Fixing the flag: A new standard for diagnosing iron deficiency

Iron deficiency affects as many as 40% of women of reproductive age, yet the problem often goes undetected—even when patients have symptoms and complications. On this episode, Dr. Blair Bigham and Dr. Mojola Omole speak with hematologists Dr. Michelle Scholzberg and Dr. Rita Selby about their structural solution to this pervasive problem: a province-wide change to how laboratories flag ferritin results. Their article, “Diagnosis and management of iron deficiency in females”, is published in CMAJ.

Dr. Michelle Scholzberg, a hematologist and clinician scientist at St. Michael’s Hospital and division director of Hematology at the University of Toronto, explains why iron deficiency without anemia is clinically important, how flawed reference standards and stigma around menstruation have contributed to underdiagnosis, why screening based on hemoglobin alone misses many patients and how structural barriers within medicine have long impeded timely detection and treatment. She outlines the evidence that drove a change to the clinical decision threshold for ferritin in Ontario laboratories and describes the movement that led to the change

Dr. Rita Selby, an academic hematologist and medical director of the Ontario Laboratory Medicine Program at Ontario Health, describes how change was implemented across Ontario’s major private labs. She clarifies the distinction between reference ranges and clinical decision limits, and how the shift helps clinicians identify subclinical iron deficiency earlier. She also discusses anticipated challenges, such as increased demand for treatment and the need for accessible knowledge translation tools.

This episode exemplifies how making structural change in Canadian medicine can be difficult, but is possible with  grassroots advocacy and inter-institutional collaboration.

For more information from our sponsor, go to MedicusPensionPlan.com

Join us as we explore medical solutions that address the urgent need to change healthcare. Reach out to us about this or any episode you hear. Or tell us about something you'd like to hear on the leading Canadian medical podcast.

You can find Blair and Mojola on X @BlairBigham and @Drmojolaomole

X (in English): @CMAJ
X (en français): @JAMC
Facebook
Instagram: @CMAJ.ca

The CMAJ Podcast is produced by PodCraft Productions

Transcript

Dr. Blair Bigham

I'm Blair Bigham. 

Dr. Mojola Omole

I'm Mojola Omole. This is the CMAJ podcast.

Dr. Blair Bigham

Jola, today we are talking about something we've, we've touched on before, but we're going to get right into the weeds today.

Dr. Mojola Omole

And also I feel like now we're actually, we're moving forward, like that, you know, we've talked about the problem, but now is the solution to the problem that we've talked about previously.

Dr. Blair Bigham

We have some some pretty impressive change here from the people that we're going to speak to on our panel today. We are talking about iron deficiency, not just iron deficiency anemia, but iron deficiency in general, and how we detect it, or more specifically, how we might detect it better. Because as it turns out, the way we look for it now maybe is pretty sexist.

Dr. Mojola Omole

And instead of writing a guideline or changing guidelines, our two authors we'll be speaking on today went straight to the lab system and changed what gets flagged as iron deficiency.

Dr. Blair Bigham

They hit the pavement and actually made it happen. So today we're going to be speaking about an article in CMAJ on this change, and we'll be speaking to two of the change agents, both hematologists, Dr. Michelle Scholzberg, who's been on with us before, and also Dr. Rita Selby, both hematologists who are going to help us understand not only why, but how they were able to enact this change. That's coming up next on the CMAJ podcast.

Dr. Michelle Scholzberg and Dr. Rita Selby are authors of the article, “Diagnosis and management of iron deficiency in females”, published in CMAJ. Dr. Scholzberg is a hematologist and clinician scientist at St. Michael's Hospital and the division director of hematology at U of T. And Dr. Selby is an academic hematologist at UHN and Sunnybrook Hospitals in Toronto, and the medical director for the Ontario Laboratory Medicine Program at Ontario Health. Michelle and Rita, welcome to the podcast, or Michelle, welcome back to the podcast.

Dr. Michelle Scholzberg

Thanks so much, Blair. 

Dr. Rita Selby

Thank you.

Dr. Blair Bigham

Michelle, we've talked a little bit about these gender biases in sort of normal labs in the past. Why are you so passionate about this? You've really made this sort of central to some of the advocacy work you do.

