best performed by assessing serum ferritin and transferrin saturation. Serum ferritin represents the level of iron stores in the body. Serum ferritin value less than 30 ng/mL is generally considered diagnostic of iron deficiency; less than 10 to 15 ng/mL is 99 percent specific for iron deficiency anemia; with the caveat or ferritin also being an acute phase reactant, and levels may be affected by inflammatory processes. Transferrin saturation is another metric used to assess iron status which represents the level of iron readily available for transport to tissues. Transferrin saturation of under 20% generally indicates iron deficiency. Iron deficiency may also manifest on a complete blood count (CBC) as a microcytic, hypochromic, anemia; however, iron status should not be based solely on red blood cell characteristics as hematopoiesis is often not affected in early stages of deficiency.
The implementation of iron therapy can be initiated on the basis of several different guidelines depending on etiology. The European consensus on the diagnosis and management of iron deficiency and anemia in inflammatory bowel disease (ECCO) suggests iron supplementation for patients with ferritin under 30 ng/mL or less than 100 ng/mL if transferrin saturation is below 20% for those with iron deficiency due to inflammatory bowel disease. Similarly, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines use serum ferritin below 100 ng/mL and transferrin saturation under 20% as an indication for therapy in patients with renal disease. The European Society of Cardiology uses ferritin less than 100 ng/mL or 100 to 299 ng/mL with transferrin saturation below 20%, in patients with heart failure.
Most oral iron formulations are considered to be dietary supplements, and as such are not subject to the same set of regulations used by the U.S. Food and Drug Administration (FDA) in the evaluation of traditional drug products. Parenteral, i.e. intravenous iron therapy is approved by the FDA for treatment of iron deficiency anemia for patients who are intolerant to oral iron or have demonstrated an inadequate response, as well as for patients with chronic kidney disease. It should be noted that further guidelines and restrictions vary by individual brand of parenteral iron.
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, which include the bone marrow for production of hemoglobin and the liver for storage.
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.
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.
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 cases of deficiency. 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 are available in a variety of formulations.
Oral iron – the most common side effects of oral iron administration are gastrointestinal upset; including nausea, diarrhea, cramping, and more commonly constipation. More serious is gastrointestinal hemorrhage and ulceration, as well as hypersensitivity reactions.
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, as well as headache, nausea, and flushing.
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.
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.
Both oral and intravenous forms of iron have the potential for causing 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.
Healthcare teams are often made up of many members from different disciplines and can include, but are not limited to a physician, nurse practitioner or physician assistant, pharmacist, and nurse.
The physician (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, as well as performing medication reconciliation. Nursing can counsel on proper administration (e.g., avoid taking calcium of calcium-rich foods within 2 hours of supplemental iron, etc.) and verify patient compliance. A dietitian or nutritionist can also weigh in to 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 not only recognize indications for the administration of iron, but must also 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 V]
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