Time Stamps

  • 02:09 Pearl 1: Spaced repetition from the last Core IM Gray Matters Episode
  • 05:29 Pearl 2: Choosing between oral and IV iron
  • 11:17 Pearl 3: Considerations with oral iron repletion
  • 24:02 Pearl 4: Considerations with IV iron repletion
  • 32:36 Pearl 5: Complications and side effects of IV iron

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Show Notes

Pearl 1: Spaced repetition from our Gray Matters Episode. 

Iron deficiency diagnosis and workup

  • Iron deficiency diagnosis
  • Iron deficiency in chronic inflammatory disorders
    • Patients with chronic inflammation have elevated cytokines and acute-phase reactants.
      • As hepcidin levels rise, ferroportin degradation occurs in duodenal enterocytes. 
      • Iron remains trapped within enterocytes and is also sequestered in macrophages. 
    • A decrease in circulating iron leads to a lower saturation of the iron carrier protein, transferrin. 
    • Thus, a low transferrin saturation (TSAT) (TSAT = (Serum Fe/TIBC) × 100) can aid with the diagnosis of ID in chronic inflammatory disorders. 
    • Instead of using established diagnostic cut-offs for ID, cut-off parameters for ferritin and TSAT should be individualized for every patient, considering underlying inflammatory disorders and comorbidities.
    • A time-limited therapeutic trial of iron can help interpret diagnostic cut-offs in patients with active inflammation. 
    • In a therapeutic trial of iron, a rise in hemoglobin > 1 g/dl over 2-4 weeks is highly sensitive for absolute ID.

Pearl 2: Oral vs IV iron repletion

  • Oral iron therapy is recommended for:
    • Patients who can tolerate oral iron 
    • Patients without active bleeding
    • No evidence of severe symptomatic anemia
    • Patients without absorption disorders that are known to be unresponsive to oral iron
    • Patients who do not have chronic inflammatory disorders. 
  • IV iron therapy is recommended for:

Pearl 3: Considerations with oral iron repletion

  • Oral Iron Formulations
    • In terms of efficacy, all compounds are essentially equivalent
    • The most important component of a formulation is the amount of elemental iron.
      • Be aware of formulations that claim to have fewer side effects. They often have a lower amount of elemental iron and may not be as effective. 
    • Common formulations include 
      • Ferrous sulfate (65 mg  elemental iron per tablet-325 mg)
      • Ferrous gluconate (37.5 mg  elemental iron per tablet-325 mg)
      • Ferrous fumarate (106 mg elemental iron per tablet-325 mg).
    • Choose an affordable formulation.
  • Frequency: Is once a day best or every other day?
    • The most quoted study was a study of two prospective, open-label, RCT assessing iron absorption. It included pre-menopausal iron-depleted women (ferritin <25 μg/L) who received consecutive vs. alternate-day iron dosing.
      • Higher cumulative fractional iron absorption in the alternate-day group (21.8% vs. 16.3%).
      • Higher cumulative total iron absorption in the alternate-day group (175.3 mg vs. 131.0 mg).
      • Lower serum hepcidin in alternate-day group
    • Criticism of the study:
      • May not be generalized to patients with anemia since most women had iron deficiency without anemia
      • Outcomes were assessed at day 14 for the consecutive-day group and day 28 for the alternate-day group. 
        • It would helpful to know iron markers if study design had been set up such that consecutive group received daily iron for 28 days and checked labs on day 28, similar to the alternate-day group 
  • A more recent study found that administering iron 3 times per week was non-inferior to 3 times per day.
    • Criticisms of the study:
      • Small study
      • While it was non-inferior, after four weeks, patients who received iron 3 times per day exhibited an about average hemoglobin level that was 1g/dl higher than those in the 3 times per week group (10.8 vs. 9.9 g/dL, respectively, p = 0.040).
  • Takeaway: Frequency can be individualized the patient depending on how you rapidly you want iron depletion to improve (with more frequent iron) vs. potential iron side effect
  • Prescription and Absorption
    • For better absorption, iron should be ingested 
      • at least 30 minutes before a meal 
      • 1 to 2 hours before taking additional medications. 
      • Avoid taking iron with milk, calcium, caffeine, anti-acids, and tea.
        • Tailor patient instructions. Too many instructions may lead some patients to forget to take their iron altogether. 
    • Oral iron therapy should be continued for 6-12 months to replenish iron stores.
  • Effect of Vitamin C and Orange Juice on Oral Iron Absorption
    • A study evaluating the effect of Vitamin C supplementation, in 1994 on 25 women who were not anemic but had iron deficiency anemia, found a slightly increased serum ferritin in patients who received vitamin C supplementation. 
    • In 2020, a JAMA RCT that included 440 adults with iron deficiency anemia showed no difference in the mean change in hemoglobin level after 2 weeks, for patients using oral iron supplementation alone versus a vitamin C-supplemented oral iron regimen. 
    • Orange juice is often enriched with calcium, which can compete with iron absorption. 
  • Post-treatment Labs
    • Post-treatment labs can be checked 6 months after initiating treatment. 
    • Post-treatment target levels depend on how anemic the patient was to begin with but in general, we should target:
      • Ferritin levels above 30-50 
      •  TSAT levels above 20.

