Time Stamps

  • 03:43 Deep Dive 1: How do we diagnose iron deficiency?
  • 16:08 Deep Dive 2: How to evaluate a patient for whom heavy menstrual bleeding is suspected?
  • 27:04 Deep Dive 3: When should a premenopausal woman with iron deficiency have endoscopic evaluation?
  • 35:15 Summary and Closing

    CME-MOC

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Show Notes

  • Symptoms often precede development of anemia!
    • Therefore, iron deficiency is a clinical syndrome and anemia is a late-stage complication
  • Why do these symptoms occur?
    • Low iron in body → Body prioritizes using available iron to replenish heme → Iron is redirected to the bone marrow and away from other highly metabolically active tissues, where it is used for cellular respiration 
      • Examples:
        • Muscles → Generalized Weakness
        • Brain → Neuropsychiatric symptoms
          • Pica
          • Restless leg syndrome
        • General neuropsychiatric symptoms: 
          • Fatigue and poor exercise tolerance, depression, insomnia, difficulty with cognitive tasks

Deep Dive 1: How do we diagnose iron deficiency?

  • FERRITIN
    • Protein used to store iron
      • Found primarily in the liver and macrophages (reticuloendothelial system)
    • How is ferritin measured?
      • Small amounts are leaked into serum 
    • WHO 2020 Guideline Recommendation: Ferritin cutoff of 15 ng/mL for adults without inflammation or infection → diagnosis of iron deficiency
      • NOTE: Very sensitive, but misses many iron deficient patients
    • Choosing a ferritin cutoff can be challenging! 
      • Ferritin cutoffs initially came from studies in the 1970s 
        • Presumed normal iron stores based on the absence of anemia or TSAT level (source 1, 2)
      • Each value will have its own sensitivity and specificity 
        • Cutoff of 15 ng/mL
          • Sensitivity of 59%; Specificity of 99%
        • Cutoff of 45 ng/mL
          • Sensitivity of 85%; Specificity of 92%
          • Physiological studies suggest iron stores and hemoglobin stop increasing in response to iron supplementation at a ferritin of 50ng/mL (source 1, 2).
          • The American Gastroenterological Association recommends using a ferritin of 45ng/mL to diagnose iron deficiency in anemic patients.
      • It is unclear if ferritin cutoffs should be different for those with or without anemia
        • Most studies are on anemic patients, but others use a mixed population of anemic and non-anemic patients
    • What if the ferritin level is not definitive but iron deficiency is still suspected?
  • TSAT
    • What is TSAT?
      • Transferrin is the protein that transfers iron around the body. It contains binding sites for iron. Transferrin saturation, or TSAT is an estimation of how many of those binding sites are currently being occupied by iron. Calculation: iron over total iron binding capacity (TIBC)
        • Note: TIBC is a measure of all proteins which can carry iron in the blood (including transferrin but also albumin), but is often used as a surrogate for transferrin given the ease of testing
    • What are the challenges of using TSAT?
  • MEAN CORPUSCULAR VOLUME
    • NEW drop → very concerning for iron deficiency!
      • Mean corpuscular volume (MCV) is typically consistent through life
      • A new decrease in MCV is concerning for iron deficiency, as other uses of acute MCV drop are rare (lead poisoning, sideroblastic anemia)
  • TOTAL IRON BINDING CAPACITY
    • Elevation can suggest iron deficiency
  • MEAN CORPUSCULAR HEMOGLOBIN
    • Decrease can suggest iron deficiency
  • RETICULOCYTES 
    • Decrease can suggest iron deficiency
  • How do we  diagnose iron deficiency in the setting of chronic inflammation?
    • Diagnosis becomes less certain! 
      • There is less data to support decision making
      • Most data is in patients with CHF, CKD, or IBD and extrapolated to other patients with inflammation
      • Inflammation affects iron testing
        • (IL-6) → Hepcidin release and drop in available iron
        • Increase in ferritin release
          • NOTE: This is mostly ferritin without iron attached (apoferritin)
        • Transferrin is an acute phase reactant. So inflammation -> decreased transferrin and TIBC -> increase in TSAT
    • Recommendations: In the setting of chronic inflammation, recommendations vary
    • TSAT may be more useful in patients with chronic inflammation than those without chronic inflammation
      • Some advocate for TSAT<20% suggesting iron deficiency in the presence of inflammation, even with higher ferritin levels
      • For patients with HFrEF, TSAT less than 20% may both outperform ferritin cutoffs and identify patients with an increased mortality risk (1, 2). 
    • NOTE: For patients with CKD, the sensitivity of these cutoffs is still poor 
      • Many iron deficient patients with CKD may be missed!
      • We do not discuss diagnosis of iron deficiency in patients with ESRD here, as this has a different approach.
  • So what is the GOLD STANDARD for diagnosing iron deficiency anemia?
    • Bone marrow biopsy!
      • This is more invasive, less practical, rarely performed
    • Clinically relevant standard for diagnosis:
      • Improvement in the following with iron supplementation:
        • Symptoms
        • Hemoglobin
        • Iron studies

Deep Dive 2: How do we approach a premenopausal woman with suspected heavy menstrual bleeding?

