Continuing Education Activity

Iron is a medication used in the management and treatment of iron deficiency anemia. This activity illustrates the indications, action, and contraindications for iron supplementation as a valuable agent in the management of iron-deficient states such as iron deficiency anemia, iron deficiency without anemia, nutritional deficiency, malabsorption, blood loss, or an increase in the body's need for iron. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with iron deficiency and related conditions.

Objectives:

• Identify the mechanism of action and administration of iron supplementation.
• Describe the adverse effects and contraindications of iron supplementation.
• Review the appropriate monitoring and toxicity of iron supplementation.
• Summarize interprofessional team strategies for improving care coordination and communication to optimize iron supplementation and improve outcomes.

Indications

Iron supplementation is indicated for iron-deficient states secondary to conditions such as iron deficiency anemia, iron deficiency without anemia, nutritional deficiency, malabsorption, chronic inflammatory state, blood loss, or an increase in the body's need for iron. Iron is an essential mineral needed for general health. Depleted iron stores lead to decreased production of hemoglobin and circulating erythrocytes in this body, resulting in anemia. Symptoms of iron deficiency can present as fatigue, weakness, shortness of breath, pica and pagophagia, tachycardia, altered mental status, hypothermia, and increased risk of infection.[1]

Treatment primarily aims at replenishing the body's iron stores and providing symptomatic relief. If left untreated, this may lead to adverse events such as neurodevelopmental delay in developing children and poor pregnancy outcomes for expectant mothers. At-risk populations are women of child-bearing age, where monthly menses and pregnancy are a common cause for anemia.[2] The elderly are more likely to have iron-poor diets and indolent GI blood loss from gastritis or underlying malignancy. Patients with chronic kidney disease or on hemodialysis often have iron deficiency and cannot stimulate their kidneys to produce erythropoietin, further exacerbating the anemia.  Some people may have malabsorptive states (such as Whipple disease, small intestinal bacterial overgrowth (SIBO), celiac disease, pernicious anemia) where they cannot effectively digest the iron in their diets.

Iron supplementation through various routes such as oral or IV and iron fortification of foods can help manage and treat iron deficiency.[3]

Mechanism of Action

Iron is a critical component of the body. Its primary role is to store and transport iron (as myoglobin and hemoglobin) throughout the body. In an iron-deficient state, hemoglobin cannot be synthesized, with resultant microcytic anemia due to the formation of small erythrocytes.

The role of iron supplementation is to replace those iron stores and to encourage erythropoiesis and oxygen transportation throughout the body. Iron transport occurs via the divalent metal transporter 1 (DMT1) across the cell membrane, where it is incorporated and stored as ferritin in the macrophage. This form then is converted to an absorbable Fe2+ ion, then sequestered by transferrin to various sites in the body, including the bone marrow for RBC synthesis. The iron combines with other components such as porphyrin and globin chains to form hemoglobin, which transports oxygen from the lung to other organs in the body.[4][5]

Administration

Oral Iron Supplementation

• Oral iron replacement therapy is the most cost-effective and readily available for the general public as ferrous sulfate (20% elemental iron), ferrous gluconate (12% elemental iron), and ferrous fumarate (33% elemental iron).
• For best absorption, the recommendation is to take iron at least 30 minutes before a meal or 2 hours before taking other medications.
• If the patient cannot tolerate the gastrointestinal side effects, they may take it with small amounts of food.
• Avoid taking it with milk, calcium, and antacids, high fiber foods, or caffeine.
• Some studies have suggested taking iron with orange juice or with vitamin C supplementation to help improve absorption.[6]

IV Iron Supplementation

An alternative to oral iron supplementation is via IV infusion; this may be preferable in patients who:

• Cannot tolerate oral iron due to side effects
• Pregnant women who already have significant nausea and vomiting
• Those who have had a gastric bypass, where reduced gastric secretion impairs iron absorption 
• Those who have malabsorption conditions that prevent adequate absorption into the body (such as Whipple's disease, SIBO, celiac disease, pernicious anemia)
• Those with chronic inflammatory states, such as SLE or rheumatoid arthritis have elevated hepcidin levels that reduce oral iron absorption[7]

IM iron is available, but not preferred as patients will have severe site injection pain and inconsistent absorption. It may also stain the skin.[8]

Adverse Effects

The most common side effects are gastrointestinal, such as nausea/vomiting, constipation or diarrhea, flatulence, metallic taste, staining of the teeth, or epigastric distress. Patients may feel uncomfortable with the change in stool caliber and color to green or 'tarry black.' Many oral iron supplements (ferrous fumarate, ferrous gluconate, ferrous sulfate) formulations are associated with higher GI side effects than IV iron or placebo.[9][10] Patients can decrease the adverse effects by taking iron supplements on an adjusted regimen (i.e., three times a week instead of daily), or taking it with food, although this may decrease the absorption and be less convenient for the patient, which may lead to non-compliance. 

