Great. Well, thank you, Dr. [INAUDIBLE]. As some of you guys are walking in, just a reminder-- this is a new format for grand rounds and really appreciate everyone being here, starting with that departmental conversation and then moving into medical grand rounds. Feedback from the first session from people listening in was that they couldn't hear the questions necessarily. So we do have mics placed now-- if you don't mind stepping up to ask a question at the mics, or we can try to pass them around as well. So it's an honor for us to have Dr. Michael Auerbach here with us today. Dr. Auerbach operates a very active clinical practice in Baltimore and is a Clinical Professor of Medicine at Georgetown University. He's originally from New York and did his HemOnc fellowship at Columbia University, staying on for a research fellowship in thrombosis and hemostasis. He then served on faculty at Mount Sinai before becoming the Chief of Hematology and Oncology at the Franklin Square Hospital in Baltimore and serving in that position for about 15 years before moving into private practice. Over the years, he's really become an expert in the field and has published widely, serving on the editorial board for the American Journal of Hematology and the Blood Transfusion journal. In particular, he's been at the forefront of investigation and management of iron deficiency. Now, as Dr. Auerbach described to me, this is not the sexiest disease topic, but it is incredibly impactful. And his work has been integral to our understanding of iron deficiency in a number of conditions and management options for it. So we're certainly very fortunate and excited to have him here to talk with us today about iron deficiency and its intricacies. So without further ado, please join me in welcoming Dr. Michael Auerbach. [APPLAUSE] Wow, this is a thrill for me. About 10 years ago, I was asked to write a review article for ferumoxytol. And I reviewed the literature, and one of the authors of the paper was Mitchell Rosner. And I wrote him an email, and he called me back, and I said, do you want to do this with me? And he said, sure. And we've had hundreds of correspondences back and forth, published three papers together. I've never met him, and I was disappointed that he had to be in London, but it's been a real privilege to interact with him. So I'm thrilled to be here. Let me just get past the-- these are my disclosures. I have research funding, and that's where it ends. So let me tell you what I'm going to tell you about today. This is going to be a polemic talk. Some of the things that I'm going to tell you violate current guidelines, which I think are in serious need of change. So I would like you to distinguish the need between oral and intravenous iron. And when we do that, you should become familiar with the formulations that are available in the United States. You should be able to differentiate-- this the most important thing-- differentiate the minor self-limited harmless infusion reaction from the vanishingly rare hypersensitivity that can lead to anaphylaxis. If you're going to give IV medicine, you have to know how to deal with anaphylaxis. I didn't say if you're going to give IV iron. If you're going to give any IV medicine, you have to be able to deal with anaphylaxis. It's very rare with intravenous iron. And then, I want to review evidence-based approaches to diseases-- things that you see all the time that I hope will motivate you to rethink the paradigm, the algorithm for the treatment of this disorder. Now, it's not sexy like lymphoma, myeloma, and leukemia, where headlines are being made every single day. But just to put it into perspective, it's 100 times more common than all cancer combined. We have 3 billion people on earth with iron deficiency. It's a big number. Sydenham first used iron filings in cold wine to treat the "green sickness" that was later called "chlorosis" by Blaud, who was the first person to use ferrous sulfate. It wasn't long after that that iron was used to treat war wounds in the Civil War. And today, it's the commonest micronutrient deficiency on the planet, affecting 35% of the world's population, more than 50% of gravidas. And I've already told you that it's 100 times more prevalent than cancer. Here we are, 300 years later, using the often ineffective, usually poorly tolerated oral ion as our frontline therapy. I see women around the room smiling. That's because you were pregnant, and you were given this drug, and it made you miserable. And no one cared. [LAUGHTER] These are the major causes. This is a world-class institution; I don't have to tell you what causes iron deficiency, but this is what you see. My colleagues, this is what you see every day, and these are the common causes. Bariatric surgery is one we're going to go over in a little bit of detail. The symptoms are vague. Fatigue-- a symptom of everything. But do you ask your patients if they chew ice? Do you ask them when they come in, do you chew ice? Pagophagia-- very common. 50% of iron-deficient patients have pagophagia, and another 50% have restless legs syndrome. If you don't think that's a big deal, talk to somebody with restless legs syndrome who can't keep their legs still, who aggravate their spouse because it won't stay still at night. Brittle integument-- you know about. I'll show you a couple of slides of that. Now, these are the tests that you order right now. But I only put this on here to show you the-- this is very fancy, this thing here. OK-- the CHr. The CHr is going to come off the auto analyzer. We just did a 790-sample cohort with parallel iron, TIBC, and ferritin, and it looks as if the CHr is going to tell you who needs iron, who was treated with iron, and who needs to be treated again. Imagine-- 40 seconds coming off with the CBC, as opposed to a day or two to get an iron, TIBC, and ferritin. To tell you the truth, I can't wait. The statistician has the data now. I sure hope it shows what I just told you. This is our standard, the total iron binding capacity. Because unfortunately, most of the patients who are iron deficient have something else going on, and the ferritin is a notorious acute phase reactant, as you will see in the cases that I show. By the way, these cases that I'm going to show you are real cases. They are not made up. OK, here's the brittle integument. These are very prominent koilonychia up here, but if you take a patient's hand and go up and down, you'll see the remnants of