#471 Iron Deficiency Anemia with  Dr. Tom DeLoughery

February 17, 2025 | By Sai Achi

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Conquer the art of managing patients with iron deficiency anemia. We are joined by the amazing Dr. Tom DeLoughery, @Bloodman (Oregon Health & Science University).

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Show Segments

• Intro
• Rapid fire questions/Picks of the Week
• Case
• History and Physical
• Laboratory Findings
• Management of Iron Deficiency Anemia
• Diet
• Oral Supplementation
• Unexplained Iron Deficiency
• Case 2
• IV Iron Supplementation
• IV iron reactions
• Case 3
• Laboratory Follow Up Post Supplementation
• When to Refer to a Hematology/Oncology specialist?
• Outro

Iron Deficiency Anemia Pearls

1. Iron deficiency anemia is a common disease process that is seen in almost 50-70% of premenopausal women!
2. A detailed history, including menstrual history when appropriate, is crucial in evaluating iron deficiency anemia. 
3. When assessing for iron deficiency anemia, one should obtain a ferritin level.
4.  Oral iron should dosed once a day 
5. IV iron should be given especially in settings where the oral formulation is not working, not tolerated,  or there is poor iron absorption

Iron Deficiency Anemia Show Notes 

What is iron deficiency anemia?

 Iron deficiency anemia is one of the most common types of anemia in the world. The peripheral smear typically shows microcytosis and hypochromasia  (Warner 2023). Microcytic anemia is defined as small red blood cells that are usually hypochromic in nature and defined with a MCV (mean corpuscular volume) that is typically less than 80 femtoliters (fL) (Massey 1992). Typical symptoms of iron deficiency anemia include fatigue, weakness, pagophagia (chewing of ice) or dyspnea on exertion (Warner 2023, Hunt 2014).

History and Physical

Per Dr. DeLoughery, history taking is important when evaluating iron deficiency anemia. Questions should look for any bleeding source or blood in the stools, any history of anemia, or presence of family history of anemia. Another question to ask is if the patient has a history of diarrhea or weight loss, that could indicate malabsorption/celiac disease (Freeman 2015).

History Take for Anemia in Menstruating Women 

Don’t forget a thorough menstrual history! This is a crucial part of the history in menstruating women– heavy menstrual bleeding affects up to 50% of women of the reproductive age. Per the WHO (World Health Organization), iron deficiency anemia is the most common micronutrient deficiency worldwide and affects more than about 20% of reproductive age women- some studies have found that 34% of the reproductive age women were iron deficiency and others found that 30-70% women were iron deficient based on the ferritin cutoff. (Munro 2023), (McLean 2008, Tawfik 2024, Weyand 2023). 

Menstrual history questions to ask include: age of menarche, length of cycles, if cycles are heavy,  number of pads/tampons, etc. Taking a good history is always important because almost 75-90% of women often view their symptoms as normal and cope with their symptoms and don’t usually mention these symptoms to their doctors (Casola 2024). Dr. DeLoughery mentions that there is an immense imbalance especially in women between the required iron supplementation and that which is obtained from the diet.

Laboratory Findings

Hgb and MCV

Dr. DeLoughery focuses on a few key labs. Aside from hemoglobin level, Dr. DeLoughery likes to monitor the MCV. A low MCV will narrow the differential to iron deficiency anemia (IDA), thalassemia, anemia of chronic disease, and sideroblastic anemia. In anemia of chronic disease, the MCV will be low but typically above 70. Sideroblastic anemia usually is seen earlier in life. So that leaves us with IDA and thalassemia. The Red blood cell number and Mentzer index are helpful to differentiate between the two disease entities.

The Mentzer Index takes into account the MCV and the Red blood cell number in millions (RBC). To calculate, you divide the MCV by the red blood cell number. If the Mentzer Index is <13 then its more likely thalassemia and if the index is >16 then its more likely iron deficiency anemia (Sun 2024).

Reticulocyte Count

The reticulocyte count is another helpful index that gives a sense of how many RBCs are produced in the bone marrow and enter the bloodstream. It gives an idea of the effective erythropoiesis. If the reticulocyte <2% that usually indicates anemia and if >3% then it points towards bleeding or hemolysis (Gaur 2021).

Ferritin

Ferritin is a measure of iron stores, and useful to assess IDA. A low ferritin indicates iron deficiency and a high ferritin points to a risk of iron overload. Per Dr. DeLoughery, ferritin level 30-50 should be considered a normal level. Ferritin level < 30 microgram/L usually indicates an iron deficiency anemia (Wen 2024, Guyatt 1990).  

