Chapters Transcript Video Anemia In Patients This talk will be about anemia. I'm one of the hematologist at U CS F. My main focus is bleeding and clotting disorders. But you know, I do see uh patients who are sent in as new referrals for anemia both in Mission Bay in Oakland. So as you all know, anemia is a very broad topic and there is only so much we can talk about in an hour. So I'll try to focus on the main um you know, kinds of anemia that you guys see in your primary care setting. Um who are the patients and that one major part being iron deficient anemia. So we'll spend a lot of time talking about iron deficiency anemia. You know, the common causes how to treat it and when are the times that you need oral versus IV iron? And when you should absolutely refer a patient to hematologist and then we'll spend some more time talking about the other common not so common types of anemia. And um I don't think I'll have time to go into hemoglobinopathy and those kinds of anemia, but hopefully we'll have someone talking to you guys about that in the future. Ok. So before we go on to anemia, I just wanted to briefly talk about, you know, the red cells and their morphology in general. Uh the normal mature looking red blood cells are biconcave sheet and you know, they have a one third of the central part or the diameter is central pallor. So if you have more than one third central pallor, that kind of means um that this is abnormal and these patients may have anemia. Normally speaking, these red cells mature over time. So in newborns, um these red blood cells have larger volume and lower hemoglobin concentration um as compared to adults. So um that means they have larger M CV when they're born and as they grow, this M CV, kind of goes down at least until six months of age and then it starts going um up. Again, normal lifespan of these red cells is usually around 120 days. But again, in newborns, it's uh shorter. So in term newborns, it might be around 60 to 70 days and it's even shorter in preterm, somewhere around 35 to 50 days. Now, these are the normal values of hemoglobin and M CV. Um that we noticed at different age. Um this is kind of uh you know, formula that we all are aware of that we use to calculate the normal M CV for age. Um But as you see in the stable until this is going on from six months to age until they are adolescent to adults. And as you can see, the main hemoglobin kind of keeps going up um as the age, you know, increases and the M CV also kind of goes up. And the reason I mentioned this from six months to 19 years of age is because newborns, as we mentioned, will usually have a higher M CV and lower hemoglobin as compared to, you know, um six months old or adults. Now, moving on to anemia. Now, the definition of anemia is really the reduction in red blood cell mass or the amount of hemoglobin. Usually, um we define as hemoglobin or red blood cell mass less than 2.5 standard deviation for that age and uh sex-based reference range. Previously, it was considered that there are differences based on race too. So it was previously considered that, you know, African Americans or blacks have lower hemoglobin as compared to whites. But nowadays, we think that this is all a social construct. So there is there should really not be any difference in hemoglobin for a patient who's self identified as African American versus um Caucasian. So really going forward, we don't expect any difference based on race. And really these differences for hemoglobin might be based on the age and their sex. Now, there is another definition for anemia too, which is physiological um definition with what we mean by that is if the hemoglobin is too low to meet your cellular demands, that is also considered anemia. So for instance, a two month old premature infant who has a hemoglobin of 7.5 that might be normal for his age. But a two year old with cyanotic heart disease, who has more oxygen demands in general for them, even hemoglobin of 13 might be abnormal just because they have more oxygen needs and more cellular needs. So, you know, ultimately all this to say these hemoglobin ranges might depend from patient to patient and vary based on their needs. Now, there is also a physiological anemia of infancy as you all are very well aware of. So, you know, as, as and when babies are born, they have hemoglobin. Um and as soon as they're born, their oxygen demand keeps going down. And because of that, the epo um demand goes down because of less epo, they are making less and less of this hemoglobin and they kind of reach their need right around the time of 2 to 3 months of age. So at that time, you can expect hemoglobin in the lower range, maybe around 9 to 12. And this is more profound and can be seen earlier than this two or three months of age in preterm infants. So, in preterm, this physiological anemia may happen somewhere around 4 to 6 weeks of age and that's usually considered normal. And this hemoglobin should keep come start coming up as they uh you know, develop. And um the age, the difference would be where you would consider that this is more like pathologic and this might just not be physiological anemia is if they also show some signs of hemolysis. So if there is a baby, two or three months old, who has this hemoglobin or eight or nine, that may be explained by their physiological anemia. But along with that, if they do have some signs of jaundice hemolysis, then I would think this is pathological anemia and may need some more work up. So, moving on to approach to anemia. Now, usually, uh we are told that, you know, there are two ways of approaching anemia, either based on pathophysiology. Is it related to less production of red cells? Is there hemolysis going on or there is ongoing loss or you differentiate based on the red cell size? Um which is the M CV. Are they looking smaller than their um reference rate? Are they looking same size, which is normal sitting or they're looking larger than their, you know, what is expected to be normal? But practically speaking, we try to think of both of these things at the same time. So we are thinking about what is really the cause along with what their M CV is looking like. So usually this is my approach to anemia. I start with the raticide count and see what the radic site count looks like if the radical site is inappropriate or inappropriately low, which may appear normal. But if a hemoglobin is seven and they have a normal radical ay count that is also inappropriately low for them. And once you ha you identify the reticulocyte count is low, then you look at the M CV and this M CV can be lower than usual, which is microcytic or it can be normal or it can be bigger or microcytic. The most common causes of