The adverse effects of IV iron may be infusion reactions and anaphylaxis. 

Iron may decrease the absorption of other medications by forming an insoluble complex with those agents. These include methyldopa/levodopa, fluoroquinolones, penicillin, or tetracyclines.  

Contraindications

Patients with iron-overloaded states such as hereditary hemochromatosis, hemosiderosis, or have a history of hemolytic anemia.

Monitoring

Labwork consistent with iron deficiency include low serum iron levels, low transferrin saturation, and a high total iron-binding capacity (TIBC). For patients receiving oral iron, patients will need to return to the office for repeat bloodwork to monitor tolerability to the medication and will need to be on supplementation for months. For those receiving IV iron, levels should be within normal limits after six weeks of therapy. Iron supplementation may cease once there are adequate iron and transferrin stores in the body. 

If there is an inadequate response to oral therapy, investigate reasons why: such as noncompliance, reduced absorption, or GI bleeding exceeding the amount of iron supplementation. This situation should prompt additional screening for other underlying etiologies in addition to inadequate iron intake, increased iron demand, and iron loss such as GI causes such as H. pylori infection, autoimmune gastritis, and screening colonoscopy for colorectal cancer.[11] 

Toxicity

Toxicity is often dose-dependent and can manifest with cardiovascular, metabolic, central nervous, and hepatic instability and damage. Symptoms of overdose include initial GI upset that slowly develops to acute metabolic encephalopathy, seizures, tachycardia, metabolic acidosis, arrhythmia, hypoxia. Amounts up to  20 mg/kg of elemental iron is usually well-tolerated, but may have mild GI symptoms.  Amounts between 20 to 60 mg/kg is mild to moderately toxic, and over 60 mg/kg can cause severe symptoms and morbidity due to circulatory collapse.[10]

Accidental iron ingestion in children under the age of 6 has been a leading case of fatal poisoning.[12]

Iron overdose can have therapy using gastric lavage with an iron chelator such as deferoxamine or GI decontamination procedures such as lavage solutions and whole-bowel irrigation.[13]

Enhancing Healthcare Team Outcomes

Initiating iron supplementation to address an iron-deficiency state is often managed by the primary care provider, however, sometimes it may be managed by specialists including the hematologist, gastroenterologist, or nephrologist, depending on the underlying cause of the anemia. 

In the early stages, anemia may be present on routine bloodwork. Initial testing includes a complete blood count (CBC) with differential, which includes values such as WBC count, hemoglobin, hematocrit, RBC count, RBC indices. A reticulocyte count is helpful, as well.  If asymptomatic, the patient can be monitored with yearly CBC to check for any changes.  If symptomatic, more aggressive methods to identify the underlying cause are necessary. If iron deficiency is suspected, these patients should have iron studies assessed to check for serum iron, total iron-binding capacity (TIBC), transferrin saturation, and ferritin levels to determine if it is iron deficiency anemia, the most likely cause of microcytic anemia vs. other etiologies. Other tests that the clinician can order are hemosiderin and hepcidin, but are not necessary. Once the iron-deficiency is confirmed, then iron supplementation may be started. [Level 5]

It is the responsibility of the primary provider and other health professionals to ensure that the patient is not assumed to have iron deficiency anemia based on a CBC and receiving unnecessary iron supplementation without a complete workup. Anemia is a significant global health issue, and healthcare professionals must coordinate to ensure that if the patient is not improving with oral iron supplementation, to try another route of administration, or to check for another underlying cause of the anemia.[14][15] [Level 5] If their anemia is indeed due to iron deficiency, then supplementation should have tangible improvements on repeat CBC and bloodwork.[16] [Level 1]

The need for care coordination of all healthcare professionals on the interprofessional team involved in the management of the patient is the recommended approach to provide symptomatic relief and improve outcomes.