koilonychia if they've been iron deficient for a long time. Please examine the tongue. It'll give you a good idea how long it's been present. This is the tongue of a totally iron-deficient patient. Look, it looks like someone's sandpapered-- no papillae. And here's a woman with Osler-Weber-Rendu who had a tongue like that whose life was changed dramatically by frequent infusions of intravenous iron. Giving oral iron to these patients is cruel. It upsets the stomach. It has no chance of keeping up with the blood loss. So you're offering toxicity without benefit. And this is what the tongue looks like. And you can see the angiomas on the tongue. She's receiving bevacizumab now, as there's new data to suggest it'll actually decrease the bleeding. So now let's talk about who should get oral iron and who should get intravenous iron. And many of you are going to say, this guy is out to lunch, and how does he have the right to say that? So let's just-- I'll have evidence-based support for everything that I tell you today. Oral iron is almost free. You can buy it anywhere. It is readily available, and if tolerated, it works, unless you have one of the conditions where it's harmful or cannot work. And we'll get to those conditions, like bariatric surgery or inflammatory bowel disease. And if there are gastroenterologists in this room who think I'm being too polemic, we'll discuss that data as we get to the IBD patient. In the first trimester of pregnancy, there is no safety data with IV iron, so I recommend oral iron in iron-deficient first-trimester gravidas. Problem-- we don't screen our gravidas for iron deficiency. And in a prospective study that we will have on clintrials.gov next Wednesday, 100 prospective non-selected consecutive non-anemic gravidas-- 40% where iron deficient based on a low TSAT. The CRP goes up in pregnancy, so the ferritin goes up a little. The ferritin comes back down later, but based on TSAT, 40% were iron deficient. That means TSAT less than 19. In the second trimester of pregnancy-- and I'll show you why later-- if the hemoglobin is greater than 10, oral iron should be OK if tolerated. If it's less than 10, there is no credible expectation that you will get enough iron to the baby. We'll see why that makes a big deal in a few minutes. Adverse events, I think you're familiar with, but greater than 70% of the people who get oral iron report significant gastrointestinal perturbation, including metallic taste; nausea; gastric cramping; thick, green, tenacious stool, which you don't ask your patients about. And especially in pregnancy, where pregnant women who are already constipated due to the high progesterone levels that slow bowel transit and the enlarging uterus pressing posteriorly on the rectum, I think giving oral iron to these patients needs to be reconsidered strongly. Intravenous iron has an infusion reaction that occurs approximately 1% to 3% of the time. It is not formulation specific, but it does depend on the amount of labile free iron released by the individual formulations, and I'll show you a slide of that in a minute. It consists of pressure in the chest, arthralgias or myalgias, headache or flushing. It's harmless. It goes away in minutes without treatment. The way to handle it is to walk away. Take your own pulse. And then we usually premedicate with methylprednisolone based on its ability to block the arthralgias and myalgias the next day, which we've shown in a double-blind study. But methylprednisolone is not without side effects. Severe hypersensitivity is not IV iron specific. If you are going to give an intravenous formulation, you have to be prepared that that formulation can cause anaphylaxis. It's vanishingly rare with IV iron, probably less than 1 in a quarter of a million doses, which is less than most antibiotics. Fair? OK. These are the labile free iron releases-- using what's called the Ferrozine method of measuring iron release-- off of the formulation after an administration of the different drugs. And as you can see, iron gluconate and iron sucrose have the most because they have a much less complicated complex carbohydrate core, and they bind the elemental iron much less tightly. Low molecular weight iron dextran-- perfectly good iron-- binds it more tightly. And you can give a much larger dose, like a thousand milligrams in an hour, safely. I'll show you that data. But you have three new irons that I referred to as the Gucci irons because they sure are expensive, but they have these very complicated cores, and the elemental iron is released very slowly. And you can actually give a full replacement dose in 10 minutes. You went to medical school. You learned oral iron once or twice a day for 12 to 18 months. We can do it in 15 minutes. Take your pick. All right, now, a couple of things-- this man asked me not to blackout his eyes, so I didn't. This is a real reaction. I'm not going to tell you which formulation because they're equally common with all of them. This is a minor infusion reaction. He's flushed. You can see the anxiety. There's pressure in the chest. 3 minutes later-- this is a real photo; it's not doctored-- the reaction is gone. We gave him a steroid beforehand because of the information that I just showed you, and we gave him the planned dose of the agent that caused this. The folklore with intravenous iron, were you believe, were you learned that this is a dangerous drug when you went to medical school-- you may well have intervened with methylprednisolone or epinephrine, changing this harmless minor self-limited reaction into a hemodynamically significant serious adverse event, ostensibly blamed on the IV iron. And supporting what I just told you is this excellent algorithm in a paper by Rampton et al. in Haematologica, where basically, the management of these infusion reactions is precisely what I just told you-- to observe, monitor, fluids, steroids if necessary. But on the right-- severe hypersensitivity-- is what you would do for any drug that can cause severe hypersensitivity. I'm not here to teach medicine internists at the University of Virginia how to treat anaphylaxis. Notice, nowhere is Benadryl on this chart. You should not premedicate. Did you know that Benadryl causes hypotension, somnolence, tachycardia, and diaphoresis? Do you know that there's published evidence that in series of patients who were premedicated with Benadryl, the vast majority of reactions to intravenous iron were actually attributed to the Benadryl? Don't