microcytic anemia are iron deficiency, which we see predominantly in the toddler age group. Um then lead toxicity, anemia of chronic disease. If it is persistent chronic disease, then in the later stage, it can appear at microcytic anemia and then hydro blastic anemia, which is not so common microcytic anemia. The most common cause would be your anemia of chronic disease early on. And then sometimes um you know, even renal disease and hyperthyroidism can give you a normal cytic anemia. And lastly, when we think of macrocytic anemia, it's more in the setting of vitamin B 12 or folate deficiency. And sometimes even uh bone marrow failure syndromes can give you macrocytic anemia. And in this case, you uh you know, in your CBC, you would see things even beyond anemia. So you may see pancytopenia, they're looking at a vertical site count which is appropriate for their um you know, counts or their age. Usually if that's the case or there is increased reticulocytosis, that means your bone marrow is trying to compensate for this anemia. And this happens usually in two settings. Either there is ongoing blood loss or there is hemolysis. And this hemolysis could be immune mediated, non immune mediated. It could be membrane defects like hereditary spherocytosis elliptocytosis or enzyme defects like G six period deficiency. And we can talk more about this. So, um I want to discuss all these different etiologies in the setting of most common cases that, you know, probably you and I both have seen in our setting. Um So the first case and this I think is probably the most common, um, you know, case that we all see, um, this is a two year old male who was overall healthy, you know, born full term, who you did routine blood work at their 18 months visit or their two year visit. And, you know, um at that time was found to be anemic and when you ask about their diet, they are saying parents do say he's a picky eater. He loves drinking a lot of milk. So he probably drinks like 30 or 32 ounces of cow's milk each day. He's eating a lot of other dairy products, mac and cheese, maybe a few bites of chicken here and there. Um, doesn't eat a lot of green vegetables. Um When you ask about other dietary uh preference mom has noticed that he is eating or craving paper um these days, but he's always healthy, you know, he's active, he is not taking any, you know, increased naps, he's able to keep up with his, you know, siblings and so on. There is no family history of anemia and a family moved recently um from Afghanistan. So there is not a lot of details in terms of anemia in family or any family history. Now, when you do do a, a point of care hemoglobin, that is um low at seven. So the things that stand out in this case for me was one the age two year old and then, you know, their dietary history, of course, they're drinking a lot of cow's milk, it's 32 ounces. Um They don't really have a lot of other dietary sources of iron and eating paper is typically unusual and it's definitely a sign of pika. Now point of care hemoglobin is, you know, uh just telling you about the hemoglobin levels, it doesn't tell you about the other cell lines. So usually the first thing to do after you do a PO CD hemoglobin is to get a complete CBC just to see if it's just the anemia or if the other cell lines are also affected and if it is anemia, what kind of anemia it might be. So, in this case, um appropriately, the other CBC was done white, don't look normal platelets look normal, but he hemoglobin was low at 9.2 and this was microcyte associated with microcytosis with an MC U of 66. And uh redick was low at 2.5%. Of course, given the concern for iron deficiency anemia, iron labs were done. Ferritin was low at three. Iron saturation was low. Total iron binding capacity was high and serum iron was also low. And because there is history of the spiker and because this is microcytosis, you also want to rule out lead intoxication. So lead testing was done and it came back normal. So this is clearly a case of iron deficiency due to poor diet and excessive milk intake. Now, one thing I do want to highlight here is, you know, um in general, when I think about iron deficiency, of course, you want to do iron labs, but usually the most accurate result is only ferritin. The other iron um um results the iron saturation, total iron binding capacity, serum iron, they are very dependent on what the child just ate. So they are most accurate if they are done fasting. But as we all know, it's impossible to do fasting labs in kids this age. Uh um So only if you know these testing was done fasting, will they be accurate if a child just ate a cheeseburger? And after that, you do these testing, then these testing may appear normal, this iron saturation in fact might be normal or sky high because they just ate so much of meat. Um And in that case, the most accurate result will be ferritin. So in generally speaking, do do these testing but um in terms of when you're deciding if this is iron deficiency or not go by the ferritin numbers because that might be the most accurate. Now, another case that we see very often, um it will be an adolescent 14 year old female coming in for an animal visit. And you, when you ask her how she's doing, she just, she feels tired all the time. Her diet is OK. She's eating a lot of varied um food items, not a lot of milk does eat a lot of vegetables and fruits. She started monarchy at age 12 years. So almost two years before and um when you ask about periods, her periods are considered, she says they are quote unquote normal. Um Mom is with her and mom also um says that she has had anemia on and off during her life has been on iron supplements, on and off. But, you know, um her periods are also normal and, you know, I think um this is a point that I want to highlight that whenever anyone sees they have normal periods, I think normal is a very subjective term. Uh What may be normal for one person may not be normal for another person. So I think it's always important to dig deeper and ask more about their menstrual history. So when we ask more, um this patient says that, you know, her periods are every 30 to 32 days, they last about 8 to 10 days for the first three days, she's changing pads every 1 to 2 hours. She plas cloths, um she has to change um pads in the middle of the night. If she doesn't, she will um stain her clothes and bed sheets. And you know, she was describing all this as normal because this is what her mom also went through. And you know, this is what she's heard in her family. So this is normal for her, but in fact, this is not normal. This is clearly heavy menstrual bleeding and heavy menstrual bleeding is defined as bleeding, which last more than seven days if