Pearl 4: Considerations with IV iron repletion

  • IV iron Formulations: # of Infusion Sitting to get 1g of iron
    • 1 infusion sitting:
      • Low-molecular-weight iron dextran 
      • Ferumoxytol (feraheme)
        • can be 1-2 visits
      • Iron desiromaltose (monoferic)
    • 2 infusion sittings:
      • Ferric carboxymaltose comes in 2 different  presentations
    • 5 or more infusion sittings:
      • Ferrous gluconate and Iron sucrose 
  • Formulations are similar in efficacy.
  • The side effect profile appears to be similar for all formulations, but further head-to-head comparisons are needed. 
  • However, there is a higher incidence of hypophosphatemia, one of the features of the 6H syndrome, with ferric carboxymaltose.
    • 6H syndrome develops 1-2 weeks after infusion: Characterized by high FGF-23 levels, Hyperphosphaturia, Hypophosphatemia, Hypovitaminosis D, Hypocalcemia, and secondary Hyperparathyroidism
    • Ferric carboxymaltose induces FGF23 to increase, which leads to renal phosphate wasting, calcitriol deficiency, and secondary hyperparathyroidism. 
    • Complications from the 6H syndrome include osteomalacia, bone fractures, muscle weakness, and respiratory failure.
  • Dose calculation
    • The optimal IV iron dose can be estimated or calculated using the Ganzoni formula. 
    • A practical approach is using 1 gram of iron without calculating the dose. 
    • However, the Ganzoni formula is available online, easy to use, and can be helpful to avoid underdosing patients. 
  • Post-treatment Laboratories:
    • Post-treatment labs should be checked 6 weeks after infusion. 
    • Checking before 6 weeks can be associated with falsely high levels of ferritin. 
      • Repeat doses are indicated if the ferritin level is not above 30-50 and TSAT above 20%. 
    • During pregnancy, iron parameters should be checked every trimester and repeat doses should be given if patients remain iron deficient.

Pearl 5: Complications and side effects of IV iron

  • IV iron is a safe treatment option. 
  • Severe reactions with IV iron are rare after the withdrawal of high-molecular-weight-dextran from the market.
    • Anaphylaxis in particular is estimated to occur in less than 1 per 250,000 administrations
  • Inpatient treatment considerations. 
  • Fishbane reactions are minor and self-limited infusion reactions.
    • Described by Dr. Fishbane, a nephrologist
    • Occurs in approximately 1 in 100 patients.
    • Characterized by flushing, arthralgias, myalgias, back and chest pain
    • Absence of anaphylactic symptoms. 
      • Fishbane is not an allergic reaction. Not IgE mediated. The mechanism is suspected to be related to labile iron.
      • No increase in serum tryptase
    • Symptoms recover spontaneously and quickly after stopping the infusion
      • Infusion should be restarted at a slower rate. 
      • Symptoms do not recur after restarting the infusion at a slower rate.
    • Do NOT administer EPINEPHRINE OR ANTIHISTAMINES (BENADRYL) as there is a high risk for circulatory collapse.

Transcript

Dr. Jason Freed: And I looked at all the curbside emails I had gotten over the past three years, and like 90% of them are about iron deficiency. It turns out iron deficiency is pretty complicated. There’s a lot of nuances in it. And everybody else also felt like, oh, I can’t bother him with a real consult about this. This is something I should just text him or email him or whatever. But actually iron deficiency deciding who needs workups, getting the treatment just right, there’s a lot of nuances in it.

Dr. Shreya Trivedi: That was Dr. Jason Freed, a Hematologist at BIDMC, and assistant professor of Harvard Medical School. Welcome to the Core IM 5 pearls episode. I am Dr. Shreya Trivedi.

Dr. Maria Fernandez: And I am Dr. Maria Fernandez, an Internal Medicine Resident at BIDMC.

Dr. Shreya Trivedi: On today’s 5 Pearl episode, we will be discussing iron deficiency treatment. I am so excited to get into the 5 Pearls we will be covering today! Remember, the more you test yourself the deeper your learning gains. 

Dr. Maria Fernandez: Pearl 1 – Let’s do some spaced repetition from the last Core IM Gray Matters Episode.  

Dr. Shreya Trivedi: What were the key takeaways on how to interpret iron labs? 

Dr. Maria Fernandez: Pearl 2 – Choosing between oral and IV iron.

Dr. Shreya Trivedi: When do we skip straight to the IV iron instead of trying oral iron?

Dr. Maria Fernandez: Pearl 3 – Considerations with oral iron repletion. 

Dr. Shreya Trivedi: How do you choose between different oral iron formulations? And, what’s your game plan for handling side effects and when do you check labs again?

Dr. Maria Fernandez: Pearl 4 – Considerations with IV iron repletion.

Dr. Shreya Trivedi: How do you choose between different IV iron formulations? And should you use the Ganzoni formula to calculate the iron dose?  

Dr. Maria Fernandez: Pearl 5 – Complications and side effects of IV iron. 

Dr. Shreya Trivedi: When do we say NO to IV iron? What is a fishbane reaction? And how is it different from anaphylaxis? 

Pearl 1: Iron deficiency diagnosis and workup

Dr. Shreya Trivedi: So before we get into iron deficiency treatment, let’s do a quick refresher on big takeaways on the last Core IM Gray Matters episode on iron deficiency diagnosis!

Dr. Maria Fernandez: So of all the iron deficiency anemia labs that we have, a low ferritin has the best specificity for true iron deficiency anemia.   

Dr. Shreya Trivedi: Yes! And we learned that ferritin’s sensitivity and specificity really changes based on the cutoff you’re using.

Dr. Jason Freed: What about 35? Now you’re up to 80% and you’re still 95% specific. So it’s still pretty good when you get up to 45, you’re now at around 85% sensitive and still 92% specific.