premedicate. These are not hypersensitivity reactions. Tryptase levels, which we've done on over 200 patients, are always normal. This is probably a mild complement activation, which is now referred to as CARPA, Complement Activation-Related Pseudo Allergy. It has not been proven in vitro, but do not intervene. Do not intervene with pressors or antihistamines in this patient population because you will change the reaction from something mild to something severe. So I'm going to tell you that oral iron should be proscribed in a variety of conditions-- proscribed. Here is a high-quality meta analysis in PLOS One a few years ago by Tolkien et al. looking at prospective studies of patients who had ferrous sulfate compared to placebo, or even intravenous iron. As you can see, all of the black boxes are to the right of the unity bar. And this is greater than 70% of patients who were given oral iron report significant gastrointestinal perturbation. Oh, I don't know how to go back, but-- the bottom button? All right, cool. None of the formulations have been shown to be better than ferrous sulfate. The newer, more expensive heme irons do not give you the same benefit with less toxicity. So far, none of the oral formulations has proven better tolerated than ferrous sulfate, with the exception of the timed-release irons or the irons that are coated with Colace, dioctyl sodium sulfosuccinate, which protects it from acidification in the stomach and the absorptive pathways. The drugs have been specifically proscribed by brand by the Textbook of Hematology, so if you're going to use Ferro-Sequals or one of the timed-release irons, you can give it to your patient twice a day, or just tell them to put it directly into the toilet; it'll do the same thing. OK, supporting what I told you about iron safety is this excellent meta analysis by Avni et al. from Anat Gafter-Gvili's group in Tel Aviv that was published in Mayo Clinic Proceedings of 103 trials of over 10,000 patients who received either oral iron, no iron, placebo, or-- shudder-- intramuscular iron. Just parenthetically, intramuscular iron is painful. It stains the buttock. It requires multiple injections. It's even been published to be associated with sarcomas. It shouldn't be given to anyone at any time for any reason anywhere, and otherwise, I have no opinion on it. [LAUGHTER] Overall, there was an increase in infusion reactions. There was. They're minor. I showed you. However, compared to any parameter including placebo-- hypersensitivity, cardiac, dermatologic, hemodynamic side effects-- no difference between intravenous iron, placebo, or oral iron in this very well done meta analysis published in Mayo Clinic Proceedings in 2015. Making it even more onerous is the now high-quality evidence just published in Lancet Hematology showing-- which mirrored the in vitro data of Moretti et al. published in Blood two years earlier-- that when we take oral iron, our hepcidin goes up, blocking our absorption of iron for the next 24 to 48 hours. And here is the clinical correlate of this showing, using radiolabeled iron, the difference between taking iron daily or twice daily for 14 days compared to alternate day. Now, we do not have outcomes on this. So you can't go out here and say, well, he said the new standard for oral iron is every other day. I think that will happen, but right now, until we have outcome data, I think it's a very reasonable consideration to take one tablet every other day, considering the litany of evidence supporting the poor tolerability of orally taken iron salts. Now, these are the formulations. The next two slides try to-- I'm going to use the brand name one time and one time only. Low molecular weight iron dextran is INFeD. It's called CosmoFer in Europe, and you can give a total dose infusion. I'll show you a gram in an hour in a second. Ferric gluconate and sucrose-- perfectly safe, effective formulations. I showed you the labile free iron after these. They're much, much higher. You can't give a big dose of this. It's five to seven visits to do what the other ions can do in one. Ferumoxytol can be given as a total dose infusion. It's approved for 510 milligrams twice. Ferumoxytol is Feraheme. Carboxymaltose is Injectafer in the United States, Ferinject in Europe. In Europe, they have a 500-milligram vial, so they give a gram all the time. We got stuck with a 750-milligram vial, and I don't know that there's any benefit of giving more than a gram. There's a recent prospective study of a thousand versus 1,500 milligrams-- at five weeks, showed a difference of 0.24 grams of hemoglobin, which is clinically insignificant for a drug that's very expensive. Iron isomaltoside, called Monofer-- cool name-- available only in Europe. Now, this is the FDA approval, and that's why I said we're going to talk about off-label usage and the best way to give it. The FDA approval for low molecular weight iron dextran is a hundred-milligram bolus given over two minutes. Countless studies have shown a thousand or more milligrams given in an hour to four hours. I never give it the way it's approved. It's a ridiculous way to give it-- 10 visits instead of one, with no safety or efficacy advantage, 10 times the chance for an extravasation. You ever see an iron extravasation? Tattoo-- it doesn't go away. 10 times the chance for an infusion reaction-- ridiculous. The reason is the company that markets this drug in the United States is really not terribly interested in it, and they haven't pushed to get the approval. Ferumoxytal is approved at 510 milligrams in 15 minutes. The problem is this drug came out with a 17-second label. I showed you the labile free iron. That was a dumb idea-- way too much free iron The drug got-- it was believed to be dangerous. It was just a bunch of minor infusion reactions. They just got a broad label now, but the 17 seconds to 15 minutes was an overreaction. The first 90 doses we gave of this drug-- three episodes of hypotension. Patients were all fine. They did well. There were no hospitalizations. But if you make three out of 90 patients hypotensive, they will shut you down. We've given thousands of doses over three to five minutes-- no problem. We've proven, we've published that you can give 1,020 milligrams in 15 minutes. That's the best way to give it. Get insurance approval. In Baltimore, the Blues, Cigna, MedStar Family Choice say yes. Medicare says no. If they say no, don't do it; it's expensive. But if you give