Dr. Michelle Scholzberg

I think that I'm so passionate about this because I have heard what feels like the same story repeatedly for almost 15 years now in my clinics, where I meet a patient who doesn't feel heard or doesn't feel understood surrounding their symptoms related to iron deficiency and iron deficiency anemia. And we end up meeting them in our hematology clinics very late, long after complications have occurred. 

And I think I've become frustrated by a pattern. I'm totally not alone in that. There's so many other people that have been frustrated by this pattern medically. And so I think I've just been searching for solutions and over time realizing that the only meaningful solution in this kind of space, especially in a condition that affects so many people, that the solution has to be structural. We just have to make it easier for people to do the right thing.

Dr. Blair Bigham

Remind us of the nuts and bolts of this problem that you've been digging into.

Dr. Michelle Scholzberg

For sure. So iron deficiency is exceedingly common, especially among females of reproductive age, so people who menstruate and people who are pregnant, and people in perimenopause. 

And when I say common, it's, you know, 30 to 40 percent of people are affected with iron deficiency. And about 10 to 12 percent of people in those same groups have iron deficiency anemia, which is absurd from a prevalence perspective. You know, like we talk about so many different diseases in medicine, but to say 30 to 40 percent of people, like in the general population, have this, I mean, it's kind of mind-blowing. And so, because of that, it's important to take a step back and ask oneself, why are so many people having this condition?

And over the years, research that has been conducted by many people, including our research group, has found that this problem has become a problem of basically pandemic proportions because there are permissive structures that allow for it to go undiagnosed. And so the ferritin lower limit of normal or the lower range of normal, the threshold that gets flagged by the lab to alert a physician or any clinician that the test is inappropriately low, has been inappropriately low for decades upon decades because the individuals that have been tested who are presumably healthy to define the lower limit of normal actually had the condition of interest because they weren't screened out of the population, because they weren't questioned surrounding risk factors of iron deficiency. Because those risk factors, again, are so common and we don't really talk a lot about things like vaginal blood loss because it's, you know, fundamentally stigmatized across all cultures, including the culture of medicine.

So we came together now almost five years ago as a group in a working group that we entitled Raise the Bar, people from across all different disciplines of medicine, from laboratory medicine to hematology, to family medicine, biochemistry, etc. And people in leadership positions at community laboratories and also leadership positions now in Ontario Health came together to say, hey, let's make this change to the ferritin lower limit of normal and truly make it evidence-based and shift from a lower limit of normal to what we call a clinical decision limit, much like we do in other areas of medicine, for example, in cholesterol panels or for the D-dimer, for example, where instead we're saying this is based on scientific evidence, based on the literature to help guide clinical care and to flag results that fall below that clinical decision limit as abnormal.

So we made that change last year at LifeLabs and Dynacare, which are the largest Canadian community laboratories.

Dr. Blair Bigham

We're going to get into the impact of those changes, but first walk me through ferritin specifically. I mean, I feel like everybody gets a CBC at some point in their life. What should physicians be looking out for either in a CBC or just in their patient's presentation that should prompt them to say, definitely time to order a ferritin?

Dr. Michelle Scholzberg

So first I would say not to rely on the CBC necessarily as the prompt to order a ferritin. Instead, we should really be thinking this more so as a screening test in patients who are seen in family medicine clinics, for example, or in OBGYN clinics, where you ask yourself, is the person in front of me at risk of iron deficiency? And based on what I've just told you, the prevalence of iron deficiency in these groups is about 30 to 40% if we're just looking at the female population.

So a lot of people are at risk. And so that means that you need to speak to the person about their vaginal blood loss. You need to know if they're currently pregnant, if they've been recently pregnant, if they're lactating, because all of those are risk factors for iron deficiency.

Because they're high iron utilization times, and because blood is the richest source of iron in our body, it accounts for 70% of our total body iron. And 50%, fully 50% of women of reproductive age who are menstruating have heavy menstrual bleeding. Fifty per cent.

Dr. Mojola Omole

So let's say you're not necessarily having heavy menses, you're not pregnant, but you are cisgendered female, would that still be something that would prompt you to evaluate their ferritin? Or just if they have those risk factors?

Dr. Michelle Scholzberg

So what we suggested in our paper was, we said that, in a menstruating female, cisgender or not cisgender, an individual who's menstruating, that it would be reasonable to screen that person with a serum ferritin every two to three years. 