Dr. Maria Fernandez: So a good rule of thumb is to use a ferritin cutoff of 50 or less for iron deficiency, but of course, everything depends on your pretest probability and the patient in front of you.

Dr. Shreya Trivedi: And then another wrench with ferritin to keep in mind, is that we know ferritin is an acute phase reactant and its going to increase increase with inflammation. But a lot of our patients have heart failure, ESRD, are recovering from some pneumonia, DKA, recovering from surgery.  

Dr. Maria Fernandez: Right, the use of ferritin in acute inflammatory conditions is mostly based on expert opinions AND extrapolated from patients who just have heart failure, CKD, and also IBD. 

Dr. Shreya Trivedi: Yeah at least for right now the current recommendation is to go with a ferritin cutoff of less than 100 in those patients or less than 300 with a TSAT less than 20%. 

Dr. Maria Fernandez: And also Shreya, my other big takeaway from the Gray Matters episode is the fact that there are so many women out there with iron deficiency without anemia, and some of that has to do with the flawed ranges of hemoglobin and ferritin ranges.

Dr. Shreya Trivedi: Yeah, and we also spoke to Dr. Michael Auerbach, a Hematologist and Oncologist and Professor of Medicine at Georgetown University School of Medicine who had some really good zingers on the topic.

Dr. Michael Auerbach: It doesn’t have to be iron deficiency anemia. It can be iron deficiency without anemia. I treated a woman today. Her hemoglobin was 12.3, which is normal. Actually, it’s normal for women, and that’s an outrage. If men had babies and periods, the hemoglobin of 12 would not be the normal hemoglobin. You were made a second class citizen by the medical society. This actually happened in 1914. This man, Dr. Whitehead, president of the British Medical Society that said, periodic heavy uterine bleeding is a sacrifice that women must make at the altar of evolution. So do your penance. I mean, this was actually belittled. I mean, the fact of the matter is that iron deficiency in women is rampant. So that’s fact. It’s a longstanding issue. So it’s really time that we address it. 

Dr. Shreya Trivedi: So much to unpack there. You know, I still remember him saying this even months after the interview and wanted to include it. For me, it really just put fire in me to do better by our patients – I’ve now actually made my clinical goal to diagnose more iron def without anemia. 

Pearl 2: Oral and IV iron repletion

Dr. Shreya Trivedi: And now that we had a quick refresher on key iron workup labs and we all feel motivated to do better with our patients, let us get into so many nuances with treatment. Our first branch point is often choosing between oral and IV iron repletion.

Dr. Michael Auerbach: So if you read my section in UpToDate, treatment of iron deficiency treatment of iron deficiency in adults for uncomplicated iron deficiency without active bleeding and without comorbid conditions or without a disorder known to be unresponsive to oral iron or in which oral iron causes harm, I would recommend one iron tablet at least 30 minutes away from food and coffee.

Dr. Shreya Trivedi: Again to reiterate, we reach for oral iron in patients who, one, are not bleeding, two, who don’t have conditions that make them unresponsive to oral iron, and three, who don’t have conditions where oral iron would actually cause harm. 

Dr. Maria Fernandez: Yeah, but another way to think about it, is to think about who are all the people who right off the bat don’t qualify for oral iron and require IV iron?

Dr. Shreya Trivedi: Oh! I like that a lot.

Dr. Jason Freed: Who are the patients that you can just jump straight to knowing that they should get IV iron? Well, the first one is if they’ve been unable to tolerate oral iron so far, assuming that they’ve been prescribed it at a reasonable dose and reasonable interval with appropriate recommendation. The second group of people is people who are highly symptomatic with severe anemia. So these are usually the hospitalized patients with GI bleed that I was talking about, or it’s the patient with fibroids and they’re terribly symptomatic. The third category is someone like that who also has ongoing blood loss and you just can’t get ahead of it.  

Dr. Maria Fernandez: Okay so to recap, there are many buckets to think about those who deserve IV over oral iron. Group 1 seems straightforward, it’s people who just don’t tolerate oral iron. But then groups 2 and 3 are a little bit less straightforward. We include patients who are really symptomatic or have ongoing blood loss

Dr. Shreya Trivedi: That reminds me of all the people that come in with GI bleeds, whose hemoglobin goes from like 13 down to 6. And often times people are happy checking off the box. Oh, we gave a unit of transfusion and now their hemoglobin is over 7. And I think some people can even make the argument oh well that transfusion has iron in it, so I don’t need to give them iron.

Dr. Maria Fernandez: So one of our reviewers, Dr. Jonathan Berry actually pointed out that this is a misconception. You see, the iron in the blood transfusion is not free. So the body cannot use that iron from the transfusion to make more RBCs easily. 

Dr. Jason Freed: A good rule of thumb, is if they got anemic enough to get a blood transfusion, they probably depleted most of their iron stores. And so even if they came in with full liver stores, right, even if this is their first GI bleed ever, they were totally nicely iron replete beforehand. They exhaust that before they get back up to normal. And so that’s why such a high percentage of people are still anemic six months later is that they get back up to nine, they get back up to 9.5, but then they used up all their liver stores of iron and they can’t really go much further.

Dr. Shreya Trivedi: Such good points! And since hearing this and thinking about how iron stores get really depleted with bleeds, I’ve been more thoughtful about giving these patients IV iron before they leave the hospital.

Dr. Maria Fernandez: So we already talked about 3 groups of people who would benefit from IV iron but there is actually a fourth.