you are needing to change pads, more often than every 1 to 2 hours or you have to wake up in the middle of the night to change pads. And if you're passing clots, which are, you know, larger than a size of a quarter, then it's clearly, um, you know, heavier bleeding. You know, some patients do ask me like, you know, why am I passing clots in case this is a bleeding problem. And I'm bleeding so much. And I think the reason for that is because you are bleeding so much, there is pooling of this blood in the uterus. So by the time they pass this blood, it just forms clot because of all the pooling. Um And that's how these clots are formed. So in general, if anyone is passing these clots, if anyone is bleeding for more than seven days. This is truly abnormal and that may explain why they have anemia. So, in this case, of course, um point of care hemoglobin was done and that was low at 8 g. And this was followed by a CBC which showed um normal white count and platelets. Again. Um microcytic anemia with the hemoglobin of 8.2 and redick was still OK. At 6.8% ferritin was low at four and iron saturation was low. Total line mind capacity is high and serum iron is again low. And all these again go along with iron deficiency anemia. And this is likely in the setting of chronic blood loss or heavy menstrual bleeding. So, as we all know, iron deficiency anemia is the most common type of anemia in childhood. It accounts for 40% of anemia in toddlers. And um and the other age group with a high prevalence of anemia would be the adolescent females. And when I'm talking about females, I'm just using it as a loner. And what I mean by that is basically anyone who has a potential to menstruate. And that will be another group of individuals who have a high prevalence of anemia. And in fact, but in a recent study done by Dr Angela W and group, they showed um that the prevalence of iron deficiency was as close as for 40% in this age group. Um So whenever we think about the risk factors for iron deficiency. It depends on the age, the most common age group where we see this is toddlers again. Um, and the risk factors in this age group is most commonly related to their diet. So they are just drinking too much of milk. So, in general, if anyone is drinking more than 12 to 14 ounces of cow's milk each day, that might be a risk. Um, for iron deficiency. And um, the reason for anemia in these cases is twofold. One because they are drinking too much of milk. They are just not eating enough of the other food items that might be rich in iron. So that is one reason and two cow's milk itself inhibits iron absorption in the intestine. So because of these two reasons, these Children are at a high risk of um iron deficiency anemia. You know, the other age group, 5 to 10 year old, male, 10 to 18 year old males, um the risk of iron deficiency in general is low. But if you do see iron deficiency in this age group, think about G I malabsorption or G I blood loss. The other age as we mentioned, we see iron deficiency very commonly would be your adolescent females or anyone with a potential to menstruate. And in them, it's usually related to their menstrual blood loss. Of course, the other causes could be diet or losing blood NG I or urinary tracts of course, rule out other things. Um but the most common reason is heavy menstrual bleeding. You know, I did mention but Pika in our two year old child, you know, this is a very common thing we notice, especially toddlers. Well, even in adolescent with iron deficiency anemia, they do crave for these unusual things to eat. Um That could be as simple as craving ice, which is very common. The other unusual items I've heard is paper, toothpaste cement. There are all sorts of things. So, and you would notice as soon as this anemia starts improving or is gone, they no longer crave for these unusual items. So it's a very common symptom to notice and to see the improvement over time as this anemia results. Um lab values which are consistent with um iron deficiency of ferritin less than 20. I know there are no specific um ranges for ferritin and you know, the ferritin values vary from a lab to lab. So in some labs of ferritin of 8 may be flagged as normal. So in general, a ferritin less than 20 is truly not normal and should be considered as iron deficiency. Now, there are times when this ferritin may be falsely high and this usually happens in the setting of inflammation. So, if a patient has some gut inflammation going on or recently had an infection and is recovering from that infection. In those cases, this ferritin may be falsely elevated and of course, you should check for the other iron markers and those other iron markers would be serum iron, total iron bionic capacity and transference saturation. Uh whoops. Again, these numbers are very accurate only if they're done fasting. Um So just take these results with a grain of salt knowing, you know, when this testing was really done. Um The other test that I really like to do, especially when I'm uh not sure if this anemia related to iron deficiency or there is some inflammation uh going on is soluble, transferring receptor or serum transferring receptor. This is a very accurate test and it helps to differentiate iron deficiency anemia from anem of inflammation or chronic disease. And if you see high soluble um transfer in a high number, usually more than 35 that is usually consistent with iron deficiency. In cases with anemia of inflammation of chronic disease. The soluble transferring receptor is usually normal. Again, if you see a low ferritin, but the hemoglobin is normal, that is still considered iron deficiency. And you should still treat these patients with iron supplements because anemia is the final stage of iron deficiency. So, if you treat this low ferritin early on, you may be able to prevent anemia treatment wise. Um you know, oral iron supplements are the standard of care. You should try to do it for all these patients. Ferrous sulfate is the first thing we try to do. Um unfortunately, it doesn't treat taste the best. So we don't have the best compliance with ferrous sulfate as you many of you may have noticed. Um So the next thing you could try could be um you know, um Nova Ferra, which is available in Amazon and you know, it has a couple of different flavors available chocolate raspberry. So depending on what your patient may like, you can try um the supplement as well. Iron is best absorbed on an empty stomach. So I usually recommend my patients take this first thing in the morning with some orange juice and then eat their breakfast an hour or two hours later. For some patients, this results in stomach upset and they don't want to do it if that's the case. I usually tell them