And the reason why I'm saying that is because it's really hard to keep up to nourish your iron deficiency because of chronic blood loss, because our diets are less rich in iron than they actually ever have been. Which is why, for example, in the United States, iron deficiency anemia is on the rise in terms of its association with cause of death in the United States, while other causes of anemia are decreasing by 25% in association with risk of death in the United States. And that's because our diets are not as nutrient dense and they're becoming less nutrient dense over time, less iron rich. So even in the absence of heavy menstrual bleeding, it's possible that somebody could develop iron deficiency if they're not nourishing their chronic blood loss, even if it's normal.

Dr. Blair Bigham

What about in the absence of anemia? Because we always think iron deficiency and anemia, you know, those two terms kind of get bound together.

Are there people with a normal CBC who are iron deficient?

Dr. Michelle Scholzberg

Absolutely. And that's such an important distinction because you're right. Historically, we only really talked about iron deficiency anemia, but we have to acknowledge that that's indicative of end organ damage of iron deficiency.

So non-anemic iron deficiency or iron deficiency without anemia, which are now two well-recognized terms in hematology, is associated with morbidity and mortality independent of hemoglobin values and cardiovascular risk factors.

Dr. Mojola Omole

Now I'm scared.

Dr. Blair Bigham

This is fascinating.

Dr. Michelle Scholzberg

No, but iron deficiency, even in the absence of anemia, is important. Why?

Because iron, I mean, Rita and I are very biased as hematologists. We're all about the cells and the blood cells, right? But iron is important for the functioning of many different cells within our body.

It's important for many heme-containing proteins like myoglobin, like our CYP enzymes in our liver. It also is a cofactor for neurotransmitter synthesis, serotonin and dopamine. So iron deficiency, even without anemia, is associated with decreased IQ because it negatively affects memory, attention and speed.

It's associated with mood disorders. So it's important beyond its impact on the bone marrow.

Dr. Blair Bigham

So let's get into the nuts and bolts of what you have done to make change, at least in Ontario. You got Dynacare and LifeLabs, two very large laboratories - private laboratories - in Ontario, to change the threshold. Tell me, first of all, how did you establish a new threshold?

How did you get them to change it? And then what did you see happen afterwards?

Dr. Michelle Scholzberg

This effort took many, many years. Rita and I like to describe it as a grassroots effort because that's exactly what it was. It was based on the goodwill of a lot of people coming together, I think, fundamentally fed up and frustrated with, again, them seeing the same problems arise.

But we came together scientifically, and realizing that, as part of this process, we not only needed to evaluate the existing evidence, we also needed to generate additional evidence. And so we conducted systematic reviews. We conducted two large retrospective cohort studies to definitively define the prevalence in Ontario of iron deficiency and iron deficiency anemia in menstruating people and pregnant people in our province.

And so we looked at that data. We also looked at, you know, what is the level of evidence and is it at risk of bias? All of the data that is informing current reference intervals for ferritin.

And we found that, of the five most commonly used ferritin assays that are used globally, that they're at extremely high risk of bias because in those studies that evaluated them to determine the quote unquote normal range, they included individuals who had never been questioned surrounding vaginal blood loss, surrounding bleeding in general, surrounding their diet, surrounding are you on an iron supplement. And they also didn't adhere to reference interval establishment guidelines, globally accepted reference interval establishment guidelines, which is problematic.

And so all of this data, plus data that goes all the way back to 1992 that demonstrated that the positive predictive value of having iron deficiency increases when the ferritin is in fact below 50, and that iron deficiency we should see as something progressive, and the lower that the ferritin goes, the higher the risk of clinical consequences, including anemia.

And we found the most robust evidence for adults that a serum ferritin below 30 is in keeping with iron deficiency and in pediatric patients below 20. And we also discussed what trade-off are we more or less comfortable with, acknowledging that there's a progression, right? So do we want that threshold to be higher or lower?

And again, it comes down to are we more or less comfortable with false positives or false negatives? And, acknowledging the high prevalence, we were most uncomfortable with false negatives, which is why we thought it was really important to make that shift from the lower limit of normal to the clinical decision limit. And I'm sure that Rita is going to speak specifically about what we mean and the distinction between those terms, because that's really important and really pivotal within the work that we've done.

