Intravenous Iron Replacement Therapy for Iron Deficiency Anemia in Adults

Nashat Gabrail, MD, is a hematologist-oncologist and founder of Gabrail Cancer and Research Center in Canton, Ohio. His areas of clinical interest include cancer diagnoses and treatment with a special emphasis on cancer inheritance and genetics.

How is iron deficiency anemia (IDA) best identified?

Most of the time, IDA is indicated by low levels of hemoglobin, low mean corpuscular volume (MCV), low mean corpuscular hemoglobin (MCH), and low mean corpuscular hemoglobin concentration (MCHC) on a complete blood count (CBC). To confirm the diagnosis, I often look at the blood smear for a clearer picture of what is going on because thalassemia minor and certain chronic diseases are characterized by the same CBC abnormalities.
 
The definitive diagnosis of IDA is confirmed by running an iron panel; this includes total iron, total ferritin, total iron-binding capacity (TIBC), and the percent saturation of the iron-binding capacity. Levels of iron and ferritin are typically low in patients with IDA and while there is high TIBC, the transferrin saturation is usually below 20%.
 
Any of those variables can be misleading in the presence of other diseases. For example, patients with active Crohn disease have gastrointestinal blood loss, but we expect the level of ferritin to be high because it is an acute phase reactant. That is why the diagnosis of IDA is not just a “numbers game” since the numbers can be tricky sometimes. Some clinicians say the ultimate diagnosis of IDA is via bone marrow aspirate and biopsy, but most of the time we do not need to do that.

What is functional iron deficiency (FID)? 

Here is a good way to describe FID: if we stain a bone marrow aspirate for iron, we find a lot of iron deposited in the macrophages. However, that iron is crusted and not dissolvable. Patients with FID have a lot of iron in their system, but it cannot be mobilized and incorporated into their red blood cells (RBCs), making the patient functionally iron deficient. Patients with cancer, for example, may experience FID regardless of whether they are undergoing chemotherapy. Iron deficiency can occur if a patient either has a cancer that causes bleeding or is receiving anticoagulants. Some patients with cancer simply have FID. It is important to remember that both cancer itself and pain medications can cause fatigue; if you add IDA to that, you are just compounding the problem. For patients with cancer, there are symptoms we can address to improve quality of life and one of these is IDA-related fatigue, which is why we talk constantly about FID. We should be cognizant of the potential for FID and to monitor patients for it.
 
In the last decade, we learned that although patients with FID have a lot of iron stores in their bone marrow, they do respond when you give them IV iron. Generally, that response is not as robust as the response seen in people with physiologic absolute IDA, but it is sufficient. 

How do you determine the best iron-repletion option for different patient populations?

I do not think that patients with IDA should receive RBC transfusions. Unfortunately, they are sometimes performed because of a perceived clinical urgency; for example, if a patient presents with a hemoglobin level of 6 or 7 g/dL. Transfusions are often requested by family physicians or surgeons. Intravenous iron or even oral iron repletion can work very quickly, with most people experiencing symptomatic improvement within 24 hours. However, it will take 3 or 4 days before the hemoglobin rises to normal levels.
 
The biggest advantage of using IV iron to correct IDA is that the RBCs you make are fresh and young so they are usually very efficient at transporting oxygen. Now, compare that to a blood transfusion of hemoglobin 20 g/dL, where you give 2 units of packed RBCs but not all of those cells are functional. When we take blood from donors, those cells have an average lifespan of 31 days if we give it to the recipient immediately. Most of the time, though, donor blood is “on the shelf” for up to 7 weeks.  We have learned that, regarding the lifespan of RBCs in stored blood, the blood loses 1% of its potency for every day the bag is on the shelf.¹ When you take a pint of blood, some of those cells will die tomorrow, some are fresh and will be functional for 120 days, and some will last 30 days. In contrast, when you give a patient IV iron, all the RBCs you make have a lifespan of 120 days; hence the clinical benefit is more robust and long term with IV iron. 
 
Oral iron is also effective, but it takes longer to work and is a bit more challenging because not all of it is absorbed in the GI tract. For a variety of reasons, some people do not absorb oral iron. For example, proton pump inhibitors are among the most commonly prescribed medications and they block acid secretion.² The problem is, we need acid in order to absorb iron.³ This is just 1 reason that many people fail to respond to treatment with oral iron or respond inadequately and at a slower rate.
 
That is why the indication for IV iron is for patients who fail to respond to or are intolerant of oral iron, or patients who need a quick iron response, such as a person with a hemoglobin level of 7 g/dL or a person with a hemoglobin level of 8 g/dL who also has congestive heart failure.

What would indicate hypersensitivity to IV iron sucrose?

Fortunately, the incidence of hypersensitivity or infusion reactions with the current second- and third-generation IV iron preparations is much lower than what was seen with the older iron dextran preparations. 

We cannot predict who will experience a reaction to IV iron, but we can try. If a patient is sensitive to penicillin or any medications they took in the past, we generally label that patient as atopic. We also have to be extra careful with patients who have eczema or asthma, because they can be at higher risk of an allergic reaction. You even have to be careful with people who are immunoglobulin A-deficient or have peanut allergies because they have a propensity to be allergic to most medications that you give them.

What are the benefits of ferric derisomaltose (FDI) preparations over iron sucrose?

If you look at third-generation preparations such as FDI, the incidence of hypersensitivity reactions is very low. It might even be a little lower than that seen with the second-generation iron sucrose preparations, but it is important to bear in mind that second-generation preparations are associated with a far lower incidence of hypersensitivity than the iron dextran preparations. In general, I think the incidence of hypersensitivity is only slightly lower with drugs like FDI.
 
The challenge with iron sucrose preparations is that you can only give up to 200 mg per infusion, so patients receive them once a week. To achieve 1 g of iron replacement, you have to give the patient 5 infusions, which is inconvenient.⁴ FDI dosing requires 1 g as a single-dose IV push over a period of 20 minutes or less. So in summary, while the incidence of infusion reactions is probably a little lower with FDI compared with second-generation preparations, and that’s certainly another plus, the convenience factor of 1 dose is the biggest advantage of FDI.