Dr. Jason Freed: The fourth category is people that we know will be unable to absorb oral iron. So those are patients who’ve had a gastric bypass. Other groups like that are patients with celiac disease, patients with end stage renal disease because of the high hepcidin levels, they don’t absorb iron well orally. 

Dr. Shreya Trivedi: As a quick refresher on what is hepcidin? Hepcidin degrades ferroportin, which is a key transporter of iron, in duodenal enterocytes.  

Dr. Maria Fernandez: So when hepcidin degrades the transporter of iron, iron gets trapped in the gut and sequestered in macrophages. 

Dr. Shreya Trivedi: And can’t be absorbed by the gut! Wamp, wamp. And then there is always an “other” bucket – I think of chronic inflammatory disorders like rheumatoid arthritis, lupus or h.pylori infection. These are people we may also want to reach for IV iron.

Dr. Maria Fernandez: And of course in heart failure too! We even have data now to back this up from the  IRONMAN TRIAL, which demonstrated that patients with heart failure do better in terms of quality of life with IV iron. 

Dr. Shreya Trivedi: Right, right. Is there any data for patients with inflammatory bowel disease, IBD? I’m just throwing ideas here – but I feel like they might fall in the fourth bucket of impaired absorption.

Dr. Jason Freed: And then the last category is people who actually have the potential for harm from oral iron and that is been described in inflammatory bowel disease. That oral iron may actually exacerbate IBD. 

Dr. Maria Fernandez: The thought is that oral iron therapy can be harmful to the microbiome, especially during inflammation. Oral iron actually really disrupts bacterial diversity. 

Dr. Shreya Trivedi: It sounds like iron doing some havoc and causing harm and wrecking havoc to the gut microbiome! Alright, let’s summarize the takeaway who would benefit from IV iron over PO iron. I think maybe one way to recap it is to think about it from the mouth to gut. So first, thinking about the mouth, who are people who just can’t tolerate that oral iron? Then moving down, thinking about the gut. Who are people why just can’t absorb it well? They have a gastric bypass or they have some inflammatory state like end-stage renal disease. Or that oral iron is wrecking havoc to that gut microbiome like in IBD, for example. And lastly, looking to see, is there just too much blood loss, right? Maybe coming from places below like GI bleeds or menstruation, or another source. And we can’t keep up with it and we reach for IV iron. 

Pearl 3: Oral Iron and Misconceptions

Dr. Shreya Trivedi: Alright, now that we have a clear picture of who’s in the IV iron club, right off the bat. Then, for the rest, we reach for oral iron. But, here is where more questions pop up! One, how do we counsel patients on which oral iron to pick up at the local drug store? And, two, do they need take it with vitamin C? And, three, does it really matter if it’s every other day or not?! Let’s clear all that up, Maria!

Dr. Maria Fernandez: Yes, Shreya! So in terms of oral iron formulations, there are tons but the punch line is that all of them are similar. No oral iron appears to be superior in terms of efficacy . So it’s just best to tell our patients to choose the most cost-effective formulation.  

Dr. Shreya Trivedi: Yes, okay! But I feel like patients are constantly bringing up the constipation or GI upset they get from their oral iron, so are there any formulations that are better tolerated then?

Dr. Michael Auerbach: They ‘re all about the same. They all cause GI side effects. They all cause constipation. They all make the stool thick, green, and tenacious.

Dr. Maria Fernandez: Yeah! So it’s really comical. You look at marketing for the different oral iron preparations because they make all these promises for quote on quote fewer side effects.

Dr. Jason Freed: All of the side effects of oral iron are directly proportional to the amount of elemental iron in the pill. That is the only thing that matters. So you’ll sometimes see these supplements that are natural and it’ll be called easy iron and it’ll say easy on the stomach and then you’ll look closely and it’s like, well, it’s only got 20 milligrams of elemental iron per pill. Of course it’s easy on the stomach. There’s hardly any iron in there.

Dr. Shreya Trivedi: Oh! What a plot twist! So compare that 20mg of elemental iron in say easy iron to 65mg of elemental iron in say something like ferrous sulfate. I guess its a balance to strike, to give as much elemental iron as the patient can tolerate before they develop side effects.  

Dr. Maria Fernandez: One thought that I have is that because our GI tract will only absorb a portion of that elemental iron, it makes me wonder if there is an ideal amount of elemental iron to give.

Dr. Jason Freed: You know, I don’t think we know the ideal dose in actual clinical practice. I tell patients to go to the store and by the cheapest bottle of ferrous sulfate that they can find, and I say start out taking it once a day. If you get constipated, go to taking it every other day.  If you’re still constipated, I want you to buy this other thing called Senna. It’s also over the counter. But I also give them the reverse contingency. If you’re tolerating it fine, taking it daily, you can actually go up to twice a day, especially if you’re very symptomatic from your anemia.

Dr. Shreya Trivedi: Oh, I really appreciate good contingency planning – something we could all get better at. Again, this is Dr. Freed’s expert counseling. Our reviewer, Dr. Layla Van Doreen says, for her, in her practice, if she’s reaching for Senna, then she would just go for IV iron at that point. So everyone has their own practices.

Dr. Maria Fernandez: And then as far as how to actually take oral iron, for best absorption, the textbook recommendation is to tell our patients to take their iron at least 30 minutes before a meal and 1 to 2 hours before taking other medications. 

Dr. Shreya Trivedi: Uh, that is so hard. I feel like the rookie mistake in my own life. I’ll take my prenatal vitamins that have iron in it and of course I’m having it with coffee that has milk in it!  

Dr. Maria Fernandez: Yeah, even if you are a chai tea lover, its good to know that the phenols in tea bind to non-heme iron, they form a complex in the gut and preventing absorption. 