Dr. Blair Bigham

Let's bring Rita in at this point. Rita, you've been standing by. What had you get interested in this topic?

Dr. Rita Selby

So I am an academic hematologist, but I've sort of pivoted to almost 100 percent laboratory medicine over the last 10 years or so. And, last year, the Ontario Lab Medicine Program was established to, as an agency within Ontario Health, to basically advise on basically anything related to laboratory medicine. So this gave me an opportunity to, in an organized way, reach out to laboratories across Ontario and strongly encourage that they implement this change.

So our message to them was, well, we know you all use different assays and we know that they're slightly methodologically different from each other and have different lower limits. But is it possible for us to not flag at the lower limit of the assay, but flag at the clinical decision limit universally, which is 30 micromole for serum ferritin?

Dr. Blair Bigham

I just want to help clarify for physicians who are reviewing pages and pages of lab results. What's the difference between sort of that reference range, like that statistical normal range, versus that clinically actionable number?

Dr. Rita Selby

Right. So reference range establishment is done originally by the manufacturer. And what they required is to take a statistically significantly large enough sample size of normals and basically establish a mean, plus minus two standard deviation. And the minus two standard deviation of that data set essentially becomes the lower bound of that assay's reference range. Perfectly legitimate. Appropriate.

What we're required to do as laboratory physicians is, when we bring an assay on board, we're supposed to get a set of normal plasmas from donors or purchased and then verify that and say, yeah, you know, when we run it, it falls between this and this. Now, because that varies from assay to assay, the lower limit varies from lab to lab. So that's an inherent unharmonization there.

Secondly, what's challenging with iron lower limit, with ferritin lower limit as a reflection of iron stores, is what Michelle said, is that a normal population may be normal because they're not anemic. But, if they have risk factors for iron deficiency and have poor iron stores, there's really no way to screen for that other than asking the question. So if your normal population has included females or people of reproductive age that have iron deficiency without any impact on their hemoglobin, they will get into your normal reference range study.

So ferritin is particularly challenged in that regard. And so the clinical decision limit then allows you to find that subclinical range of people who are not yet anemic, but are iron deficient and are still symptomatic. And you don't want to wait till they become iron deficient.

You want to, you know, you want to act now. So I think the clinical decision limit sort of flags it earlier. And then, you know, while we are implementing this change, the downside becomes, well, you're going to detect a lot more iron deficiency, so a lot of people are going to go on iron. So what's the flip side of that? Because that's something that has to be very carefully considered, right, is side-effects of oral iron, docs identifying it, but not knowing what to do. And so along with that, there has to be a knowledge translation toolkit and the what to do piece, which Michelle and her team at Unity have specific expertise in developing KT tools.

Dr. Blair Bigham

One more question about your process here before we get into what I think is going to be really interesting for our listeners, which is how do you actually get people iron? Because I can't, I mean, the only way for me to get an iron infusion is to have someone go to the emergency department and say, hi, sorry, I showed up here, but I need an iron infusion. But before we get into that, just tell me, have you guys had any pushback or significant challenge in your efforts to make this happen? Or was it really a slam dunk right from the get go?

Dr. Michelle Scholzberg

No, there was definite pushback along the way. There was concern that if we are flagging more individuals with iron deficiency, that that may lead to an increase in GI endoscopies. So we had to respond to that concern using the evidence, explaining that this clinical decision limit is a very appropriate clinical threshold and that that individual, in fact, does have iron deficiency. And, if they don't have another reason to be iron deficient, it is clinically appropriate for that individual to be evaluated for gastrointestinal losses. So we had to, you know, argue that point using the evidence. 

There was another concern surrounding possible misdiagnosis or lack of diagnosis of thalassemia. So we had to, again, use the evidence to refute that concern, indicating that individuals with thalassemia trait, for example, can also experience iron deficiency. Those who have thal major or thal intermedia are at risk for the opposite disorder, which is iron overload. So we weren't concerned.

There was also a very justifiable concern from the community laboratories, which really drove a lot of the knowledge translation efforts surrounding. We knew that we were going to increase the proportion of abnormal results, abnormal flags, by 20 percent by making this change, which is a big change. And so they wanted support and advice on how to manage concerns that may be voiced by their clients, right, the physicians or other clinicians who ordered the tests.