This ferritin cut-off is still a debatable topic. Ferritin can also be elevated in inflammation and infection because it is an acute phase protein (Garica-Casal 2021). Some recent studies have been undertaken to come towards a consensus and some of the confounding factors are that in cases of inflammation/infection that ferritin can be elevated, or in women due to menstruation a cut off of 50 ng/ml could be applied which may not be applicable to men (Tarancon-Diez 2022).  According to Dr. DeLoughery, there is a movement/project in Canada that encourage raising the ferritin cut-off level to 30 mcg/L in adults and 20 mcg/L in pediatrics patients as a way to try and improve the screening, early identification, and management of patient with iron deficiency anemia 

For restless leg syndrome (RLS), there are studies that show that a higher cutoff ferritin should be maintained. Though the exact pathogenesis of restless leg syndrome is not fully understood; some of the mechanisms include iron deficiency in the brain along with dopamine dysregulation, etc. (Earley 2022). In iron deficiency, though it is thought to be less impactful in the RLS pathogenesis, it can also augment the RLS symptoms. A low ferritin can worsen RLS (Li 2023). Therefore studies have proposed a ferritin goal of >75 (Allen 2018).

There is also an association with alopecia and ferritin levels. According to a study 70% of female associated alopecia was associated with iron deficiency and decreased levels of ferritin and with supplementation of iron there was improvement in prognosis (Lin 2023).

Any use for TIBC, iron saturation, RDW?

Dr. DeLoughery relies more on the ferritin level than TIBC, iron saturation or RDW due to their limited and nonspecific utility. 

When to do a GI workup?

Dr. DeLoughery doesn’t usually turn to a GI workup in menstruating women who are being assessed for iron deficiency anemia. Exceptions to this would be in women above 40, any GI symptoms, or any family history of colon cancer.

Dr. DeLoughery will send a celiac disease workup to evaluate iron deficiency in all men if there is presence of any GI symptoms, and if the clinical scenario is not adding up. In a study, 39% of the 434 celiac disease patients had anemia (Kochhar 2012).

Management of Iron Deficiency Anemia

Diet

Dr. DeLoughery likes to encourage patients to take their oral supplements with any type of meat to encourage iron absorption. Interestingly, iron absorption is more readily available in animal-based diets compared to a plant based diet (Moustarah 2024).

Of note, spinach contains oxalic acids and iron absorption inhibiting factors thus can actually chelate iron (Noonan 1999, Singh 2016). 

Coffee and tea have been shown to decrease iron absorption and per Dr. Deloughery should be consumed at least 1 hour before or at least 1 hour after taking iron supplementation (Morck 1983).

Oral Formulations

Oral formulations are the first line of treatment. Dr. DeLoughery says that there is no need to do a three times a day dosage and once a day is preferable. The recommended dosage for iron deficiency anemia has been between 150 mg and 200 mg daily; with higher doses in those patient populations with poor absorption such in chronic dialysis patients. It was found that low dose iron therapy (15 mg)  is recommended that raises the Hgb and ferritin levels without much adverse effects. (Rimon 2005).

Dr. DeLoughery’s preferred oral agent is ferrous sulfate. It should be taken with meals. It is affordable and can also be taken as tablets or syrups. If ferrous sulfate isn’t tolerated, ferrous gluconate or ferrous bisglycinate can be used, but may be more expensive (Pantopoulos 2024). 

Vitamin C Supplementation

Is there a benefit of taking Vitamin C with oral supplementation for iron deficiency anemia? Vitamin C has been shown to augment iron absorption by promoting an acidic environment thereby preventing ferrous iron to ferric iron formation; however, it is controversial if this is really necessary (Li 2020). If one is taking their iron with a meal; vitamin C blocks the inhibitory effect of fiber and calcium on absorption (Hurrell 2010).

Daily vs Alternate Day Dosing-Any Difference?

 Studies have shown in patients with iron deficiency anemia; there is an increase in hepcidin hepcidin, after receiving iron supplementation for 24 hours and takes about 48 hours to return back to baseline levels. Hepcidin is a peptide hormone that regulates iron homeostasis and tightly regulates the delivery of iron to the plasma by degrading the membrane transport of iron- ferroportin (Girelli 2016, Stoffel 2019, Chambers 2023). Numerous studies have been done to elicit the differences. Alternate day dosing may have lower GI side effects compared to daily dosing; the alternate day dosing didn’t cause higher ferritin levels but did overall reduce iron deficiency at the 6 month mark (von Siebenthal 2023). However as Dr. DeLoughery says that for some patients they may have difficulty in remembering to take daily pills that maybe the every other could be harder to remember. He usually starts with daily dosing and then cuts back if people are not tolerating.

Unexplained Iron Deficiency

In a subset of patients the etiology of the iron deficiency anemia cannot be explained. According to studies, there could be sometime due to obscure GI bleeds that might be detected on upper, lower, and capsule endoscopy or could be aggregated by NSAIDs (Rockey 2005, Dahlerup 2015, Herskho 2014). Dr. DeLoughery counsels patients that the workup has been done and though he may not be able to point to underlying etiology for the iron deficiency anemia, he has ruled out the dangerous etiologies.

IV Iron Formulation

Reach for IV Iron formulation when there is not much response to oral supplements, if there is any intolerance to oral supplementation, or in scenarios where patients have GI symptoms so absorption is expected to be reduced (eg IBD). You can use IV iron in those with heavy menstrual bleeding, angiodysplasia, hereditary hemorrhagic telangiectasia, bariatric surgery patients,etc (van Doren 2023).