it as a double dose in 15 minutes, you're saving the cost of the second visit. I've already told you about ferric carboxymaltose. A gram in 15 minutes in Europe is standard. This drug's a rock star in Europe. In the United States, it's becoming less popular. It's associated with hypophosphatemia. The clinical significance of that is unclear. And this new drug, Monofer-- you can give 2 grams in an hour. However, whether or not there's any reason to give 2 grams is not clear. So I told you about a gram in an hour. We did this. It's 1,288 infusions in 888 patients in my practice who received a gram of low molecular weight iron dextran in one hour. And here you see the change-- the mean hemoglobin change greater than a gram in 51% and greater than 2 grams in 26%. And these were at four weeks. One patient of the 888 was transfused because of severe angiodysplasia. So now, I'm going to take you-- by the way, I didn't show you the safety data. There were no serious adverse events in the 1,288 infusions. We had about a 2% to 3% incidence of minor infusion reactions, consistent with what one would expect with intravenous iron. So let's go through five cases. We don't have electric stuff, so you keep the answer in your own head, and we'll see what I come up with as an answer at the end. So our first patient, a 58-year-old-- this real-- exercise enthusiast who overstretched. Had a tear of the obturator internus-- abductor of the hip-- big hematoma, got infected, very sick. IV antibiotics-- got better. Hemoglobin 9, MCV 83, ferritin 34. What's ferritin 34? Normal. TSAT 8. Her initial therapy should be oral ion daily; oral iron every other day; oral iron ferrous sulfate if tolerated, followed by IV iron; IV iron up front; B12 and folate. So now let's talk about who she is. We don't have that toy. I use these slides for the American Society of Hematology Consultative Hematology course that I'm going to do in December. So I think most of you know this, but let's take a second. Iron is regulated. The absorption and utilization of iron is regulated by the hepatic-synthesized protein hepcidin, which is genetically regulated. Its absence is hemochromatosis. Hepcidin, when elevated, after iron gets into the cell, inactivates ferroportin-- the only known iron export protein in humans. So it blocks absorption, and in the macrophage, highly expressed with ferroportin. The macrophage release of iron is inhibited by the elevated hepcidin. After an infected hematoma, you can be sure that this gal's hepcidin was very high. Now, there's no in vitro data for this, but this is not from me. I didn't make this up. This is from Clara Camaschella-- one of the world's leaders in iron biology from Milan in Italy, who actually gave the Ham-Wasserman lecture at ASH, the very prestigious lecture-- and told me that when we give IV iron-- and we don't know how much goes onto transferrin during the life of the iron in blood. It saturates transferrin immediately. You can't even measure TSAT for three to four weeks after you give IV iron because of interference by the intravenous iron. The macrophages pick up what they can pick up. Nancy Andrews-- who just stepped down as Dean of Duke University, who was at Harvard at the time-- elucidated an enormous amount of this activity, said that macrophages can carry about 600 milligrams. Remember, these macrophages are blocked by hepcidin interference with ferroportin, but when iron itself gets into the cell, it upregulates the synthesis of iron regulatory proteins 1 and 2, which I had not heard of until I had spoken to Clara on this day. And these proteins in turn re-upregulate ferroportin, getting past some of the hepcidin block. This does not occur with oral iron because its absorption is inhibited, and it's quantitatively insignificant to make this happen. And consistent with what I just told you-- without in vitro evidence to support what I said-- is the huge decrement in erythropoiesis-stimulating agent usage seen in chemotherapy-induced anemia and anemia in dialysis that you were able to achieve with the use of intravenous and not oral iron to synergize with erythropoiesis-stimulating agents. So the answer is IV iron upfront. There's no reason to subject this woman to the gastrointestinal perturbation. Where she has active inflammation is unlikely to get maximum benefit from oral iron. She received 510 milligrams of ferumoxytol on two occasions, and her hemoglobin was back to 13 four weeks later. Yeah, by the way, in this case, any one of-- I'm not selling ferumoxytol here. Low molecular weight iron dextran, ferric carboxymaltose, or if you were in Europe, iron isomaltoside are fine. There's no reason to subject someone like her to five to seven doses of iron sucrose and ferric gluconate when you can do it in one. OK, next, chemotherapy-induced anemia-- we sure see a bunch of that in hematology and oncology. Please note, this is a real case. In a patient with metastatic colon cancer to the liver, anemia developed during treatment. The hemoglobin was 8.8, the MCV 94. The retics were normal. The ferritin was 1,186. Hemochromatosis. TSAT was 7. B12 was normal. LDH-- slightly elevated. Intervention should be ferrous sulfate every other day, IV iron now, IV iron plus an ESA, blood transfusion, or psychiatry consult to assist with the fatigue? OK, this is a very well done meta analysis by Gafter-Gvili from Tel Aviv published in Acta Oncologica. There are now 14 papers that support this. When IV iron is added to the treatment paradigm of chemotherapy-induced anemia, there is a ubiquitous increment in improvement time to target and decrement in ESA usage. There are now 14-- it is uncontradicted data. If there is anyone in this audience in HemOnc who remembers the Steensma paper that said intravenous iron was not beneficial and was associated with more side effects, that paper was redacted at the following ASH by David Steensma, the author-- an extremely reputable scientist, now at Harvard-- who took the intention-to-treat population, where the data came out, and switched it to the per-protocol population. And when those patients who received 80% or more of the planned dose were looked at, they had the same benefit that all of the other studies show. So there is no contradictory data. And here you see need for a blood transfusion, which actually, did you know that's what the indication for ESAs is? A decrement in blood transfusion-- it's not improvement of quality of life. It's not improvement in