  • How common is iron deficiency in women?
  • The common hemoglobin normal ranges may lead to under-diagnosis!
  • Iron deficiency is a leading cause of “years lived with disability” in women!
    • Risk factors:
      • Menstruation
      • Underdiagnosed heavy menstrual bleeding
      • Lower circulating blood volume (compared to men)
      • Fewer red blood cells (compared to men)
  • What symptoms might your patient with iron deficiency (without anemia) have?
  • What are best practices for taking a menstrual history?
    • Heavy menstrual bleeding is bleeding of enough volume that affects quality of life
      • The classic definition is 80mL per menstrual cycle, but strict quantification is unreliable and impractical!
    • During an interview, start with open-ended questions, followed by more detailed questions
      • Patients may have normalized their HMB and so a careful history is still important…
        • Example: Your patient changes their pad 3 times per day
          • Ask them: “Is the reason that the pads are fully soaked, or another reason?”
    • Findings in the history that suggest heavy menstrual bleeding (HMB)
      • Bleeding >7 days 
      • Passing clots larger than a quarter (or > 1 inch) 
      • Episodes of gushing 
      • Overnight “accidents” (e.g. bleeding through products overnight)
      • Adaptive behaviors 
        • Changing products every couple of hours
        • Wearing extra products or protective padding
        • Lifestyle changes to accommodate heavy menstrual bleeding
    • Supplemental tools to the history
      • Pictorial charts
        • Pictorial Bleeding Assessment Chart (PBAC)
          •  Very high scores have a good sensitivity for HMB, but not the best specificity (8% in one study- source 1, 2, 3). 
          • Can be useful for tracking bleeding over time
      • Menstrual multi-attribute scale
        • Quantifies how menstrual cycle affects quality of life (such as whether someone’s social life, daily routine, or relationships are affected by their cycle)
        • Validated tool (source 1, 2
      • FIGO-AUB System 1 and FIGO-AUB System 2
        • Standardized parameters and terminology for abnormal uterine bleeding (AUB) 
        • Developed by International Federation of Gynecology and Obstetrics (FIGO)
      • Additional resources to help guide the evaluation of heavy menstrual bleeding!
    • PRO TIP: Negative or invalidating experiences from providers leads to many women not seeking care…
      • Every patient is different!
      • May not be aware of what is considered “average” menstrual volume 
      • Substantial variation between what different individuals consider light and heavy flow
      • Many parents do not discuss menstruation with their children
  • Are there any guidelines for screening for iron deficiency in women?
    • Of 22 different guidelines for HMB, only 3 recommended initial iron testing
    • Pregnancy guidelines 
      • Recommend checking a blood count but no screening iron tests.
      • Many advocate for screening for iron deficiency in pregnancy. Particularly as there is evidence that perinatal iron deficiency without anemia can shunt heme from the developing brain and contribute to neurodevelopmental delay
  • Heavy menstrual bleeding is a symptom, not a diagnosis. Something is causing the abnormal bleeding!
    • What is the standard work up for HMB?
      • CBC 
      • Coagulation studies
        • It is suggested that initial tests include PT, PTT, Von Willebrand factor (VWF) panel, fibrinogen level or thrombin time, and platelet aggregation. If these are unrevealing and coagulopathy is suspected, factor testing (notably VIII, IX, XI) should be considered.
        • Note that von willebrand factor levels and platelet aggregation time may be elevated in the setting of heavy menstrual bleeding, and repeat testing once bleeding has resolved is advised.
      • Iron testing 
      • TSH
      • Pregnancy test 
      • Endocrine testing and a pelvic exam
        • May be warranted based on a patient’s history 
      • Ultrasound
        • If there is concern for structural cause or for patients 40 years and older
      • NOTE: HMB since menarche + a personal or family history of bleeding → consider coagulopathy! 
        • Seen in as many as one third of patients with HMB
          • 13% of HMB patients have von willebrand disease 
    • What about treatment?!
      • Remember to treat both HMB and iron deficiency
        • Prevents further iron depletion
        • Can be a diagnostic aid. Iron deficiency persists after HMB stops, a secondary process may be driving iron deficiency!
      • For more information on the treatment of iron deficiency, look out for treatment episode on 3/27/24

Deep Dive 3: When is a gastrointestinal evaluation appropriate in premenopausal women?

  • How common are lesions found on endoscopic evaluation?
  • But how common are lesions in premenopausal women?
    • For asymptomatic premenopausal women with iron deficiency undergoing endoscopic evaluation, lesions were found in 5.9-6.5% of patients
      • Lesions included gastritis, hemorrhoids
      • Only 1 case of colon cancer detected
    • Rates of GI cancer in younger patients is increasing! Exact incidence is uncertain, studies are inconsistent
      • Meta-analysis of 70 studies:
        • 0.1% risk in patients <50 years old
        • Included men
      • Meta-analysis of 10 studies
        • 0.2% risk of upper GI malignancy (premenopausal women) 
        • 0.9% risk of lower GI malignancy (premenopausal women)
        • Included those with GI symptoms (higher risk)
    • Cancer risk is not equal for all premenopausal women and risk may be higher based on:
      • Age
      • GI symptoms
      • Medical or social history
      • Family history of GI cancer
  • What non-invasive workup can be pursued for premenopausal women with iron deficiency?
    • Serologic testing for celiac disease
    • Consider H Pylori stool antigen testing
    • Fecal occult blood testing → flawed test!
      • 58% sensitivity; 84% specificity 
        • Many lesions only bleed intermittently and thus may be missed on such testing
  • When should you refer your premenopausal patient with iron deficiency for bidirectional endoscopy?
    • Must balance risks and benefits
      • Evaluates for malignant and benign GI causes
      • Serious complications do occur
        • 5 per 1000 colonoscopies (including complications from both colonoscopy and procedural sedation)
    • Recommended for premenopausal women WITH GI symptoms
    • When to refer patients WITHOUT GI symptoms?

Transcript

Dr. Ali Trainor: Welcome to Gray Matters, where we unpack how medical management is rarely black or white.

Dr. Nick Villano: We go on deep dives along the way! I’m Nick Villano, an internist at Beth Israel Deaconess medical center.

Dr. Ali Trainor: And I’m Ali Trainor, a pulmonary and critical care doctor at Mount Auburn Hospital. So Nick, I understand we’re diving into a case from your past today?

Dr. Nick Villano: Yeah! That’s right, this happened back when I was in residency and still seeing patients in primary care clinic. 

Dr. Ali Trainor: Man, so this must be impactful if it’s still something you think about?

Dr. Nick Villano: Yeah, yeah it was. So I was seeing a 32 year old woman to establish care. Her past medical history really just notes iron deficiency anemia and depression. And so you know I asked how are you feeling. She said “you know I’m a little tired lately but who isn’t?” Basically, small talk, she was at her baseline. We had gotten some labs, BMP and TSH were within normal limits. But seeing her CBC made me pause, her hemoglobin came back at 7.2 g/dL. 