have this after your meal, but at least keep a gap of 1 to 2 hours between your meals and when you take your iron and try to avoid any milk or dairy products within two hours of taking iron because that may inhibit iron absorption. Um Once a day dosing is totally ok and is recommended, you don't have to give it two or three times a day or more. Um You know, if you give it, in fact, if you keep giving it more often that may result in lesser absorption of iron. So once a day is totally fine. In fact, there are studies which say you can do it every other day and that's still ok. But I find like if you do it every other day patients um tend to not have that kind of an adherence because, you know, they tend to forget. So I usually tell them every day um once a day dosing. And in that case, if you know, even if they're taking five times a week, that is still enough iron for them, um usually minimum of three months of iron supplement is needed um to correct iron deficiency anemia. And you would notice when patients start taking their iron supplements regularly. Um You should see a rise in radical aytes, which is the first sign um within one week. So if you know, if you are starting someone on iron supplements, and you want to see if they are really adherent with their iron. And if this iron is doing something for them or not, you can repeat the reticulocyte count and you should see a rise in reticulocyte within a week. Normally, hemoglobin should come back to normal within a month or so. And um iron stores are the last to correct. And these iron numbers may take at least three months uh to come back to normal. Um And again, this is all, you know, this is like an ideal setting. Practically speaking, it takes up to 4 to 5 months for these iron stores to come back to normal. And for this hemoglobin to resolve it may take 2 to 3 months. And of course, even if you're treating, treating the iron deficiency, you also have to ultimately treat um, the underlying etiology. I obviously always tell my patients that even if you take your iron supplements and in three months, your iron deficiency is gone. It can always come back if you don't eat a healthy diet or we don't correct your heavy menses. Um, so, you know, just making sure, um, for kids who are drinking tons of cow's milk that you limit the amount of milk intake to eight ounces or less. Um you know, increasing their dietary sources of iron. And um if you're worried about G I blood loss, checking a fecal calprotectin and if that's positive, sending them to G I just to make sure we are ruling out IBD or other sources of um iron deficiency anemia and in women who have heavy menstrual bleeding, of course, they should be started on some kind of hormonal contraceptives to control their bleeding. And um of course, do a tier one bleeding work up to make sure they don't have an underlying bleeding disorder. Now, let's say you, you know, this patient did everything right, continue to take um their iron supplements three months later, they still have anemia and this is what we see most often very commonly. Um And majority of the time, the reason is just that they were not taking their iron or they were just not taking enough of the iron supplements. So just going over, you know, how much iron were they taking? Were they really compliant with. It is um very important. I think in majority of the cases, this is the reason why their iron deficiency um is not corrected yet. But in some cases, it might be that it's just not iron deficiency anemia. It might be something beyond iron deficiency anemia. You need to do some further work up and that could be some G I inflammation going on. So, celiac disease, IVD um doing some work up for that just to make sure their absorption is ok. Um or um you know, this was not iron deficiency at all, this was, you know, thalassemia or something else going on. So that's the reason they are not responding to iron deficiency, um iron supplements and lastly something which is very rare. And um I don't think I have seen it ever. And I think um one of my mentors who does most of her work in iron deficiency anemia. She was saying in her 20 to 30 years of practice, she probably saw one case of this is Irida or iron refractory iron deficiency anemia. And in these cases, how much ever oral iron supplements you give these patients will just not re um respond to it just because they have this mutation that is impacting iron absorption. But again, this is like extremely, extremely rare. Now, um one of the refers that I get very often is for IV iron. And usually the reason is, you know, the ferritin is two or three. but usually, you know IV iron, even for a ferritin of two or three, it's ok to try oral iron supplements, it will essentially work the same way. And uh you know, we get a lot of pushback from the insurance in terms of when can we give Ivin. So the only cases where giving Ivin is approved is technically in chronic kidney disease patients. And if you can prove that these patients were intolerant to oral iron, that those were times when, you know, we can actually move ahead and give IV iron to these patients. The other situations where I use Ivin will be in case they have concomitant um inflammation going on, you know, G I inflammation. In that case, they're just not absorbing iron as much or if they have IBD or Crohn's, we know that their absorption is impacted. And in those cases, I would absolutely move ahead with Ivin. And then again, lastly, iron refractory iron deficiency anemia, it's extremely rare. But if in case your patient truly has um rita in those cases, um the standard of care would be Ivin dosing is based on the iron deficit and we usually uh measure it using a formula. Um Now, in majority of the cases, we have to prove that these patients don't have uh you know, they are not responding to the oral iron. And uh one easy way of checking if they're responding to oral iron or not is doing this oral iron challenge test. And um usually what you would notice is in a patient who is iron deficient, if you give oral iron to them within an hour, you see this group too, this is the group um which is has iron deficiency anemia. And in this case, within an hour, their serum iron should go above 200 almost and this keeps going up and then it would kind of um you know, reach a trough level somewhere around four hours. So if you see, if you do want to check, if this person will res respond to iron or not, you should, you can give them, you know, oral iron supplement and check the serum iron at two hour or four hour. And this serum iron should be above 200 or 250. And if the serum iron doesn't go up, you know, it stays in the range of 5200, this means either this per person is not