energy. It's decreased transfusion. If you can see, when IV iron is added to the paradigm of erythropoiesis-stimulating agents, there is a statistically significant decrease in blood transfusion. Now, I'm showing you this because it's my-- I did the first study on this. It was published in the JCO in 2004. It's my data. It's easier to show than other people's data, but they're all the same. As you can see, ESAs alone work a little bit. You get a small benefit from oral iron, assuming it's tolerated. But the bang for the buck, irrespective of how the iron is given-- by bolus or total dose infusion-- comes with the intravenous iron. And as you can see here, this is the percentage of patients who reach a peak hemoglobin of 12 or more or a hemoglobin increase of greater than 2 grams, which we refer to as hematopoietic response. In a Cochrane systemic review just published in the Cochrane Database, the addition of IV iron to ESAs was said to offer a superior hematopoietic response. The risk of RBC transfusions is reduced-- ubiquitously associated with worse cancer outcomes in any study. Now, may not be cause and effect, but transfusion is clearly something you would like to avoid in oncology patients. Hemoglobin levels are improved, and it was well tolerated. The answer here is this is severe iron restricted erythropoiesis. You're not going to fix this person with IV iron alone because they have chemotherapy-induced anemia as well. So intravenous iron should be added upfront to the use of erythropoiesis-stimulating agents. You'll get to your target much sooner. You won't have the gastrointestinal misery associated in a group of people who are already being given medicines that significantly alter GI side effects. In this case, oral iron would be unable to bypass the iron restricted erythropoiesis that I showed you with the high ferritin and low TSAT. And any of the formulations are fine. Because these are patients who are coming frequently, you use the one you're most comfortable with here, but an adequate dose should be given. Moving on-- inflammatory bowel disease is tough because the European guidelines are different than the American guidelines. This is a 38-year-old man with well-controlled Crohn's who presents with a hemoglobin of 12, MCV of 79, restless legs interfering with sleep on a nightly basis, chewing ice all the time. Everything else-- normal. Ferritin's 11, TSAT-- 14. There's no visible bleeding for months, and you should recommend oral iron daily, every other day, IV iron alone, IV iron plus an ESA, or probiotics? And let's get past this. In patients with IBD, oral ion has been associated with severe side effects, pathological worsening of the IBD itself. What's that wonderful word you taught me? Dysbiosis. What? Dysbiosis. I'll show you that data in a second-- and has limited efficacy. In my opinion, giving oral iron to a patient with inflammatory bowel disease borders on cruel. It offers side effects with minimal benefit. There is a small number of individuals who may be able to benefit for a short period of time, but they're going to have to take it for months and months and months instead of 15 to 60 minutes for a complete course. In a high quality paper in Gut, the prestigious gastroenterology journal, Lee et al. show that the use of oral iron is associated with negative growth of bacteria, altering the gastrointestinal microbiota in a negative fashion and suggested that intravenous iron may have specific benefit in this patient population. In Europe, intravenous iron is frontline therapy for patients with inflammatory bowel disease. And frankly, I think it should be frontline therapy for anybody with significant gastrointestinal disease, such as ulcer, esophagitis, gastritis, or anything else that will negatively impact the gut. Here is one of multiple studies in inflammatory bowel disease showing the clear benefit of intravenous iron at any point along the study period without any of the gastrointestinal perturbation of oral iron. And what's more, adherence is 100%. Once you get IV iron, you can't give it back. So the answer's IV iron alone. This is pure uncomplicated iron deficiency-- TSAT low, ferritin low. There is no reason to subject this person to oral iron at any dose, and there's no reason to subject this patient to iron sucrose or ferric gluconate. Any one of the formulations you want to use, where you can give a total dose infusion in one 15- to 60-minute visit would be preferable and the most efficacious means of-- and felicitous means-- of treating this miserable disorder in patients with inflammatory bowel disease. These folks are sick. I don't have to tell anybody here who's not a gastroenterologist how miserable it is to have inflammatory bowel disease. Another area where I'm extremely hopeful we will be able to get the guidelines changed-- we're doing a prospective double-blind, double-dummy study of oral vs. Intravenous iron in bariatric surgery. You know what double dummy-- you know what double-- everyone gets an IV. Everyone gets a pill. One's fake. So here's a 42-year-old woman with a BMI of 46. 18 months after a Roux-en-Y came down 146 pounds, now has a BMI of 26. Fatigue and restless legs syndrome-- major complaint. Oral iron was recommended. The American Bariatric Association guideline-- oral iron was recommended. Fatigue increased, the hemoglobin was 12, MCV 81, GI side effects were reported. Retics, liver, renal function-- normal. Ferritin 96, TSAT 4. You should discontinue the oral iron, increase it to twice daily, increase iron-containing foods, give IV iron, or revise the Roux-en-Y? Now, this marvelous little cartoon was given to me by Jerry Spivak, the former chief of hematology at Johns Hopkins. In us, oral-- any iron needs to be conjugated in the presence of gastric acid, the vitamin C, amino acids, and sugars to protect it from the massive alkaline rush that occurs in the proximal duodenum from pancreatic secretions that are necessary for digestion. Absent that, the iron gets converted to ferric hydroxide-- which you know better as rust-- and will not be absorbed when it gets to the distal duodenum or proximal jejunum and will end up in stool. Oh, I hate when this happens. What did I do wrong? Battery. Battery? All right, so do I have an alternative? The alternative is just to have this there. What do I press? [INAUDIBLE] That one? Help me. [INAUDIBLE] an alert came up, I guess. OK? So what do I do? Yeah, this works now. This works now? Cool. And