Dr. Ali Trainor: Huh, ok. So that’s not, like an emergency, but still. For a young healthy woman, 7.2? Most of the chronically ill patients I see have a higher hemoglobin than that. Did she seem okay?

Dr. Nick Villano: Right. So she was totally unfazed when I told her what her hemoglobin was. She basically said that she has had heavy periods for years and SHE can tell when her hemoglobin is starting to fall. And she knew it was low! That’s why she wanted to establish care. 

Dr. Ali Trainor: Okay so how does she know her hemoglobin is low?

Dr. Nick Villano: She told me that, basically…she can’t really complete her normal running circuit. She’s making mistakes at work she’d never normally mistake. And she’s almost falling asleep after lunch. 

Dr. Ali Trainor: Wait, that’s crazy! This is her normal life and she just deals with this? That’s terrible! So you’re saying that she has known heavy periods…and this gets so bad that she regularly has severely symptomatic anemia? This is her life?

Dr. Nick Villano: Yeah! It sounds like an awful thing to be used to. But not an uncommon one. When I looked into it, roughly one in five to one in six women in the world are estimated to have iron deficiency. According to the WHO it is among leading causes of years lived with disability in women. 

Dr. Ali Trainor: That is insane, I knew iron deficiency was common in women, but to be one of the leading causes of years lived with disability is just wild, and seemingly so preventable?

Dr. Nick Villano: I know! So that’s what we’re talking about today – how can this debilitating problem that is so easily treatable remain so widespread among women in the 21st century?

Dr. Ali Trainor: Yeah…that’s just crazy…So to bring this back to our patient, clearly we’re worried iron deficiency was driving the patient’s anemia. But how do we know if that’s what’s causing her symptoms?

Dr. Nick Villano: Right, exactly! That’s what I was wondering. We sent her for repeat labs right away. Her hemoglobin was 7.0, so still low. Her MCV was only 71. And now for her iron panel. Her iron was low at 14, a ferritin of 23 and TSAT of 3%. 

Dr. Ali Trainor: I want to say that…that seems iron deficient…but I’ll be honest that this is something I could use a refresher on. It seems iron deficiency is a slam dunk like oh their ferritin is 5 I know what this is, but often times the numbers are all over the place or borderline and honestly I don’t know what to do with it! Like do I use ferritin, % saturation, both?

Dr. Nick Villano: Or TIBC, or one of the dozen other RBC indices that used to feel like extra channels in a cable package to me? But it’s interesting, right, that iron deficiency is this really common thing and I think we all approach diagnosing in different ways based on how we were taught or what our institution calls normal. Of course that led me down my first deep dive, the simple question of how do we diagnose iron deficiency? 

Deep Dive 1

Dr. Nick Villano: Spoiler, I lied. It’s not so simple. Iron deficiency is its own disease, and anemia is just one way it presents. And the anemia is actually a really late complication.

Dr. Malcolm Munro: The available iron is prioritized to heme. And when there’s a deficiency and available iron, it’s taken away from other either developmental or functional processes. So in the adult, in the human human, it’s taken away from brain function, from heart function, from muscle function.

Dr. Nick Villano: That was one of our discussants, Dr. Malcolm Munro.

Dr. Malcolm Munro: Hello, my name is Malcolm Munroe. I am a gynecologist clinical professor at the University of California Los Angeles.

Dr. Nick Villano: So outside of making heme for RBC production, the body uses iron for cellular respiration. That’s important for organs like the muscles and brain. And yet still, if iron is low, the body will shunt iron to heme. At the cost of the BRAIN. The body hardly ever makes the brain ride shotgun.

Dr. Ali Trainor: Wow! So what you’re saying is if your hemoglobin drops, the body has used all the backup iron it has. If you’re anemic, your iron levels are REALLY low.

Dr. Malcolm Munro: Iron deficiency anemia is the extreme end of the iron deficiency spectrum, and indeed cognition is compromised, physical functions compromised even before anemia occurs.

Dr. Ali Trainor: Man, that is crazy! So what you’re saying is I can blame how confused and tired I was during pregnancy because my ferritin was 7? I’m working on that by the way!

Dr. Nick Villano: I had no idea all these neuropsychiatric symptoms can show up before anemia develops!

Dr. Ali Trainor: “Iron deficiency anemia” has always just rolled off the tongue as almost one word so I’ll need to unlearn that. Because iron deficiency can be its own thing even without anemia. So with that in mind, I’m guessing we should start with the iron panel then?

Dr. Nick Villano: Yes, definitely. So first I wanted to examine the most commonly used test – ferritin. A quick refresher, ferritin is a protein that lets us store iron until we need it. So the iron that is stored in the liver is stored as ferritin, but the ferritin that we measure is the small amount circulating in serum. 

Dr. Ali Trainor: So most people are familiar with the ferritin test. But I think the real question is, what is the best way to use it? 

Dr. Nick Villano: Well the WHO weighed in on this in 2020 when they released guidelines and recommended using a ferritin cutoff of 15 to diagnose iron deficiency. 

Dr. Jason Freed: And it’s true that has a very good specificity, 99% specificity for iron deficiency anemia that it’s the cause of the anemia, but it was only 59% sensitive. So you were missing a huge percentage of people who would’ve benefited from iron by using such a strict cutoff for ferritin. 

Dr. Ali Trainor: That was our second discussant, Jason Freed a hematologist at Beth Israel Deaconess Medical Center, who many of you listeners know, he’s trying on a new hat today as discussant.

Dr. Jason Freed: Now, how did that become the cutoff in the first place if that has such terrible sensitivity? Well, it’s mostly because the way cutoffs are established is by taking a lot of healthy people and finding a 95% confidence interval of the uh ferritin in that population. The problem is that a large number of healthy women have iron deficiency even when they’re not anemic. And so as a result, we have created these cutoffs for ferritin that are really, really too low.