responding to oral iron or has some underlying inflammation, which is, you know, obstructing this iron absorption. And those patients we should consider um Ivin um now just explaining how this iron absorption is impacted in the setting of inflammation. Now, hip side and usually in normal setting, this iron is transported via Ferro Potan and is absorbed in your intestinal cells. Now, in the setting of inflammation, hep Cidon, which is an enzyme that inhibits in um iron absorption goes up. So in the setting of inflammation. This HEP CIN is kind of sky high and this inhibits iron absorption. And that's the reason how much ever iron you give to these patients, they will not res respond to oral iron. And that's why giving IV iron might be a better choice because um just this will pass through this HEP side and route and will have better absorption. Um This just goes through over the different I iron formulations that are available. As you can see, there are so many iron um IV iron formulations that are available, the ones we use most commonly would be of Ferric carboxy, Morse and iron sucrose and dextran. Um And the choice between, you know, carboxy dose versus others depends on usually um patients insurance and what the insurance will approve. Um, in general, I like using ferry carboxy dose more than others because usually it has you give more IV iron in one dose. So usually ferry carboxy dose, patients usually need one or two doses and that's about it. And the risk of allergic reactions is super low with f carboxy more dose usually with Dextran, we are not seeing that many allergic reactions either. Um but um for Dextran, they do need a couple of more doses. So majority of the patient need like 3 to 4 doses of Ivin in this case. So coming back to our cases and what we did for our patients, um for the case, one the toddler with uh excessive cow's milk intake. Um, you know, um we just uh recommended them to limit their milk intake to eight ounces or less and started oral iron supplements three MC per cake once a day. And for a second case, um, the adolescent um, girl with heavy menstrual bleeding and having anemia, um, we started oral fr sulfate 65 mg elemental iron daily. Um Also, um you know, recommended they start hormonal contraceptives. Um And that was done um uh you know, in conversation with the adolescent medicine doctors and she was started on heavy um hormonal contraceptives. And we also did tier one bleeding work up to rule out one Billy Brand's disease or any other bleeding disorder that may explain heavy menstrual bleeding. Now, for the first case, um there was a follow up at three months. Now by three months, ideally, um we would expect hemoglobin to come back to normal ferritin would be normal, the iron source would be normal. And if this patient was truly adherent to their iron and doing everything right. And when we asked m more about the history, it looks like the family was doing just the right thing. They limited uh milk intake to almost nothing. They would give one bottle a day max, which is like eight ounces. Um They increased um you know, dietary sources of iron, um gave him iron every single day for three months. His spiker completely resolved. He was feeling better but repeat labs unfortunately, still showed microcytic anemia. His hemoglobin was 10.1 with M CV of 66. But his iron numbers were all back to normal. So, what do you do next? So, this is a patient at this point, you have, you know, you have corrected that iron deficiency, but they still have microcytic anemia. And this is again one of the common things that we notice now in this case, because of the significant microcytosis, um with normal iron stools at this point, I'd be worried if there's something else going on. And the most common thing you're worried about is thalassemia. Usually, you know, if there's a hemoglobin of nine or 10, it's probably thalassemia minor or thalassemia trait. But you do want to test for it. In some cases, you already know the family history and then it's easy, you can check for that any time. Um But in other cases like this one, you don't have any family history. Um And you just look at the labs and see how they're doing. I tried even if I'm worried about um thalassemia, I try to correct iron deficiency first. And once the iron stores are normal is when I move ahead with thalassemia testing because sometimes significant iron deficiency anemia can mask beta thalassemia. So it's important to correct iron deficiency first and then move ahead with um thalassemia testing. And again, thalassemia can coexist with iron deficiency anemia. So if you have a patient who is known to have beta thalassemia trait or alpha thalassemia trait, even they are at a risk of developing iron deficiency anemia. So, it's important to give that counseling to them, encourage iron rich foods and check um iron deficiency anemia. You know, annually or how much ever often you would do. So, moving on to thalassemia, thalassemia is um group of disorders which is also a um associated with microcytic anemia. And in this case, this is because of defective production of alpha or beta subunit of the hemoglobin and that results in ineffective erythropoiesis. There are two types of thalassemia depending on which globin gene is affected alpha thalassemia and beta thalassemia. It is an inherited disorder. It's usually inherited in an autosomal recessive form. Um alpha globin gene has four alleles and beta globin has two alleles. So, depending on the number of alleles that are affected, um will essentially um you know, determine how severe the anemia and thalassemia will be. So, let's say for alpha globin gene, if it's only one allele that is impacted, these patients usually have silent anemia, meaning they may have microcytosis with or without um anemia. Um And they're usually asymptomatic versus uh you know, if three of the four alleles are fitted, they will have significant anemia and same goes for beta globin gene. Um And again, because of this ineffective erythropoiesis, these patients not only have anemia if they can also have, you know, extra medullary hematopoiesis. And because of that, there might be bone marrow expansion, um increased intestinal iron absorption. And um this is more profound if more of those alleles are affected. And more of these patients have like, you know, beta thalassemia or alpha thalassemia major. Usually in minor or trade cases, you would just notice anemia and not many of these other things. Um when you do newborn testing, um sometimes alpha thalassemia can be picked up on that testing. But for beta thalassemia, even if you do hemoglobin electrophoresis, it's not accurate until like six months of age. And the reason being, you know, when