Dr. Shreya Trivedi: Ah, no tea, no milk in my coffee. All that being said, Dr. Freed did say in his clinic he does not usually mention all this textbook complex jitsu timing the oral iron. For him, he just thinks going to be too complex trying to time that iron and he doesn’t want patients to forget taking it all together.

Dr. Maria Fernandez: Yep so we just need to titrate our counseling to each patient and recognize what will overwhelm some patients. 

Dr. Shreya Trivedi: Right! And another important absorption point is to look at that medication list. And PPIs rear their head again. Turns out prolonged use of PPI’s or antiacids can also affect that oral iron absorption.

Dr. Maria Fernandez: Oh wow! So definitely good time for deprescribing the PPI or antacid if they don’t need it. 

Dr. Shreya Trivedi Exactly! And I think the other interaction we often counsel on is taking iron with vitamin C. Or patients even bring that up themselves.

Dr. Jason Freed: One I will highlight was that for a long time people said this thing like, oh, iron is better absorbed with vitamin C. If you look, you’re like, where did that come from?  You’re like, okay, let me follow the paper trail on PubMed goes back to this very tiny study. I wouldn’t even call it a study. It was sort of like a  proof of concept from 1994 with a small number of iron deficient women who weren’t even anemic and they were just trying to look at the absorption after getting a single dose. This was not a clinical trial.

Dr. Shreya Trivedi: Wow, so this study included 25 women in the 1990s and found a slight increase in just serum ferritin and now we’ve created daily recommendations to have iron with vitamin C for a slight increase in ferritin!?

Dr. Jason Freed: Turns out when someone finally got around in 2020 to publishing a randomized trial of vitamin C or not with oral iron for women with iron deficiency anemia, it made no difference. It made no difference at any time point. Now, look, I don’t think a lot of people are out there suffering because they took vitamin C with their iron. I just think it was mostly a distraction. So I say you can still get the cheap one. You don’t need to get the one that’s three times as expensive that has vitamin C in it.

Dr. Shreya Trivedi: You know, I do feel empowered going through all of this because now I can prioritize my counsel and can deemphasize the vitamin C point. 

Dr. Maria Fernandez: But just a quick point, we may wanna point out the difference between taking iron with vitamin C versus orange juice.

Dr. Jason Freed: Why don’t you take your iron with orange juice? The problem is that a lot of orange juice in the United States is fortified with calcium, and calcium actually may compete for absorption with iron. 

Dr. Shreya Trivedi: I really appreciate that nuance! And the calcium is the same reason why we say avoid dairy with iron.

Dr. Maria Fernandez: A lot of rules, Shreya!

Dr. Shreya TrivediA lot of rules! Complex jijitsu, as Jason calls it.

Dr. Maria Fernandez: Yes! The last thing to dive into, is what is the ideal frequency to order oral iron. Do you tell patients to take iron every other day or everyday?

Dr. Shreya TrivediYes! That’s a good question.

Dr. Jason Freed: This is the most misquoted study in the time that I’ve been practicing medicine. It’s astonishing how many people change their practice because of a doc alert. 

Dr. Shreya Trivedi: Oh man, this got Jason really fired up. There was just so much about this actual study that makes you pause!

Dr. Jason Freed: It was people with iron deficiency without anemia. Why should that make a difference? Well, anemia is an extremely strong suppressor of hepcidin, and so iron absorption is very different if you are anemic versus not anemic.

Dr. Maria Fernandez: And actually this is a big deal because most people we are treating are people with iron deficiency anemia, and not iron deficiency alone.

Dr. Shreya Trivedi: Yep and then another kicker is that the study included only 18 patients in each arm!

Dr. Jason Freed: Then I ask people, okay, what do you think the study design was? Okay, so in the month of April, people were getting it every other day. They got 14 pills over the course of the month of April. The people who got it daily, what do you think they got? 28 pills over the course of April every day. No. That is not what they did. They just gave it to people for the first 14 days of April and then did nothing else. They didn’t compare to what would be real life, which is that they would take it all the days of the month, and meanwhile, there was barely a difference between every other day and daily. And the daily people only took it for 14 days. They could have taken it for 28 days, for sure, 100%. I’m a 100% confident if they kept taking it for the entire month, they would’ve had significantly more almost double the iron absorbed than the people who took it every other day.

Dr. Shreya TrivediSo this study asked if taking 14 iron pills everyday for 14 days would be better? Or if taking those 14 pills every other day for 28 days be better. Now, we don’t know the very real world question of what is the best frequency, say over 4 weeks. Right? Is it daily? Which would mean 28 doses. Or is it every other day, which is 14 doses? And how does that look in terms of efficacy, toxicity, and compliance. 

Dr. Maria Fernandez: I’m glad we broke all that down but there have been newer but smaller studies since then. For example one  study recently found that giving iron three times  per week vs three times per day was non-inferior.

Dr. Shreya Trivedi: Yeah! So that was the headline read of it. But I think for me, the most important finding was at 4 weeks, people who had three times a day iron, which is also crazy, did have a higher hemoglobin. An average 1g/dl hgb higher than the three times a week group  So, clearly you get better faster the more iron you give. Right? So I think its just depends on how people want to balance how you rapidly you want things to improve versus potential iron side effects.

Dr. Maria Fernandez: Yeah for someone who is symptomatic I might reach for daily iron versus for someone who is not symptomatic, I would probably be okay with giving iron every other day! 