Dr. Ali Trainor: Wow okay, so essentially our reference range was created by taking a population that included iron deficient women and calling them healthy? 

Dr. Nick Villano: Yeah! I didn’t know that either! And I get no test is perfect. My instinct would be to use a higher cutoff and optimize sensitivity, even if it’s at the cost of specificity.

Dr. Jason Freed: So it kind of like going up ferritin less than 25, it’s more sensitive, 73% ferritin, less than 35, 80% ferritin, ferritin less than 45, 85%. And even when you get to the 45, that’s still pretty specific. It’s still 92% specific. So I think 45 is a pretty good number to have in your head as being like, well, if it’s less than 45 in someone who is anemic, you can be pretty confident in your decision to give that patient iron. 

Dr. Ali Trainor: So it makes sense that any ferritin cutoff we pick is going to have its own sensitivity and specificity, but if a ferritin of 45 gives us a sensitivity of 85% and a specificity of 92% when compared to bone marrow biopsy, why not use a ferritin of 45? 

Dr. Nick Villano: And so it happens that 45 happens to be the ferritin level recommended by the American Gastroenterological Association’s to diagnose iron deficiency in anemic patients. And there’s some physiological data to back that up.

Dr. Jason Freed: Because that seems to be when our bodies essentially stop absorbing any significant amount of iron, it sort of goes down to this basal level of if your body considers itself fully replete around then such that it just absorbs some minimal 5% amount of it, but it enhances it anytime you’re less than 50. So clearly the body wants iron if you’re less than 50.

Dr. Ali Trainor: It’s great that this ferritin cutoff of 45 captures more people. But that makes me wonder about patients with a ferritin in the gray zone. Maybe it’s like 45, but what about 60?

Dr. Nick Villano: Yeah, I actually talked about that with Jason. When it comes down to it, iron is a relatively safe treatment. If your suspicion is high enough and the testing is not definitive, you can go ahead and just treat and see if patients respond. 

Dr. Jason Freed: That’s a strategy that I think is often undervalued is this idea of a time-limited trial of iron, but it’s actually endorsed by the British Society of Gastroenterology guidelines on iron deficiency anemia. We recommend that a good response to iron therapy, like the hemoglobin going up more than one gram per deciliter within two weeks in anemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal. That recommendation had a hundred percent consensus and had a statement strength of strong. So that’s the group where I really think that time-limited trial of iron I use the most often is when they’re in that 50 to 100 range because those are the perfect people to see, are you right about your diagnosis before your start ordering a million other obscure tests for anemia. 

Dr. Ali Trainor: Okay so for me, takeaway is it’s reasonable to use a ferritin cutoff of 45 because it has more sensitivity without sacrificing much specificity, and then if, maybe the ferritin is in the 45 to 100 range, a time limited trial of iron therapy and rechecking to see if the hemoglobin responds can confirm your suspicions. 

Dr. Nick Villano: Exactly and to give you a specific number to keep in mind, the British Society of Gastroenterology said to look for a rise in hemoglobin of 1 g/dL in 2 weeks. Side note, there will be a whole 5 pearls episode next week on nuances of iron deficiency treatment

Dr. Nick Villano:  Okay, so there’s obviously other tests that hint toward iron deficiency. Things like a low reticulocyte count as the body struggles to make RBCs or an elevated TIBC. But in most cases the ferritin alone can be really helpful. But there is one more clue towards iron deficiency that our basic labs give us, the mean corpuscular volume.

Dr. Jason Freed: People actually have fairly stable MCVs through their life And so if someone’s MCV drops from 95 to 86, it went from definitely normal to also definitely normal. That’s actually a meaningful change that is often another clue that they are developing iron deficiency because not a lot of other things cause your MCV to change.

Dr. Ali Trainor: I never knew you could use MCV that way! I may need to pause this episode and go check on all of my patient’s historical CBCs.

Dr. Ali Trainor: Okay, so I feel like there’s an elephant in the room for me here. Most patients I see are in the hospital. Which means most also have inflammation and we know that ferritin is an acute phase reactant so it’s high in these patients, so what do we do here?

Dr. Nick Villano: Okay so with inflammation, we’re getting into a lot murkier waters here where ferritin is hard to interpret as a way to diagnose iron deficiency and you know the little data we do have is mostly in those with CKD, HFrEF, and IBD.

Dr. Ali Trainor: And this then gets extrapolated to all of the wildly different inflammatory processes we see.

Dr. Nick Villano: Yeah like do these ferritin cutoffs apply to the patient who was found down for hours who has DKA and bacteremia? Or all the other one-liners in my list in the hospital?

Dr. Ali Trainor: Right! So poor data extrapolated from a specific patient population and applied to all inflamed patient populations is not great. But I have this number in my head of a ferritin of 100 to 300 being used to diagnose iron deficiency in inflamed patients. Is that a ferritin range we should be using?

Dr. Nick Villano: So using the data we do have, in 2017 the American Journal of Hematology published a consensus recommendation. That suggests using a ferritin <100  or a ferritin <300 with a TSAT <20% to diagnose iron deficiency. But, here come the caveats. One, this was specifically for patients with chronic heart failure, CKD, or IBD. And two, again, this was a consensus expert opinion.

Dr. Ali Trainor: So ferritin is still helpful in chronic inflammatory conditions, but it sounds like it’s not as helpful. Like we’re not going to be hanging our hat on it as much when inflammation is in the mix. I’m guessing we’re going to have to turn to other iron tests. You mentioned TSAT, can you remind us what that is?

Dr. Nick Villano: Yeah, so briefly, transferrin is the protein that transfers iron around the body (hence the name transferrin). TSAT essentially estimates how much iron is taking up all of the available binding sites on transferrin. It’s like, how full is the bus?

Dr. Ali Trainor: Ok so the thought being that if you have iron deficiency, then iron isn’t taking up as many binding sites, but what do we consider a low TSAT? I feel like I’ve heard a range, anything between 15 and 20%.