supporting what I just told you, more than 75% of bariatric patients-- most of whom were supplemented with oral iron-- had significant iron deficiency anemia by five years. Now, you may say, well, what's-- these folks really need to not be iron deficient. They have continued exercise requirements, continued dietary requirements. They went through a life changing procedure because of obesity, and they can't be walking around exhausted due to iron deficiency because the current recommendations are to take a useless medication. This slide's really busy, but just look at the colors. The red is IV. The turquoise is oral. And the green are the differences. There is no credible expectation that you can come close to achieving what you get with intravenous iron. And this data, this group of studies, is absolutely consistent with the curves that I showed you that are uncontradicted in the gastroenterology literature. So the answer here is IV iron. This person has absolute iron deficiency. The ferritin of 96 is because bariatric surgery is associated with elevated hepcidin levels. Ferrous sulfate's unabsorbed due to its inability to be conjugated. The current guidelines of the American Bariatric Association recommend oral iron as frontline therapy, and the preponderance of published evidence suggests that the guidelines are in need of revisiting. Once again, any one of the irons that you can give as a single infusion on one day-- by the way, I heard that you all take care of a lot of underserved populations. In this institutions, where patients have to come at considerable expense and it's difficult to get here, there's just no reason to subject patients like that to iron sucrose or ferric gluconate, when you have three other choices where you can completely correct them in 15 minutes. Now, pregnancy-- this one is-- are there any OB/GYNs here? No. OK. I asked that they do, but didn't happen. 24-year-old gravida 2, para 1 presents in the second week of pregnancy. Violating the guidelines of the United States Preventative Services Task Force that says there is insufficient evidence to recommend routine screening-- I think that the conclusions of that task force need to be revisited. In my opinion, insufficient evidence means they didn't read the neonatal literature, which I'm about to show you. An iron panel was ordered. You don't get an iron panel when you go to your gynecologist, your obstetrician and say you're pregnant. You get a CBC. If you're not anemic, they don't check your iron. I'll show you why that's not a good idea. TSAT's 7. Ferritin's 38, consistent with the elevated CRP that you see in pregnancy. And menses were normal when not pregnant. You should now recommend-- ignore the TSAT and repeat in eight weeks, one ferrous sulfate every other day with repeat labs at 14, ferrous sulfate twice daily, IV iron with follow up at week 30 to 33, or large amounts of organ meat-- one of my ubiquitous silly answer. So the guidelines differ, and wait till you see how much they differ. I've already told you what the United States Preventative Services Task Force said. American College of Obstetrics and Gynecology Bulletin says-- their guidelines-- intravenous iron is recommended in the rare patient who cannot tolerate or will not take oral iron, with the caveat that if you have severe malabsorption, you may benefit from intravenous iron. I'm sorry to be this polemic, but if rare means 70%, we need to redefine rare. The United Kingdom says that parenteral iron should be used from the second trimester onward during the postpartum period with confirmed ID who fail to respond to or are intolerant of oral iron. And a marvelous paper by Achebe from Harvard and Gafter-Gvili from Israel, "How I Treat Iron Deficiency in Pregnancy." They recommend that intravenous and not oral iron be given in the second trimester if the hemoglobin is 10 or less and any time in the third trimester because there's no credible expectation that you will get iron to the baby. And I'll show you why that's essential. In the first trimester, iron need is about the same as in the non-gravid state, but when you get to the second and third trimester-- pregnancy's common; it's a good bit of it-- it goes up six- to eight-fold. You absorb 10% of the iron that you swallow. There's no credible expectation that you will get anything close to that with oral iron, especially when 70% of pregnant women, already constipated because of the high progesterone levels, will report significant problems with it. It is not unusual for one of my patients-- we treated 4,000 pregnant women with IV iron now without a single serious adverse event-- and it's not rare for a woman to cry when told she doesn't have to take the iron pills anymore. Remember, they think they're protecting their babies, which is what they're doing. It's a big difference. So maternal iron deficiency is a big deal. It's not just fatigue and constipation. It affects fetal, neonatal, and childhood brain growth and development with adverse effects on myelination, neurotransmitters, and brain programming. And children born iron deficient-- referred to in the pediatric literature as formerly iron deficient-- even after repletion, demonstrate lower cognitive function, memory, and motor development that's recognizable with neurophysiologic correlates of cognition and concentration up to age 19. This is high quality evidence in the neonatal literature. Iron deficiency in pregnancy has been associated with an increased risk of adverse events-- and you notice I said iron deficiency not iron deficiency anemia-- including preterm birth, double; low birth weight, triple; and small for gestational age infants, triple. When the mother's ferritin is low, almost none gets to the baby. Why? In a 2,400 prospective urban iron deficient pregnant population who were repleted with oral iron, a significant number of the mothers had improvements in their hemoglobin and iron parameters. And yet, 45% of the babies were born iron deficient. We don't screen babies in this country. Now this is going to-- this is like sour grapes. We screen for phenylketonuria-- 1 in 250,000. But we don't screen for iron deficiency, which is 1 in 2. Iron deficiency at birth is not a good idea. You can give oral iron. We've talked about the GI distress. And in a study of adverse events, an adherence of three different ferrous sulfate regimens, the authors concluded that the incidence of gastrointestinal side effects was unacceptably high. This