Dr. Shreya Trivedi: Yeah, I think that’s a good nuanced read of the literature and there’s not a one size fits all. I think, Marisa the last thing we could touch on, something that we’re not good at doing is counseling patients on is how long might it take for those iron stores to be replete with oral iron? 

Dr. Maria Fernandez: Can you actually believe that Oral iron needs to be taken from 6 to 12 months, to fully replete iron stores?!

Dr. Michael Auerbach: Take it for a year and you’ll have correction of your iron deficiency as long as you’re not bleeding and your periods aren’t too heavy, and if you tolerate it and take it in a year, you’ll have reasonable iron stores and a correction of your iron deficiency anemia. 

Dr. Maria Fernandez: Okay, but let’s close that loop. If we start oral iron, how do we know if there is a good response?

Dr. Jason Freed: The British Society of Gastroenterology wrote guidelines in 2021 for the management of iron deficiency of anemia in adults and their number five recommendation, which had 100% consensus and the statement strength was strong is we recommend that a good response to iron therapy like a hemoglobin going up one gram per deciliter within two weeks. I should be seeing a response of about a gram per deciliter of hemoglobin. And so if I don’t, it suggests that probably giving more is not going to have a lot of benefit unless there’s some other reason it didn’t go up.

Dr. Shreya Trivedi: Okay, so you can know within 2 weeks or so and some people say within 4 weeks if there is a response or not. You see that hemoglobin go up by 1g/dl, but how long does it take to actually normalize hemoglobin levels with oral iron, caveat again, if there’s no further loses of course.

Dr. Jason Freed: Hemoglobin will normalize within about six weeks, but it takes about six months to replete their iron stores. Now, those shorthand’s like six weeks to get a normal hemoglobin, six months to replete your iron stores, those very much depend upon how anemic were you to start.

Dr. Shreya Trivedi: So Maria, do you want to remind us again, if we do re-check labs, what thresholds are you looking for when it comes to for ferritin and TSAT?

Dr. Maria Fernandez: Yeah, Shreya! But again, it really depends on how anemic a person is to begin with. As a general rule of thumb, we should be looking for ferritin levels above 50 or TSAT levels above 20 if 6 months of adequate treatment.

Dr. Shreya Trivedi: Nice! Alright! I’m glad we covered all of this. Let’s recap! My big takeaway in terms of counseling patients is asking them, you know what, you can feel comfortable getting the cheapest iron formulation, but just be aware if it claims to have less side effect, it probably has a minimal amount of elemental iron in it.  

Dr. Maria Fernandez: Those are great learning points! For me, my biggest takeaway is that the evidence isn’t all that strong for taking vitamin C or taking iron every other day instead of daily, when it comes to improving hemoglobin or symptoms. These are the things we really care about.  

Dr. Shreya Trivedi: Yep, yep! And technically we should counsel out patients to avoid taking their iron with food or other medications for the best absorption. 

Pearl 4: IV Iron

Dr. Shreya Trivedi: Now, we have a confession to make. Yes! We started out with Pearl 2 with Dr. Auerbach’s recommendation for who he gives oral iron, which as a reminder “Uncomplicated iron deficiency without active bleeding and without comorbid conditions or a disorder known to be unresponsive to oral iron or in which oral iron causes harm” and at the same time, Dr. Auerbach was pretty real with us about his practice and who meets that recommendation for oral iron.

Dr. Michael Auerbach:I would say of the 4,000 people per year, that’s a real number that I treat for iron deficiency. Fewer than 10, get that recommendation. Out of 4,000. Because suppose it’s you suppose. Let’s say you had an ulcer, alright, and your gastroenterologist fixed it and it was no longer bleeding. And I’m going to give you a choice. Say Maria, you can take one iron pill. Take it for a year and you’ll have correction of your iron deficiency as long as you’re not bleeding and your periods aren’t too heavy, and if you tolerate it and take it, in a year, you’ll have reasonable iron stores and a correction of your iron deficiency anemia. Or I can fix you in 20 minutes right now. All done, take your pick. 20 minutes, 20, minutes. That does what a year. And it’s enormously less toxic.

Dr. Shreya Trivedi: I just love that point and still remember him saying this months after interviewing him and honestly do factor in how symptomatic someone is and how likely they would benefit from IV iron for my threshold to reach for it.

Dr. Maria Fernandez: Yeah, I wish we could give IV iron to everyone but IV is more expensive than oral iron so we should definitely individualize it. 

Dr. Shreya Trivedi: Ah! A+ for cost consciousness. So, say, we do choose to give IV iron to and we open up the EMR to order, and there are so many different IV iron formulations. I know for me, before this episode I just kept ordering the same one I’m familiar with and didn’t have a nuanced understanding of the differences.

Dr. Michael Auerbach: So there are seven formulations in the United States. So you have ferric gluconate and iron sucrose. Thats ferrlecit and venofer. They’re good, they’re safe. They’re just as effective and just as safe as the next five. Now, low molecular weight iron dextran takes about an hour, by the way, in terms of safety and efficacy, no difference. Thousands and thousands of patients in head-to-head studies, no difference. No difference! And they were all compared to iron sucrose, which has the longest history of the standard for safety. Iron sucrose is a good drug, but you got to come five times, okay? Instead of once.

Dr. Maria Fernandez: I had never thought about this way but it sounds like the main difference is the time of infusion, and the number of visits or “sittings” required to get to 1g of iron.

Dr. Shreya Trivedi: And there is an awesome infographic by Dr. Dexter Nwachukwu on that really helps visualize those difference but lets summarize the key  high level points.