Dr. Nick Villano: Yeah depending on where you look it seems to varies. I found 15% and 20% both listed as the lower limit of normal. It seem like this traces back to a study in the 60’s that looked at 132 patients with no iron in their bone marrow and found their TSAT tended to be 2-16%. 

Dr. Jason Freed: So a low TSAT in those patients gives me a little bit more confidence to sort of make a presumptive or suspected diagnosis of iron deficiency that I’m going to test with a therapeutic trial.

Dr. Ali Trainor: Okay so for patients without inflammation, TSAT can be sort of helpful, but it’s not as persuasive as ferritin. But it sounds like you’re saying that for patients with chronic inflammation, TSAT can help us out?

Dr. Nick Villano: Yeah so if you think about it, transferrin is a negative acute phase reactant. So inflammation lowers transferrin. Which  means less available binding sites for iron. And that means a higher TSAT. And so conversely a low TSAT despite all of that, it can suggest iron deficiency. (there will be a graphic that will go through all this)

Dr. Ali Trainor: So the takeaway is for patients with inflammatory conditions, the evidence is not as strong and guidelines are mostly expert opinion extrapolated from patients with CHF, CKD, and IBD. However a ferritin cutoff of less than 100 or less than 300 with a TSAT less than 20% is the current recommendation we have to go on.

Dr. Nick Villano: Right, exactly! And you know I think the jury is still out for figuring out when iron deficiency is complicating chronic inflammation. And honestly even with these cutoffs, we’re probably still missing a lot of iron deficient patients with CKD. But back to my patient. With a ferritin of 23 and a TSAT of 3%, she seems to have clear iron deficiency.

Dr. Ali Trainor: But what is causing her iron deficiency? I mean I know that she said she had heavy periods, but are they heavy enough to cause this much iron loss?

Dr. Nick Villano: Yeah, I had the same questions and no answers when I first saw her. When does menstrual bleeding become heavy menstrual bleeding? And how do you even take a good menstrual history? And so that led me down my second deep dive on how to evaluate a patient for whom heavy menstrual bleeding is suspected?

Deep Dive 2

Dr. Nick Villano: So Ali, I’m going to start with the really basic question I was asking myself. How likely is it that my patient’s iron deficiency is from heavy menstrual bleeding? I mean, is it that common that women become iron deficient from menstrual bleeding alone? I was thinking about this and then Dr. Munro told me about a study from the ‘60s that was conducted on 110 healthy college-aged women.

Dr. Malcolm Munro: They managed, think of this, they managed to do bone marrows on all of these healthy girls who were not, they were just volunteers. They did bone marrows. 70% of them had virtually no iron in their bone marrow, none or virtually none, seven zero.

Dr. Ali Trainor: Wow! So these were just average healthy women? 

Dr. Nick Villano: Yeah! Not only that, but the hemoglobin cutoffs that we use are probably missing a lot of anemia in women anyway.

Dr. Angela Weyand: The WHO defines anemia for our men as less than 13 and women as less than 12. And then if you look at that, it’s all based on this one study. But then they actually gave all the women iron and they gave all the men iron, and it didn’t shift the hemoglobin lower limit of normal for the men, but it shifted it for the women basically to be equivalent to men.

Dr. Nick Villano: That’s Dr. Angela Weyand, our third discussant.

Dr. Angela Weyand: Hi, I’m Dr. Angela Weyand. I’m a pediatric hematologist at the University of Michigan.

Dr. Ali Trainor: I can’t believe the hemoglobin ranges for men and women come from a study in the 60s. And that women who had “normal hemoglobin” had improved hemoglobins after iron supplementation and these reference ranges for men and women 60 years later are still different!

Dr. Nick Villano: I know, it’s kind of mind blowing! The good news is that WHO is reviewing their guidelines on anemia, including how sex and age affect a normal hemoglobin. More to come in the future.

Dr. Ali Trainor: So the CBC is not a great screen for iron deficiency. In fact, hemoglobin ranges make it falsely reassure us! So how should I know to suspect iron deficiency in a woman with a normal CBC? 

Dr. Nick Villano: Yeah, good question! A good history is key to find iron deficiency before anemia develops. You won’t always find classic symptoms like hunger for things like ice, also known as pica. But if a woman is reporting poor sleep, fatigue, depression, not being able to work or exercise, just a general poor quality of life…know that all of these have been associated with iron deficiency and heavy menstrual bleeding. 

Dr. Angela Weyand: A lot of these symptoms of sleep disorders, restless legs, some of the mood things that are associated with iron deficiency people think have to do with actual how much iron is getting into your brain.

Dr. Ali Trainor: It sounds like LOTS of women are living with these effects of low iron on the brain. Your patient reported she basically lived with daily fatigue and depressive symptoms even before her hemoglobin dropped.

Dr. Nick Villano: Yeah, very true! Even if we caught my patient before her anemia developed, the million dollar question is…how do we determine if the iron deficiency is due to menstrual losses. I mean, how do we diagnose heavy menstrual bleeding?

Dr. Ali Trainor: I can think of the questions we’re taught to ask. How many days do your periods last? How many products do you use? But I don’t really know what I would do with that information. Like what am I looking for and when is it actually considered heavy? 

Dr. Nick Villano: You’re definitely not the only clinician who feels under-prepared to take a menstrual history. Surveys have shown not all women even agree on what is considered light or heavy bleeding.  

Dr. Angela Weyand: They did a big really international survey a few years back and 41% of girls, parents of girls never talk to their children about menstruation. So there are people who start their periods and no one ever even told them that was going to happen, let alone what would be expected in terms about much bleeding they’re having.

Dr. Ali Trainor: So if both patients and clinicians  may struggle to communicate during a menstrual history, maybe it will help to start with the basics here? What is heavy menstrual bleeding, exactly? 

Dr. Angela Weyand: Historically they defined heavy menstrual bleeding as more than 80 milliliters per cycle, but clearly no one’s measuring how much.

Dr. Ali Trainor: Umm yeah, I definitely don’t do that. I mean, it makes sense to have an exact definition for studies. But it seems so totally unreliable and impractical to measure menstrual losses in milliliters! 