is not my data. And numerous publications report the safety and efficacy of IV iron and pregnancy. But none of it has the highest level of safety for FDA. And excessive fears of anaphylaxis keep it from being used. This was the first prospective study ever done in the United States. It was my study. I couldn't have a comparator arm. Because the FDA required oral iron intolerance. So it would have been unethical. But look at the p values for hemoglobin. Four zeros and a one. And for iron parameter, it's five zeros and a one. There's no credible expectation this could have achieved with iron pills. So ferrous sulfate every other day is the right answer. There's no safety data in the first trimester. I told you that. But after the first trimester, you recheck the iron, and if still iron deficient, the woman should receive-- the mother should receive intravenous iron to protect the fetus from being born-- the maturing baby from being born iron deficient. Low serum ferritin is associated with restless legs. If you have restless legs, in this audience, you know what I'm talking about. It's miserable. Oral iron reduces it when the ferritin is less than 75 but doesn't get rid of it. And when compared to intravenous iron, it's markedly inferior. The prevalence is high. 50% of iron deficient patients have restless legs. We usually don't ask. And this was an epidemiologic study in my practice. And as you can see, a huge number of patients report a significant benefit-- a significant distress to where it markedly impairs performance. And the frequency is very high. And the sufferer reports moderate to extreme distress. And we don't ask this question of this extremely common problem. And you can see the huge number of patients that achieve the complete remission or very much improved. And only 30% reported no change. So now this has nothing to do with anything we see. I like to end with this. We don't see patients that go up on mountains, very often. But this data is so cool and so high quality, I like to show it. Because it's amazing. Mountain sickness is caused by hypoxia. And it's highly related to iron through the hypoxia-inducible factor link. The Lake Louise score is the standard for measuring the severity of mountain sickness. And you can see, compared to placebo, IV iron markedly improved the symptoms of patients going up to 15,000 feet or more. And supporting this paper in the Journal of Clinical Investigation, two years ago, [INAUDIBLE] et al subjected patients to isocarbic hypoxia chambers for six hours and measured pulmonary artery pressures before and after intravenous iron, and in both iron deficient and iron replete patients. And you can see how much the IV iron abated the increase in pulmonary artery pressure. So who knows? Maybe going up to a mountain at 15,000 feet, we should recommend IV iron beforehand. I just think this is gorgeous data in a marvelous journal. So what have I just told you? I think the results support that a single infusion of a gram of IV iron across a host of conditions associated with iron lac should probably be a new paradigm for the management of this incredibly common problem. I think oral iron should be proscribed in inflammatory bowel disease in pregnancy if the hemoglobin is less than 10 in the second trimester or any time in the third. And all risk newborns should be screened. And those are babies of diabetic mothers, smokers, mothers who are iron deficient or anemic. And they should be screened at birth and treated. Sunny Juul, the Chairman of Neonatology at the University of Washington gives intravenous iron to her preemies. Little doses of iron. So today, conclusions. Oral iron's frontline. It's frontline. And you should use it in those circumstances where you don't have significant comorbidity, and it's well tolerated. For heavy uterine bleeding, late pregnancy, IBD, chemotherapy induced anemias, or other comorbid conditions such as gastric bypass, Osler-Weber-Rendu, which is hereditary hemorrhagic telangiectasia, or any oral intolerance, the intravenous route is preferred and should be moved to frontline. And the preponderance of the published pediatric and neonatal data suggests that the recommendations of the United States preventative Services Task Force need to be revisited. Four formulations in the world, three in the United States allow a complete infusion in 15 to 60 minutes. And intravenous iron is much safer than most physicians realize, and should be moved forward in the treatment paradigm for iron deficiency and anemia. Thanks a million. It was a privilege to be here. [APPLAUSE] Thank you so much for the talk. We'll take some questions, if you don't mind coming up to the microphones. Or otherwise, we can pass them around. I forgot to mention the preamble. But Dr. Auerbach has literally written the up-to-date guidelines on this topic. So let's pepper him with some questions. Mark, I'll get you next. [INAUDIBLE] from those guidelines. But two questions about the black box warning. Yes, sir. [INAUDIBLE] So first, [INAUDIBLE] people who get the test dose have a risk of anaphylaxis. And I think you alluded to this. But do you think that's just a question of how the test dose is protocolized? No. I think it only occurs with the test dose. Because if it occurs, it occurs in the first few minutes. The KDIGO guidelines actually say there is no physiologic reason to monitor a patient for 30 minutes after IV iron is given. The reason that that black box warning is there, and it's not present in Europe, is that the company has done nothing to try to get rid of it. The infusion reaction incidence is the same across the formulations. And it's really unfair that it has it. But unless someone is going to go to FDA and say, remove it, they're not going to take it off voluntarily. OK. I guess my question was, did they observe people who got the test dose and tolerated it, and then subsequently had anaphylaxis? Or do you think that's what-- It almost never happens, almost never. It's so rare for that to happen. It occurs with the test dose usually within minutes. And it may have been other infusion reactions. Other than that, it's an infusion reaction. And in my opinion, the administration of epinephrine or diphenhydramine, which converts this reaction, is responsible for the overwhelming majority of ostensible serious adverse events attributed to iron. My second question is, there's a comment about ACE inhibitors increasing the risk. I'm not aware of that. I