babies are, they have alpha and gamma, the hemoglobin F they start ma making their beta hemoglobin, which is hemoglobin A but the, you know, um hemoglobin A becomes the predominant kind of hemoglobin only by the time this done six months of age or beyond. So for accurate testing for beta thalassemia, you want to do this testing only once they're six months or beyond. If you do this testing earlier, um you may not get accurate results. Um And again, for minor or treat patients, usually they're asymptomatic or they may have mild anemia. So these patients, we may not be caught until they are, you know, in their late, even in their late teens. Um but usually the ones who have major thalassemia or transfusion dependent thalassemia, these patients present very early on and we catch them, you know, sooner in their life for diagnosis of thalassemia. Um first of course, correct their iron deficiency if they have any. And then for thalassemia testing. Um hemoglobin electrophoresis is the standard testing we do. But in hemoglobin electrophoresis, you are not testing for alpha thalassemia. So if you're worried, a patient has alpha thalassemia that will be missed on hemoglobin electrophoresis. And for that, you do want to do alpha globin gene testing and for beta thalassemia um on hemoglobin electrophoresis, you may notice the hemoglobin A two is higher than usual, that is more than 2.5%. And um once you notice that you obviously want to do beta globin gene testing as well to identify what mutation they may have. Now, these are some of the um you know, key differences in terms of labs that you noticed between iron deficiency and thalassemia minor. Uh As you see here, they are pretty much the same, there is not a lot of difference. So, um the one thing you may notice is ferritin, ferritin might is absolutely low in iron deficiency in thalassemia minor. It might be normal to high in that case. Um Usually the one thing I notice is iron saturation. Usually, if there is uh iron deficiency, the percent is iron saturation is usually on the lower side. And the other thing you could do will be soluble transfer receptor. Again, soluble transfer receptor would be higher in iron deficiency and it may be normal in thalassemia, minor management wise is usually if it's thalassemia minor, these patients are asymptomatic. Um and all we need to do is just prenatal counseling and tell them about the risk of, of concomitant iron deficiency anemia and encourage a good diet. So they don't develop iron deficiency for thalassemia major. These patients usually present early on in their life and depending on how severe the anemia is, they may need, you know, regular blood transfusions um and that increases the risk of iron overload. So they need inflation and that of course, um needs um you know, proper care at a thalassemia center which um you know, as you all know, we are fortunate to have at Oakland. Ok. Now moving on quickly um to normocytic anemia, normocytic anemia, I usually think about it in case of, you know, even early cases of iron deficiency may present as normocytic anemia and um cases of um inflammation, anemia, inflammation or chronic disease may also present early on with normocytic anemia. So even in those cases, do check for their iron numbers. Um other things that can be present as normocytic anemia would be, you know, um anemia related to hypothyroidism or chronic renal disease. And in those cases, you just need to treat um their underlying condition. And in some cases, we do consider Ivin and that would be, let's say if this is anemia in the setting of renal disease, sometimes they need epo sometimes they also need Ivin if they have um you know, ongoing inflammation and they have significant um microcytosis or anemia, they may need Ivin in that case too. Ok. Um Quickly moving on to macrocytic anemia. Um Now, macrocytic anemia, we usually think about it in the setting of B 12 deficiency or folate. The other thing to think about is, you know, bone marrow failure. So that's why it's important whenever you get a low point of care hemoglobin to check an entire CBC, just to see what the other cell lines look like. If all the other cell lines are also affected, it might be something beyond just anemia. It might be bone marrow failure or you know, other things going on um anti epileptic drugs. Um they usually tend to cause macrocytic anemia. Um And then Trisomy 21 there is some correlation of Trisomy 21 with macrocytic anemia. And lastly, as we said, newborns usually have macrocytosis and that is considered normal for them because of high amount of hemoglobin F which has um you know, larger M CV uh macrocytosis slightly different from me gallop, blastic anemia. What I mean by megaloblast is there is um impact on their DNA and how the red cells are generated. And because of that these cells have, if you look at the peripheral smear, these patients will have not only big um red cells, they will also have something like hyper segmented neutrophils and megaloblast anemia will have M CV, you know, greater than 100 100 and 10. Um And usually this is in the setting of either B 12 deficiency or folate deficiency. When we think about beta deficiency, most commonly, it's related to their diet. Usually you can notice this more in patients who are um you know, vegan or they have board absorption and for diagnosis, you do want to check their B 12 levels but they are not the most accurate. So, um checking their homocysteine levels and methymalonic acid levels is also helpful and both these numbers will be high. Treatment is giving BB 12 supplements. And for folate deficiency, again, this is mostly a regular diet. And in these cases, classically, um these Children are drinking more of goat's milk and sometimes because of impaired absorption, Crohn's disease I BT. And again, I know a lot of people check serum folate levels. This is not the most accurate. Again, the more accurate testing would be R BC folate. Um And the other testing that you could do is again, homocysteine and methylmalonic acid. And in this case, the homocysteine will be high, but the methylmalonic acid is normal and treatment again is just supplementation. Ok. I do wanna quickly um I don't have a lot of time. So I wanna quickly touch on hemolytic anemia as well. Now, in hemolytic anemia, um there is anemia along with increased markers of hemolysis. So these individuals may present with um anemia, increased reticulocytosis, jaundice history of gallstones in the family cla colored urine, somebody requiring splenectomy and so on. Usually the etiologies can be twofold one which is affecting your red cells itself. And that is because of, you know, defect in the red cell membrane, spherocytosis, elliptocytosis. Um