And there have been no voiced concerns from their clients since the launch. So, again, we had to just ensure that there was a good framework for people to access, that the result now with the clinical decision limit comes with a link to the website guiding the physician on what to do next. 

So, there were a lot of responses that were required over many years and a lot of input from a lot of different experts. And ultimately, what was really important was for us to record and document all of this. And we have retained all of this information because we want to, and we are, making this available to other geographical jurisdictions within Canada, outside of Canada, the United States, parts of Europe, Australia, New Zealand. We've had lots of conversations with lots of people, including large professional organizations, to essentially have a toolkit to help individuals make this change elsewhere.

Dr. Blair Bigham

So let's get into the bedside stuff here. So I'm a family physician who sees a ferritin that's flagged at this clinical level, 28 or 30 micrograms per liter. 

The patient seems well. Their hemoglobin is not that low. What do I do?

Do I start oral iron? Do I talk about diet? Do I chase bleeding?

What's my next step?

Dr. Michelle Scholzberg

Great question. So I think like any good clinical encounter, it requires a fulsome discussion surrounding how the patient is really feeling, including asking them about their concentration, how they're doing at school and work, their mood, whether or not they have the urge to eat inedible things like ice, whether or not they have restless legs. And I certainly, in an individual who is flagged for iron deficiency, I would absolutely speak to them about any blood loss.

And in a person who's menstruating, I would definitely speak to them about their menstruation. I would speak to all people. So there are two encounters, one where you already have the result, the other you have the patient that's in your clinic and you're talking with them to determine, do I or don't I even order a ferritin?

We think it's reasonable to check a ferritin in an individual who's otherwise asymptomatic of reproductive age and female to check it every two to three years. And it's important when you're speaking about menstruation to say, tell me about your period. How many pads or tampons are you changing in a day?

What type of absorbency are you using? Because different levels of absorbency carry different amounts of blood. And for example, having to change two overnight pads is equivalent to 100 milliliters of blood.

Anything over 80 milliliters of blood loss in a menstrual cycle, the entire cycle, is in keeping with heavy menstrual bleeding. And that individual could have met it in a couple of hours. So it's important to be informed about the definitions of heavy menstrual bleeding, to talk to people about heavy menstrual bleeding, not to ask the patient, “Do you have heavy menstrual bleeding?” Because if they've bled heavily their entire lives, they have no idea what's normal or not. So do not make any assumptions or introduce or invite bias from the patient. And then to speak to them about gastrointestinal symptoms and et cetera, and their diet.

So I will say that in almost all patients who are females of reproductive age, it's almost always their menstruation that is contributing to their iron deficiency or pregnancy, which does not mean that we don't ask them about gastrointestinal symptoms, for sure. And then did you want me to speak about treatment?

Dr. Blair Bigham

Maybe I'll throw it over to Rita. Rita, can you help our listeners know when oral iron versus IV iron is the right route? And at what point do you say, I can't get this fixed with iron and refer them to a hematologist like you?

Dr. Rita Selby

So oral iron is obviously the easiest way to go because it's readily available. There are many preparations that have been discussed in the paper. The challenge with oral iron sometimes is that the tolerability is not great, but there are options there.

You can switch around preparations. You can go, instead of iron salt, you can go with, depending on the patient's affordability, you can go with heme-derived iron preparations. Going alternate day, there's evidence to show that alternate day dosing actually helps, but sometimes compliance can drop if you do that. And encouraging people, like I don't know how many times I've had to specifically tell people to take it on an empty stomach or take it with orange juice because vitamin C enhances absorption. 

So you probably want, unless it's a situation where you're dealing with pretty severe anemia and you want to correct the iron deficiency quickly, I think it's reasonable to go with oral iron. And generally we would go with intravenous, either like in a bleeding situation, hemoglobin compromised situation, moderate to severe anemia, or if there's been a total inability to tolerate oral iron despite a good trial, with all of the caveats.

Access to IV iron is a challenge from a system perspective, from a healthcare system perspective. I think that does need some systematic thought to address. It's multifactorial. It's not easy. Michelle, I'm sure, has lots to say about access to IV iron, as well as oral iron and how to encourage people to stick with it.