Dr. Malcolm Munro: The National Institute of Care Excellence in the United Kingdom developed the definition that we use and that is bleeding of sufficient volume to adversely affect quality of life. And you can break that down into what part of quality of life or quality of life, sexual function, physical function, cognitive function, having to abstain from activities, et cetera. 

Dr. Ali Trainor: Yeah it seems so much easier to ask someone ‘hey, do you stay home from work the first day of your period’ rather than ‘hey, how many milliliters of blood loss do you have.’

Dr. Angela Weyand: So, I always start with open-ended just to kind of get a sense of what they think about it, and then I kind say, this is going to feel weird, but I just need to get a lot of information about how much you’re bleeding. I am just kind of interested to know what they think about their periods. And it really is fascinating because I would say at least half of the patients that I see who have really abnormal periods, if you just say, how are your periods? They’ll say, fine, normal, I’m not concerned. And then those are the same patients who then you find out they bleed for three weeks at a time and they just have no idea that that’s not what’s supposed to happen.

Dr. Ali Trainor: Wow, so much to learn from these opening ended questions. And then what are the specific questions that are the highest yield?

Dr. Angela Weyand: I think the biggest piece of advice I have for people is just you have to ask so many detailed questions because we have a lot of adolescents who change their products all the time because it grosses them out to see the blood. So if there’s any blood on the pad, they change it. So things that I typically get more concerned about are bleeding for more than seven days, having to change products more than every couple of hours. Other things that are concerning are clots that are bigger than the size of a quarter. If you’re having to change overnight having accidents or having a gushing sensation, which most people that have heavy bleeding, the second you say that they’re like, yes.

Dr. Ali Trainor: To summarize here, when taking a history for heavy menstrual bleeding we want to know if heavy flow is affecting a patient’s quality of life, and we should ask them this directly. It’s also helpful to ask the patient how they feel about their periods in their own words. Then, ask about more specific signs of heavy flow such as bleeding for more than 7 days, passing clots larger than a quarter, episodes of gushing or overnight accidents. 

Dr. Malcolm Munro: So what happens is women are given these ways of compensating, or the word we’re using is adapting. So they adapt to their loss by putting on these extra pads and all this sort of thing. So you have to also take that into account. No, it doesn’t adversely affect my quality of life because I wear a diaper.

Dr. Nick Villano: Right, also ask about adaptive behaviors like changing products every couple of hours or wearing extra products or protective padding. 

Dr. Ali Trainor: Okay, starting to feel like I have a better handle of how to take a menstrual history. So what did your patient say when you asked about her menstrual history? 

Dr. Nick Villano: So she definitely DID feel that her life was affected by her menstruation. She reported bleeding for 7 to 10 days per cycle with clots that were frequently dime sized and occasionally quarter sized. She had to change pads 5 to 6 times per day, but had no gushing or overnight accidents.

Dr. Ali Trainor: So we’ve established that she has iron deficiency, her menstrual bleeding definitely seems to be heavy, and she’s clearly symptomatic from both. And this has probably been going on for years! So seems like we should start treating her.

Dr. Nick Villano: Yeah, I agree with that! But Dr. Munro reminded me that I wasn’t quite done with my workup.

Dr. Malcolm Munro: Heavy menstrual bleeding is not a diagnosis…it’s a symptom just like headache and abdominal distension, et cetera. It’s not a diagnosis at all, just a symptom. 

Dr. Ali Trainor: So it’s not like heavy menstrual bleeding is this singular entity. It’s the manifestation of so many different things…bleeding issues, fibroids, cancers..

Dr. Angela Weyand: In adolescents, like the most common causes of heavy menstrual bleeding are anovulatory cycles and coagulopathy, versus structural causes that you would think of more in older adults where you worry more about things like malignancy or endometriosis, those sorts of anatomic things that you don’t see necessarily as much in adolescents.

Dr. Nick Villano: The differential for heavy menstrual bleeding is so important but also could be its own episode and is definitely more than we can get into here. But I did find one takeaway from our discussants particularly surprising.

Dr. Angela Weyand: I’m always kind of thinking about does this person have Von Willebrand’s disease? Does this person have another underlying bleeding disorder?

Dr. Malcolm Munro: And the next question then is, is that lifelong? Was that with you your whole life? If the answer to that is yes, then there’s a really good chance they a coagulopathy, a bleeding disorder. And if you look at Von Willebrand type 1, 2, 3, the whole von Willbrand spectrum, that’s about 13%. 13% of women with the symptom of heavy menstrual bleeding have von willbrand.

Dr. Ali Trainor: That is way more common than I thought. 

Dr. Nick Villano: Yeah, I know, right! And so basically, once we’ve diagnosed heavy menstrual bleeding, our job is not done. Something is causing that bleeding, usually something treatable! Finding it can mean one less person living with chronic fatigue, depression, and insomnia.

Dr. Ali Trainor: So did you get to the bottom of your patient’s heavy menstrual bleeding?

Dr. Nick Villano: Okay, so here’s what I learned. So she did have a history of heavy and irregular periods for most of her life. She didn’t really have any significant family history. Her coagulation tests and TSH were normal. She did actually report having had a low VWF once, but repeat testing was normal. She had a reassuring pelvic US. Ultimately she was referred to gynecology and had a levonorgestrel IUD placed with the presumption of an ovulatory disorder. 

Dr. Ali Trainor: Alright! I’m really looking forward to a happy end to this case. Did that help?

Dr. Nick Villano: Her heavy menstrual bleeding? Yes! Her periods stopped with the IUD in place and she was so happy. She was started on iron supplementation and her hemoglobin and ferritin improved. 

Dr. Ali Trainor: Thats amazing!

Dr. Nick Villano: Yeah, well don’t get too excited vs. but…her labs improved but  didn’t quite go to normal. And then they got worse again. 

Dr. Ali Trainor: Uh oh.