Dr. Maria Fernandez: So my favorite IV iron formulations of course are the ones that require only 1 sitting to get 1g of iron infused. That’s going to be iron dextran and iron derisomaltose (this one is also called Monoferric) but keep in mind that monoferric has a 10 times more expensive price tag to it!

Dr. Shreya Trivedi: Okay! So thats the practicalities of the different iron infusions and cost. What about the side effect? 

Dr. Maria Fernandez: So this is one good thing! Almost all IV iron formulations have similar side-effect profiles

Dr. Shreya Trivedi: Nice! One less thing to remember.

Dr. Maria Fernandez: But there is one caveat to that statement. 

Dr. Jason Freed: I never use ferric carboxymaltose, and the reason for that is that it has this interesting but annoying thing, which is that it stimulates fibroblast growth factor 23. 23 is one of your natural regulators of phosphate levels, and it actually drives your phosphate levels down. For most people that has no harms. But there is a small number of people who actually have serious consequences from hypophosphatemia. And as a result of that, you either have to check everyone at this one to two week interval afterwards when it typically occurs, which means you’re bringing them back for an extra visit for a lab check.  

Dr. Maria Fernandez: So, 1 to 2 weeks after infusion, patients can develop something called 6H syndrome. What is this? 6H syndrome includes a bunch of things. Hyperphosphaturia, Hypophosphatemia, Hypovitaminosis D, Hypocalcemia, and also secondary Hyperparathyroidism. 

Dr. Shreya Trivedi: Oof! What an alliteration, Maria! I’m proud of you for getting through that. Okay so it sounds like this syndrome can lead to life-threatening complications such as an increased risk for hip fractures, osteomalacia, muscle weakness, and even respiratory failure. 

Dr. Maria Fernandez: Yes! So clinicians should be careful with patients complaining of generalized weakness and fatigue after ferric carboxymaltose infusions. 

Dr. Shreya Trivedi: Yeah! Aaybe just best to stay away from if possible! Is my take away. Maria, we went over the different IV iron formulations. And it sounds like everyone is iron deficient to a different degree. So is it like a one size fits all? We give the same 1 gram of IV iron to everyone or is there a way we can be more thoughtful about how much IV iron someone needs? 

Dr. Maria Fernandez: There is! So it’s the Ganzoni formula. I actually use it quiet a lot. But it is not absolutely necessary. Some people’s practice is just prescribe 500 mg to 1 g of IV iron. 

Dr. Shreya Trivedi: Yeah! And I’m guessing there is another group of clinicians advocate in favor of using the formula, and don’t want under dose patients. 

Dr. Jason Freed: So they’re really easy to use. They don’t require a lot of details that are hard to get. So if you just Google iron deficiency calculator, you will get an MD calc for the Ganzoni equation. The reason why I do use these calculations is because people are often under dosed, especially people who are severely anemic. And the problem is if you weigh 200 pounds and your hemoglobin 7.5, and normally it’s 15. Your iron deficit is 2,100 milligrams, you need twice as much. You will still be anemic even after getting a thousand milligrams of IV iron.

Dr. Shreya Trivedi: Yeah, and another tricky thing that will be an evolving conversation is in that Ganozi formula it asks you whats your goal hemoglobin? And we all have to pause here. For women do you put the lower limit of normal, 12g/dl?! Knowing that some of those ranges are flawed and we could actually be under dosing women.

Dr. Maria Fernandez: Oh, Shreya! We are all going to be under dosed. Thankfully some of our discussants and reviewers are writing the new iron deficiency guidelines and hopefully will give some nuance to the sex differences of hemoglobin ranges.

Dr. Shreya Trivedi: Nice, nice! Can’t wait for that. Alright, last, but not least. Let’s wrap up with, if we give IV iron and we recheck labs on our patients, when is the best time to do that? 

Dr. Jason Freed: Iron parameters are uninterpretable for the first six weeks after getting IV iron. The problem is that ferritin shoots up way above the level that would actually be reflective of your iron stores. And then by around week six, it’s actually reflective of your true iron stores.

Dr. Maria Fernandez: Alright, so after 6 weeks of IV iron we are looking for a TSAT >20 and  ferritin >50.

Dr. Shreya Trivedi: One think I will mention because I am such a stickler for transitions of care and love deprescribing, is once we’ve given IV iron, we can feel comfortable stopping that oral iron for a patient! 

Dr. Maria Fernandez: This is something I would totally forget! So thank you for mentioning it, Shreya. So I think this this may be a good place to summarize, what I took away from the different IV iron formulations. Basically they are similar in efficacy. IV iron formulations that require only 1 sitting to get 1g of iron infused include iron dextran, monoferric, and also feromoxytol.

Pearl 5: SE Effects with IV iron

Dr. Shreya Trivedi: Okay! And last but not least, should we go over complications and side effects with IV iron treatment, particularly the worry of infection and reactions to IV iron?

Dr. Maria Fernandez: Yes, this is one of my favorite parts! 

Dr. Shreya Trivedi: Lets start with the thing that comes up all the time, which is IV iron and infections.

Dr. Maria Fernandez: Well this is complex. There has been conflicting evidence on this matter. If you look at one meta-analysis in 2021, it did find a higher rate of infections in patients treated with IV iron when compared with oral iron or no iron therapy. But, oh my god, studies were highly heterogeneous and the diagnosis of what “infections” constituted was not standardized across trials.

Dr. Shreya Trivedi: Yeah! Great points, great points. On the other side of this spectrum, there was this larger meta-analysis that looked at more than 10,000 patients who had IV iron and they did NOT have a higher rate of severe adverse events or infections. Which was a win!