Formulations include iron sucrose and ferrous gluconate which can be administered in multiple doses due to having more labile iron (Schaefer 2020).

Dr. DeLoughery prefers to use iron dextran; one time 1000 mg IV iron dose. His second line agent is ferumoxytol which is a rapid infusion medication. The one caveat is that this agent is an MRI contrast agent as well; radiologists should be notified if one has taken ferumoxytol prior to imaging studies (van Doren 2023). Studies have shown that the agent can affect MRI readings up to 3 months after administration (Bowser 2016).

Another IV iron agent is ferric carboxymaltose. It is available in 750 mg doses in the US and a benefit of it is that it results in the least labile free iron however a major side effect is severe symptomatic hypophosphatemia. The ferric carboxymaltose will increases the FGF-23 (fibroblast 23) levels which will cause a renal excretion of phosphate due to a decrease of the proximal tubule’s phosphorus reabsorption.The upregulation of FGF 23 will also lead to a decrease in gut absorption of phosphorus and calcium thereby  leading to a secondary rise in PTH and further propagates a hypophosphatemia (Martens 2023).  The hypophosphatemia even occurred after a single dose and manifestations included: muscle and diaphragmatic weakness, nausea, asthenia, etc. In one study, it was shown that effects of hypophosphatemia could occur months after administration of ferric carboxymaltose. It was also shown that the hypophosphatemia was blunting the fatigue response to the iron supplementation. One must check phosphorus levels prior to a second dose. Also interestingly in situations of hypophosphatemia giving phosphorus can worsen  symptoms and there is no treatment for these manifestations.. (Adkinson 2018, van Doren 2023, Zoller 2023). 

Ferric derisomaltose is another formulation that is currently being used (van Doren 2023). Is given as a single dose and tends to be more expensive.

IV iron reactions

Per some studies, the majority of IV iron infusion reactions are non IgE mediated hypersensitivity reactions. True anaphylaxis reactions are rare. It is important to counsel patients as well about the infusion process and for possible infusion reactions that may occur. Controversies still exist in regards to the use of premedications for these reactions. They should be used in patients who have severe risks for developing infusion reactions (i.e those with multiple drug allergies, history of reactions to IV iron, etc) (van Doren 2024).  There are protocols in place to help manage minor and moderate reactions (Rampton  2014). You can typically stop the infusion for 15 minutes and alleviation of symptoms and restart the infusion. A benefit with IV iron is that the symptomatic relief/improvement of anemia is very quick (i.e. in a study it was seen that the patient’s pagophagia nearly was gone during the IV iron infusion!) (Auerbach 2016).

Laboratory Follow Up After Iron Administration

After oral administration, Dr. DeLoughery recommends checking Hgb and ferritin within a few weeks time usually around the 3 month mark to assess to see if the ferritin is at goal. However after IV iron administration, there is not as much clarity in terms of frequency of labs and when to follow up; Dr. DeLoughery likes to check ferritin at around the 1 month mark and then every 3 months. If the ferritin is below 50 then he will plan for another IV dose (Reed 2021).

Anemia of chronic disease/inflammation/Malignancy

Briefly, the mechanism of action is that the hepcidin is dramatically elevated and thus blocks the iron uptake and absorption. There is double damage to the RBC because it is not getting enough iron due to iron deficiency and whatever iron is there is not getting absorbed/taken up due to the elevated hepcidin in response to the inflamed state (Weiss 2002).

In these situations, if there is an aspect of iron deficiency as well as cancer; that could be another place to give IV iron per Dr. DeLoughery. This is because oral iron may not be well absorbed due to inflammation and IV iron can bypass the hepcidin induced iron sequestration and the cancer induced inflammation and thereby increase the Hgb (Lim 2023).  

There is a study done in dialysis patients receiving IV iron and there wasn’t an increase in infection due to the IV iron (Macdougall 2019).

Dr. DeLoughery doesn’t usually give IV iron in septic shock patients.

When to refer to Hematology/Oncology?

Dr. DeLoughery says a good time to refer would be in cases where a patient is requiring IV iron multiple times, in cases where the story is not adding up, or in cases where there are other lab abnormalities as well.

Links

1. The Wind Up Bird Chronicle (book)
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC7467495/

Goal

Listeners will develop a framework to approach the diagnosis, evaluation, and management of iron deficiency anemia. 

Learning objectives

After listening to this episode listeners will…  

1. Develop a framework to diagnose and work up a patient with iron deficiency anemia
2. Assess when to use oral vs IV iron formulations 
3. Develop strategies to for assessing treatment options which include diet, laboratory assessments and IV reaction and  responses to iron supplementation

Disclosures

Dr. DeLoughery reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Achi SS, DeLoughery T, Williams PN, Watto MF. “#471 Iron Deficiency Anemia”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast 17 February 2025.