enzyme defects like G six period deficiency being the most common and because of hemoglobinopathy like sickle cell disease and thalassemia and sometimes it can be extrinsic to the RB CS. So some external toxins most commonly being drugs or um you know, um auto antibodies that these patients can develop or in the setting of, you know, TT P and D IC. Again, in these settings, these are more like medical emergencies and these patients use are sicker than your straight up anemia patients that you notice in, you know, on annual follow up and these patients will uh m majority of these patients will have anemia along with um an impact of other cell lines. So they may have thrombocytopenia, they will present with, you know, increased bleeding and so on. Ok. So now talking about hetic anemia, I just wanted to talk about um some of these cases that we see, you know, um anemia and routine follow up at a pediatrician's office. So this is a patient who presented recently to us um five year old male with no significant past medical history and he was just admitted to hospital recently for anemia. He had been sick on and off for almost a month with vital symptoms. Um you know, cough congestion, mom was giving Tylenol Motrin as needed for fever. Mom just noticed that he looked more pale and jaundiced to her as compared to usual. So she just went to the uh you know, an urgent care to get labs done. And at that time, the labs showed anemia but otherwise there was no history of, you know, any recent antibiotics used or any other medicines beyond Tylenol and Motrin, no family history of jaundice, splenectomy, gallstone cola colored units. So really no other history labs show um normal white count and platelets. But hemoglobin was 9.6 with an M CV of 86.8 and a red of 1.2%. Um because of this history of maybe jaundice, they also did hemolysis labs. And as you can see, haptoglobin was 365. L DH was slightly elevated. 255 uric acid was 2.6 D ad negative. Um smear showed some oocytes and G six PD was low at 1.8. Um Now there was this concern for G six PD deficiency. So he saw me three weeks later for this concern for G six PD deficiency. At this point. He was doing very well. Um you know, this anemia result, um his jaundice was gone. He looked much better and we decided to repeat the labs. His hemoglobin now was actually normal 12.5. Um other, all the cell lines looked OK. Um His bilirubin was uh normal 0.4 0.2. His periplus smear looked normal and I repeated the G six PD which again came back low at 2.9. So this was clearly a case of G six PD deficiency. What was throwing me off was, you know, initially when his G six PD came back low in the setting of hemolysis. And the reason I say that is because, you know, usually when you have G six BD deficiency, these patients usually have hemolysis in the setting of a trigger. That could be, you know, some food items they ate classically, we know fava beans can cause um this hemolysis sometimes in the setting of, you know, viral infections, antibiotics that can trigger hemolysis. And when you have hemolysis, you're just making a lot more ra radical sites, right. So when you're making a lot more radical ays, these radical aytes actually have a lot more amount of G six PD, almost five times normal uh five times higher than the usual RB CS. And because of that reason, we usually say even if you're concerned about G six PD deficiency, do not test for G six PD during the phase of hemolysis because this number may, you know, appear falsely normal, which in this case, for whatever reason, it was low and we repeated again, it was low. Um The classical thing that you will notice on a peripheral smear is um blister cells and you know, they appear something like this. Um These are excellent. So there will be some family history of um hemolysis and G six P deficiency. But in many of these cases, patients don't know and family is not aware of anyone having these kind of symptoms. Ok. Another case that we recently saw was um on an inpatient consult. So a two week old male admitted for acute severe anemia and jaundice, we were initially consulted because there was this family history of hereditary spherocytosis on dad's side. Um We he didn't know much about it other than he was diagnosed. Um in Italy, he and his sister both had splenectomy when they were young for eroc IOS. He has otherwise done. Ok. He's doing well right now. And there is also a history of a bo incompatibility. Mom is a positive. Dad is a positive, baby is a positive and Coombs was one positive. So it was unclear, is this anemia related to, you know, phey tosis or is this through to uh a bo incompatibility? His hemoglobin um thankfully looked ok at 13.6. So he went home and the plan was just to do weekly um CBC S and on weekly CBC S, as you can see his hemoglobin continued to drop down. It went to 9.8 on day of life eight and 5.5 by day of life 14. Now, um this one, this is too soon for physiological need, right? Usually that you would notice by four or six weeks and 25.5 is a little too low for physiological need. You know, for physiological need, hemoglobin, usually somewhere on the age um in the range of 8 to 9 may still be normal, but 5.5 is too low. So if you see a patient with this low in hemoglobin, think about other reasons for anemia beyond just physiological anemia. So, in this case, um of course, with the hemoglobin of 5.5 this patient was admitted, um we did hemolysis labs again, his red was high. His bilirubin was elevated at 2.5 and this time was cos was negative. So that rules out a bo incompatibility as a reason and probably this was related to um you know, the family history of HS. So we did send R BC band free testing and unfortunately, that came back borderline. So, you know, we don't know much about um if this is truly HS or not. So at that time, we decided to send this A G OS panel. Um I don't know, I don't know if any of you are aware of this, but this is a G OS do have a hemolytic anemia panel. So if you're worried about, you know, hemolytic anemia of any of your patients, once they um hemolysis and this anemia episode results, you can send this um uh hemolytic anemia panel and that test for, you know, the most common mutations associated with hemolytic anemia. So, we did send this testing and the results came back consistent with hereditary spherocytosis with a hetero cyg mutation and one gene. So, hs is the most common membrane um defect um presenting with hemolytic anemia that you would notice uh in general. Um because of the membrane defects, these individuals have increased R BC fragility and that predisposes them to hemolytic anemia. It can be inherited both autosomal dominant and recessive. Um recessive is less common, but it's usually