Dr. Maria Fernandez: That’s good to know! But you know, Shreya, the real pain points happen in the hospital. Sometimes want to give IV iron but the patient may already have an infection. 

Dr. Jason Freed: I think that anyone who is actively bacteremic, I will not give IV iron. And that is based upon a very clear pathophysiologic rationale, which is that bacteria like iron. And there’s a reason that all mammals restrict the amount of iron in their bloodstream when they’re inflamed because they want to keep it away from bacteria that is very evolutionarily conserved. However, people have over extrapolated that concern to being like, ah, anyone who’s even possibly at risk for infection or recently had an infection, maybe I can’t. If they’re not actively bacteremic, they likelihood of harm is extremely low. So someone came in and they had a UTI at the beginning of this admission, they’re not going to have a breakthrough UTI because you gave them IV iron. No way, no how.

Dr. Shreya Trivedi: No way, no how! I love that. I’m dropping that on rounds next time. Sounds like either way, it may be good to wait till end of the hospitalization.

Dr. Jason Freed: I also don’t prioritize it when they’re in the hospital and infection early on because they’re actively inflamed. So even though you’re not worried about absorption of iron, if you give IV iron, you still have inflammatory cytokines that are suppressing hematopoesis, so you’ve given them a bunch of iron that they’re not going to use right away anyways. So I sort of wait until they’re clinically better from their infection. And then if I’m like, okay, this person has significant iron deficiency anemia that hasn’t been addressed, they would really benefit from getting IV iron. Their hemoglobin is extremely low, they’re a hospitalized patient, they’re not going to be able to tolerate oral iron. Then they get constipated, it’s going to set back their recovery. Those are the people that I will give IV iron to usually like a day before their discharge.

Dr. Maria Fernandez: Yeah I really appreciate thinking of the end of an admission as opportunity to replete iron when indicated. I really still remember a patient that I took care of with heart failure. We gave her IV iron later in her hospitalization, and she was strutting down the hallway saying that she felt so good!

Dr. Shreya Trivedi: Aw! That always makes me feel so good as a doctor. Okay, so now that we have squared away the worry of infections, what about patients who ask us, hey, doc, am I going to get a reaction to IV iron? 

Dr. Michael Auerbach: We see a minor infusion reaction, which is self-limited in 1% of patients. I’m not lying. I’ve given about a hundred thousand doses since 1981. I’ve never seen anaphylaxis, not once. Yeah, anaphylaxis is vanishingly rare. It occurs in fewer than one and a quarter of a million doses.

Dr. Shreya Trivedi: Okay, so anaphylaxis to IV iron exceedingly rare. Like case reportable rare. What people often mistake as an anaphylaxis reaction is actually something completely different, a Fishbane reaction!

Dr. Jason Freed: If you give it fast enough, 100% of people will have this reaction. And if you give slow enough, like give it over the course of a day, no one will have this reaction. But at the rates that we commonly infuse IV iron so that people aren’t sitting there all day, somewhere around 5% of people will get this kind of reaction. And then the key thing is this is not an allergic reaction. It is not IgE mediated. This has been studied.

Dr. Shreya Trivedi: So if we can shout out on the rooftops – a Fishbane reaction is NOT an actual allergy and definitely not anaphylaxis. But what exactly is the reaction and how do we tell it apart from anaphylaxis?

Dr. Michael Auerbach: Patient’s sitting comfortably about 30 seconds after the iron’s given the flushing occurs and there’s pressure in the chest, might be some anxiety, but there’s no stridor, wheezing, periorbital edema, or shock.

Dr. Maria Fernandez: And when we see this happening, it’s really important to know how to manage the flushing and chest pressure that comes with Fishbane reactions.

Dr. Michael Auerbach: We stop the infusion, which is what we always do. We hang fluids. And we wait until the reaction is over. And you’re going to see that it’s going to be over in about three to four minutes.

Dr. Jason  Freed: You can then turn the infusion back on at 50% the rate and then they will be able to tolerate the rest of the infusion.

Dr. Shreya Trivedi: It’s so good hearing that symptoms quickly recover after stopping the infusion, and they do not reoccur when the infusion is restarted at a slower rate. But I can see a lot of people mistaking the flushing as possible hives or that chest pressure, anxiety as being short of breath.

Dr. Jason  Freed: So a lot of people mismanaged Fishbane reactions. And how do they mismanage them? They’ll commonly give IV Benadryl. Problem is IV Benadryl makes you lightheaded, makes you hypotensive and can worsen Fishbane reactions. So people think, oh, it’s benign. I might as well give it. You turn what would’ve been a transient self-limited reaction into a thing where the person’s feeling terrible for hours and then the reaction starts to look even. And then they get a little confused. And they’re like, ok this is anaphylaxis. Get the epinephrine. Right? So the key thing here is you don’t give them IV Benadryl, you don’t give them anything. They get better. 

Dr. Shreya Trivedi: Please, please, please do not give IV benadryl and epinephrine if you are ever called to the bedside. It is not necessary and will make things worse. Just stop IV iron infusion for an hour and restart at a slower rate. 

Dr. Maria Fernandez: And that is a wrap for today! This episode was made as part of the Digital Education Track at BIDMC! Thank you to all the mentors and everyone involved!

Dr. Shreya Trivedi: Yes! If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! Thank you to our peer reviewers, Dr. Jonathan Berry and Dr. Layla Van Doreen. Thank you to Daksh Bhatia for the audio editing. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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