Dr. Nick Villano: She came back when I wasn’t in clinic to review that her ferritin was still in the 20s. My preceptor ended up sending her for a double endoscopy. And they found a 3cm nearly circumferential mass was seen in the ascending colon with signs of recent bleeding.

Dr. Ali Trainor: I’m shocked! So she had heavy menstrual bleeding, and now we find out that there was also a colon mass this whole time??

Dr. Nick Villano: It was such a surprise! Even more so when the pathology showed colonic adenocarcinoma. I mean, fortunately it was localized. She had a right hemi-colectomy with negative margins and did well.

Dr. Ali Trainor: I’m glad to hear that. But this is so uncomfortable to sit with. I mean this poor woman’s ordeal. And honestly, the biggest thing is how easy it would have been to miss this.

Dr. Nick Villano: I know. I was so relieved that my preceptor made the call to send her for the scope but I kept wondering if I would have done the same thing? And so for our third and final deep dive I want to ask when a premenopausal woman with iron deficiency should have endoscopic evaluation?

Deep Dive 3

Dr. Ali Trainor: Okay, if I have a patient who is older or who isn’t menstruating patient this feels like a no-brainer. New iron deficiency means you need an endoscopy and colonoscopy. But for younger patients with iron deficiency, I don’t really know at what point I would recommend a scope. And she had another cause, she had heavy menstrual bleeding!

Dr. Nick Villano: Exactly! Yeah, most people would agree that an older patient with new iron deficiency needs a scope. We’re worried about missing that cancer or polyp that could turn into cancer. But I was curious – when we do those scopes, how often do we FIND something? So Dr. Freed told me about this study from 2017. And it’s pretty compelling data. This study enrolled over 4,500 asymptomatic patient of all ages. Men and women with a hemoglobin of less than 9. So they all got an upper endoscopy and colonoscopy, and if those were unrevealing they then got a video capsule endoscopy. 

Dr. Jason Freed: When they did that, 89% of patients had a cause identified for their iron deficiency anemia, 89%. It’s crazy actually. And of the patients, 13% had cancer. So a big chunk had colorectal cancer, but also people had gastric cancer, esophageal cancer. So this dogma that you have to rule out GI cancers is totally right when you have unexplained iron deficiency anemia. Now, those aren’t the only important diagnoses to make. There were tons of other diagnoses that are important to make, right? There were a ton of people with colitis. There were a ton of people with stomach ulcers who needed treatment. There are tons of people who duodenal ulcers that needed treatment. There were a ton of people with celiac disease. Again, these are people who weren’t clinically suspected to have celiac disease.

Dr. Ali Trainor: Yeah! I guess I don’t really think about the fact that often, actually in this study MORE often, a GI evaluation for iron deficiency finds these other important things like colitis, ulcers, and celiac.

Dr. Nick Villano: Yeah, and remember these were iron deficient men and women of all ages with no GI symptoms. Premenopausal women were included, except for those with known heavy menstrual bleeding..

Dr. Ali Trainor: I guess the question we’re getting to is when should we refer patients with low iron and no GI symptoms? 

Dr. Nick Villano: So there are guidelines from the American Gastroenterological Association, and the first answer is that all adult men and postmenopausal women with new iron deficiency anemia of unclear cause deserve an endoscopy and colonoscopy.

Dr. Ali Trainor: I mean that makes sense. But I can already sense that premenopausal women are their own group for a reason.

Dr. Nick Villano: Good instinct. So let’s start with what most people agree on. Just like we said before, if a premenopausal woman has iron deficiency and GI symptoms then, yeah, a GI evaluation makes sense and that’s often going to include endoscopy and/or colonoscopy. But what if that premenopausal woman with low iron has no GI symptoms? Then what do we do?

Dr. Jason Freed: One thing I will say though, and the guidelines support this is even if you have heavy menstrual bleeding, it is worth checking young women for celiac disease serologically, right with a tTg-IgA antibody because celiac disease is much more common than we used to realize.

Dr. Ali Trainor: Okay so all iron deficient women deserve serologic testing for celiac and an evaluation for signs or symptoms of GI disease to see if further testing is needed. But if they don’t have GI symptoms, I’m still really struggling with who needs a scope. One on hand, menstrual bleeding is still the most common place they’re losing iron. But on the other hand, these GI pathologies can be really silent. So, I guess a question that might be helpful is understanding how common are things like colitis, ulcers, celiac, or even GI cancers in young women?

Dr. Nick Villano: That’s a great question and I found it was surprisingly hard to get an answer. There was a study from 2006 where about 250 asymptomatic premenopausal women with iron deficiency had endoscopies. About 6 to 7% of them had a relevant finding, with only 1 cancer. 

Dr. Ali Trainor: Okay, so we’re not seeing the 89% positive rate that the other study we talked about showed that included all age groups, but endoscopies are still making diagnoses in these women. And 1 of those 250 women had cancer! And I know that’s not a ton, but it’s not nothing. I mean, isn’t colorectal cancer getting more common in young people?

Dr. Nick Villano: Yeah, it seems to be but specific numbers are hard to find. One study quoted 0.1% risk of colorectal cancer in men and women under 50 years old. Another one that pooled 10 studies saw a 1% risk of GI malignancy in premenopausal women with iron deficiency. That’s a lot higher but this included those with GI symptoms, a higher risk group. So colorectal cancer is more common in young people than it used to be. But how common is it specifically in asymptomatic premenopausal women? Unclear.

Dr. Ali Trainor: I mean, if we scope every iron deficient woman without GI symptoms, that would be millions and millions of women. Costly, logistically challenging, and scopes aren’t harmless! Serious complications are rare but they do happen. So there isn’t a strong recommendation driven by data, but how do the experts advise us on which premenopausal women with iron deficiency should have a double endoscopy?

Dr. Nick Villano: So those American Gastroenterological Association guidelines do give us a conditional recommendation for upper and lower endoscopy in premenopausal women with iron deficiency anemia. This assumes that there is no other “unequivocal” cause of iron deficiency anemia. And I thought this was really interesting- they say that the “benefit of endoscopy in iron deficiency anemia quickly diminishes as age declines and therefore, the harms of endoscopy will eventually outweigh the benefits. But there is no reliable data were found that further defined this age threshold.”