Dr. Michelle Scholzberg

Yeah, I totally agree with everything. I mean, it's really frustrating, to put it mildly. And I'm aware that, in downtown Toronto, our access to intravenous iron is greater than access elsewhere in the GTA. And then we're not even talking about the rest of the province. So it's really, really hard. I completely agree with everything that Rita said.

There's truly no rhyme or reason as to which oral iron supplement works best for which patient. It's just what you can tolerate, what you can take consistently. And as long as you're absorbing things well, you're tolerating things well, and you're not bleeding excessively, or your demands for iron aren't enormous, or you don't have an upcoming deadline, like a surgery or labour and delivery, oral iron absolutely should be considered first-line therapy.

I can say that when Rita's talking about systems level and structural issues, those structural issues go really far back, right? So oral iron currently isn't considered a treatment, per se, from Health Canada. It's a health supplement. And so that means the level of evidence that is required is far lower than what we are accustomed to as physicians for other treatments. And that's very…

Dr. Rita Selby

And it's also not covered, right? It's not covered by health plans because there's no DIN number associated.

Dr. Michelle Scholzberg

Yeah, there's just recently, there's the first oral iron that is now going to be covered by a private insurer, like private insurers, like it's the first time ever, right? 

So all of this, you know, works against us when we're trying to make change because it's not even recognized by our regulatory bodies as a treatment, right? Which is very frustrating.

And so the level of evidence is questionable at best. So, this is probably one of the most prevalent conditions to affect human beings on this earth. And I can say definitively that we don't have a handle on the best first-line therapy.

And that's a disturbing statement.

Dr. Blair Bigham

It sounds like you've done amazing work to move the needle, but that there's, of course, more work to be done. But I think we'll wrap it up there. Thank you so much, both of you, for joining us today.

Dr. Michelle Scholzberg

Thank you. 

Dr. Rita Selby

Thank you so much.

Dr. Blair Bigham

Head on over to CMAJ to check out the paper, Diagnosis and Management of Iron Deficiency in Females, out now. Our panelists today, with my thanks, Dr. Scholtzberg, a hematologist and clinician scientist at St. Michael's Hospital, and Dr. Selby, an academic hematologist at UHN and Sunnybrook. 

So, Jola, I guess we have two things that we can talk about here. The first is this whole crazy idea that we have not been detecting iron deficiency properly and that we are grossly under-treating it, particularly in women. But also sort of like this remarkable, boots-hit-the-pavement and just knock on doors until you actually get the change that-you want to see in the world to happen.

Dr. Mojola Omole

This is a structural fix, right? It's not just about physician education. It's going to the source.

We know as part of our health care system that physicians, our primary care practitioners, are overwhelmed. And this actually enables them to be able to detect and then enact a treatment much faster and correctly.

Dr. Blair Bigham

The passion and emotional endurance that our panelists displayed, it really does go to show that, you know, traditional knowledge translation is sort of dying, right? This idea that you can do posters and go to conferences and even some guidelines, they just don't get picked up the way they can be when you have dedicated people going out and actually bringing on that emotional will to have private labs change, to have provincial labs change, these reference standards so that people can know when should I take clinical action. 

It makes me wonder what other areas of medicine could actually change in meaningful ways if we sort of got out of our offices and off of our laptops and actually went out and built these relationships.

And we've heard this from Dr. Tunde-Byass and her clinic at North York General in a previous episode. But I think for me, Jola, I don't know about you, but the guests that have actually been able not only to generate science or recommendation or guidelines, but take it forward and actually get it to stick, I find that so impressive.

Dr. Mojola Omole

And I do think that they could be a model for other physicians who notice certain structural inequalities within their practice to be able to also use some of their methods to be able to effect change.

Dr. Blair Bigham

That's it for this episode of the CMAJ podcast. Thank you so much for listening. And we hope that you can share either online or just with your friends.

Let them know. We'd love to get the message out there. The podcast is produced for CMAJ by Neil Morrison at PodCraft Production.

Catherine Varner is our deputy editor at CMAJ and senior editor for the podcast. I'm Blair Bigham. 

Dr. Mojola Omole

I'm Mojola Omole. Make sure you get your iron checked.