don't know. OK, thanks. I don't know. All right, you had a question, sir. I just wanted to find out whether there are certain situations, like inflammation, that having low iron and being [INAUDIBLE] with anemic might be helpful and whether giving iron might be [INAUDIBLE] and some of the same [INAUDIBLE]. Well, it's a marvelous question. It's asked all the time. But you've only seen it recently. Because if you remember-- [INAUDIBLE] Yes. In other words, when there's inflammation or infection, is it good to be iron deficient? And in the huge number of dialysis patient, millions and millions of doses, there was no increase in infection. There was no increase in morbid events. And IV iron had no relationship to the incidence of infection. But catheters and numbers of manipulation did. But what happened in the last few years, you all went to a bundled paradigm for payment. And the use of erythropoietin went way down. And the use of intravenous iron went way up. And it's now considered that the dialysis community was giving too much IV iron. And there was an increase in infections. And as a result, they cut down the ferritin from 800 to 500 and the TSAT down to less than 40. So up until the point where this occurred in millions and millions and millions of doses of intravenous iron, there was no evidence of increased infection. In actively infected patients, there is a conjecture, based on physiology of bacterial growth, that IV iron may be necessary for the bacteria. And although there has been no outcome data to suggest, we recommend that IV iron, or for that matter, oral ion, not be given to actively infected patients until the infection is at least chilled with appropriate therapy. So it's a marvelous question. But I think it's only the result of what happened as a result of bundling. Yes, sir. You mentioned CARPA. And CARPA has been traced to the surface charge of the nanoparticles. So the question that I have is, are these particles different in terms of their surface charge? Is there a chance to reduce the side effects further by keeping them neutral and not strongly negative, as ferumoxytol [INAUDIBLE]? Ferumoxytol and ferric carboxymaltose and iron isomaltoside. It seems the infusion reactions are reduced. But they still occur. And I think once the elemental iron gets off of the carbohydrate core, it has the potential to generate this reaction. And quantitatively, the studies are not done. So maybe that is not CARPA. Because CARPA happens, for instance, with negatively charged liposomes. Well, I can't answer you. It's a published-- the CARPA data has been extensively published with intravenous iron. And I don't know if there is adequate in vitro data to support it. But as a result of your question, I'm going to call Ian MacDougall on Monday and ask him whether or not it's a negatively charged ion that may be responsible for CARPA. So it's on the nanoparticle. There's a surface that is negatively charged of a nanoparticle that will activate complement. And I don't know what the charges are on the carbohydrate cores of the carriers. So, because ferumoxytol carries a negatively charged polymer. OK. And it's very rare for ferumoxytol to cause an infusion reaction. OK. Thank you. OK. Unless given to fast, like 17 seconds. Are there any other questions? OK. [INAUDIBLE] I appreciate the lecture from nephrologists. We've been using virtually only [AUDIO OUT] ever. One of the reasons I haven't given the 1,000 milligram dose is not because I don't think it's tolerated, it's because I wonder whether you can utilize all that iron. I know it's, again, [INAUDIBLE]. I purposely have been spacing them out for at least a week to give the 500 a week apart. Because maybe it works better. Well, I think your point is extremely well taken. But up to a gram, I think there's a fair amount of prospective clinical evidence that a gram's a great dose. When you go higher than a gram, it looks as if we don't utilize it. And you may be right about 500 versus 1,000. I mean, didn't you say that the macrophage can handle 600? It seems like you're going to saturate your particular [INAUDIBLE] system. Correct. But you get 600 in the macrophages. Then we have no in vitro data, so far, to tell you how many milligrams of the injected iron gets put onto transferrin, delivered to the transferrin receptor, used for erythropoiesis, over the lifespan of iron in circulation. And I have actually gone to Tom Ganz and Clara Camaschella and Fleming at Harvard to ask them, aren't you interested in this? And frankly, the answer is, no. They're much busier trying to define the pathway from the time you swallow iron until it gets onto the heme molecule. And that's where their interest lies. But it sure would be nice to know how many milligrams. But I think the study that was just done, the [INAUDIBLE] study, 1,000 vs. 1,500 of iron measured as a secondary outcome at five weeks-- 0.24 gram difference. Right. So clearly, more and more is not better where they're dividing the dose. So would 500 twice have been even better? Maybe. Because at least with the symptoms and the hemoglobin rise, you get most of the action out of the first 500 milligrams. So the patients feel better. I tell them, just filling the tank. [INAUDIBLE] I think you're right. I'd love to know the right number before this career is over. OK. Oh, another question. OK. I take care of CF patients. And the sickest patients have chronic infections. And they come frequently in the hospital with frequent exacerbations. And iron deficiency is very prevalent in that population. Their hepcidin is very high. So they don't absorb any oral iron. And you said that IV iron is contraindicated in that situation. Because I think-- Oh, no, no. --or you don't want to give it. Yes. I'm sorry. I said, in the actively infected patient, until you have them on appropriate therapy, I think you shouldn't give iron. Once you have them treated, I think they're fine. Yeah. But these are patients who come in, like, three or four times on IVs every two weeks. So they are chronically actively infected. So what do you think about them? I think you need to be careful. [LAUGHTER] I mean, I don't know. But that would be a marvelous study to do. That would be a marvelous study to do to see whether or not the treatment of your cystic fibrosis patients exacerbated or improved the clinical scenario. It's a marvelous question. Should do that study. Are we done? Yeah. Pretty much. All right. It was a pleasure. [APPLAUSE]