Dr. Ali Trainor: Yeah, I understand where that guideline came from. But I am not sure how to best apply it. When does a cause of iron deficiency become the “unequivocal cause”? And at what age should we start recommending endoscopies?

Dr. Nick Villano: I think this is where it starts to get gray and you’re going to get different opinions here. But let’s see how our discussants approach this question.

Dr. Angela Weyand: You could stop their periods and give them IV iron and kind of see, right, at least do the things that you can do to try to tease this out. And then if oh, they’re miraculously better and they still haven’t gotten into see GI maybe they don’t end up needing to have to see GI. 

Dr. Jason Freed: I recommend it for women over age 40. For women between ages 30 and 40 I really usually would address their heavy menstrual bleeding first and replete their iron. And if they develop recurrent iron deficiency anemia after that, then I would certainly send them for a GI workup. 

Dr. Malcolm Munro: For young women, let’s say below 40 where the prevalence of colon cancer is extremely low, unless their Lynch syndrome or some other inherited high risk circumstance, then you’re really thinking they’re heavy menstrual bleeding. In that 10 years, that decade from 40 to menopause, you know, the incidence and the prevalence of cancer increase. 

Dr. Nick Villano: So, I like the idea of approaching this stepwise. Instead of putting pressure on just having an answer right now, you need some time to know if this woman has heavy menstrual bleeding and if treating this will improve or cure their iron deficiency. But that balance tips more towards scope at the age of 40 and beyond.

Dr. Ali Trainor: So, if I can summarize here. For men and postmenopausal women, new iron deficiency should be evaluated with double endoscopy to look for cancer but also things like colitis, ulcers, and celiac. In premenopausal women, we should always be evaluating for heavy menstrual bleeding as this is the most common cause of iron deficiency. And it’s also also worth sending celiac serologies. 

Dr. Nick Villano: And double endoscopy may be indicated if that woman has GI symptoms, if they don’t have heavy menstrual bleeding or another obvious cause of blood loos. Or if stopping the heavy menstrual bleeding doesn’t cure the iron deficiency. It should also be considered if they are 40 years or older, or if they have another factor that increases their risk of cancer like a genetic disorder or family history. 

Dr. Ali Trainor: So…how is your patient doing now?

Dr. Nick Villano: She’s doing well. She recovered well from surgery to remove her colon cancer and when I had last seen her, the IUD had stopped per periods. Her ferritin level is finally normal.

Dr. Ali Trainor: That’s amazing I’m glad to hear that. This poor woman has been on such a roller coaster ride. 

Dr. Nick Villano: Truly.

Dr. Ali TrainorI’ll start summarizing what we learned. In Deep Dive 1, we looked at different ferritin cutoffs. We said that a ferritin under 45 increases sensitivity when compared to a ferritin of 15. And ultimately checking whether iron deficiency improves with treatment after 2 weeks is a great way to confirm that your patient has true iron deficiency.

Dr. Jason Freed: Using time as a diagnostic test is such an important component of longitudinal care of patients in general, but it turns out to be extremely helpful in iron deficiency in a number of different ways. Both the example we talked about earlier, the time-limited trial of iron, seeing if it works, using that as a diagnostic test, but also looking for recurrence after you fully repleted someone as a way of finding occult blood loss that you might not have gone after upfront. And so I really think that doing this thoughtfully can really help you not excessively over treat and, you know, do a million things for everybody

Dr. Nick Villano: That reminds me how accepting that we may not know everything in the moment and appreciating time as a diagnostic tool is so undervalued. We also discussed that the evidence is much less clear for diagnosing iron deficiency with chronic inflammation and a ferritin cutoff of less than 100 or less than 300 with a TSAT of less than 20% is the current expert opinion.

Dr. Ali Trainor: In Deep Dive 2, we discussed that iron deficiency is common in women and often due to heavy menstrual bleeding. And specifically look for bleeding that lasts more than 7 days, changing products every few hours, passing clots larger than a quarter, episodes of gushing, accidents, or adaptive behaviors. I was amazed at just how common it is and how much it affects people’s lives!

Dr. Angela Weyand: Society has normalized suffering through your periods. Right? And so it’s like, oh, that’s just what happens. That’s what it takes to be a woman. Like what are you going to do? We would do something about that. I have patients who I’ve had such horrible periods, they drop out of school, they just stopped going to school, and you’re like, that shouldn’t ever happen. But it does.

Dr. Ali Trainor: This important to keep in mind and I think one of the biggest takeaways for me as a pulmonologist is I am often the one seeing these young healthy women in pulmonary clinic because they come to me for shortness of breath and routinely I check PFTs and send a CBC to look for anemia, but I don’t check iron studies, but after doing this episode I am definitely going to check iron studies going forward.

Dr. Nick Villano: It is so easy to get focused on what we “own” in medicine, to stay in our silo. But iron deficiency is a problem that really reaches across several specialties. 

Dr. Ali Trainor: I think everyone stepping up to own  or do their part in iron deficiency is a great goal to keep in mind.

Dr. Malcolm Munro: Again, I think most countries, maybe all countries have been saddled with this siloization, normalization, lack of awareness of impact. We just need to get everybody, as many people as we can under one tent to kind of become aware and then figure out how we deal with some of these questions like the ones you’re answering. 

Dr. Ali Trainor: And in deep dive three we reviewed that premenopausal women with iron deficiency deserve an evaluation for signs or symptoms of GI pathology, celiac testing, and consideration of endoscopy if a patient is over 40, has a risk factor for GI cancer, or if her iron deficiency persists once the heavy menstrual bleeding has been addressed. 

Dr. Nick Villano: And that is a wrap for today! 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! 

Dr. Ali Trainor: If you have a case you’d like to bring on air, please email us at hello@coreimpodcast.com. Thank you Dr. Jesse Powell for the awesome accompanying graphic on iron testing and reminder on how to take a good menstrual history! 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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