more severe. And these are, you know, the genes are enlisted here which are associated with um HS in general. Um for HS diagnosis, we do osmotic fragility test and B three testing. But the most important diagnostic testing would be genetic testing in terms of treatment. You know, this patient's dad did have, he um did have spill toy for his HS. But um you know, we try not to do splenectomy anymore. We try to individualize treatment based on the symptoms. So usually if it's just mild anemia, these patients don't really need anything. They're usually asymptomatic, they may need blood transfusion once in a while during trying times of the hemolysin, severe anemia. But otherwise they do OK. If they have moderate hemoglobin in the range of 8 to 11, then I think it truly depends on um you know how this patient's phenotype is. And at that time, you have a shared decision making with family um and decide if these patients will do ok with just blood transfusion once in a while of or if they truly need splenectomy. Um because they are requiring uh frequent blood transfusions. And if these are the patients who have severe anemia, less than 6 to 8, these are the patients who will have frequent blood transfusions. And um in these patients, you truly do want to consider a splenectomy that could be partial or total splenectomy. Um depending on, you know what the symptoms look like uh based on a decision uh making with parents. But these are the patients who truly um do benefit from splenectomy and given the amount of time we had, I don't think I have time to go over everything. So this is um just a flow chart of showing how I think about the different hetic anemias and the work up um for different hemolytic anemia. Again, things like, you know, hu STD PD IC, these patients are much more sick and they usually don't walk into a clinic for the routine and will check in these patients will usually present to er or urgent care because they are just not feeling well and they have, you know, um pedic or uh you know, renal injury and other things going on beyond just anemia, things that I do think need urgent referral to he hematology. Of course, if a patient has symptomatic anemia, I think either refer to Hema hematology or usually sending them to, er, for, you know, IV I and, or blood transfusions. Um, if they have anemia along with waited markers of hemolysis, then I think these patients should be sent to hematology just for a work up for different causes of anemia. Beyond just iron deficiency. If they have other cell lines affected as well, then you're worried about, you know, um, other things like bone marrow invasion or Evans Syndrome, those kind of things, then absolutely send them to hematology. And if this anemia, even if it is iron deficiency and it's not improving with your standard of care, then I think these patients do um require to hematology. But in general, I think um you know, if it's any anemia patient and you think this is, this just looks um something beyond iron deficiency or they're not responding to the usual um um oral iron supplement. I think it's totally ok to send them to hematology and we'll be happy to see these patients and that's all I have. Sorry, I went almost on time. Thank you so much. And this is a key word. Question is. Mhm You, you did a great job. Thank you so much. Um Well, this QR code I know we are at times we will ensure that that um we do have a handful of questions. Uh Super is, yes, I do. I can, I can see these questions. I can just go over them real quickly. Ok. Um So the first question is, uh redick of 4.5%. Um, you know, I think depends on um, what their hemoglobin is. So, if a hemoglobin is seven and redick is 2.5% I would say that is low for that kind of anemia. And, um, that has to be, you know, you need to do some more work. But yeah, 2.5%. Um, metic is kind of on the lower side iron of three MC per cake. Yes, I think um usually iron, three MC per cake is considered ok for supplementation. So in infants, 3 to 6 mics per cake, but in toddlers, usually three MC per cake, I think is ok. And um, you know, for adolescents and beyond usually 65 MC per K, uh 65 mix of elemental iron is usually ok. Are there any side effects of Ivin? Um, not really, I think um side effects might be in terms of, you know, sometimes some patients have kind of an allergic reaction um to Ivin, but we try to give it slowly at least the first round and if they do ok, that's when we slowly increase their infusion rate. So usually there are no side effects of Ivin but you know, the fact that they have to stay in a hospital, um, have an IV place, stay there for a couple of hours. Um, and you know, come back for another round of IV um iron, I feel like it doesn't suit many of our patients and it's not really patient friendly in terms of, you know, their routine and so on. So I usually try to do oral iron first and then move to IV iron only in case they don't um do so well with um oral iron. Do you recommend a specific OCP for heavy menstrual bleeding or a minimum amount of estrogen? Um I don't have a specific OCP in mind. I usually try to do a combined OCP. I try to start it with minimum amount of estrogen and um you know, depending on how heavy the menstrual bleeding is and how significant the anemia is. Sometimes in some patients, if they have, you know, heavy menstrual bleeding, what you want to do is complete suppression of their menses at least until their anemia resolves. So for that, they may need higher doses of estrogen. Um So, you know, depending on how severe their hemo um their heavy menses is at what he hemoglobin level. Would you check a CBC for toddler? Um For that's a good question. I think usually hemoglobin is um you know, flagged as a low hemoglobin and you are worried that, you know, this is iron deficiency or something else. I usually for any low hemoglobin for the range, I would move ahead, check a complete CBC and do a ferritin just as a minimum work up just to make sure of this, you know, anemia is truly related to iron deficiency or this is something else. And same for female adolescent, I think for adolescents, anything less than 12, I think would be low. And I would absolutely check ferritin and iron numbers for them. Should you worry about ferritin being elevated from vital illness? Um and be falsely reassured. Um, fasting. Good question. And I think that does happen very often that ferritin is elevated from a recent viral illness. Um So I think in that case, if possible, I would try to do these testing only once, you know, their viral illness has completely resolved and they are back to their baseline and then do the testing and yes. Um I think it's ok if they can't do fasting because I think majority of the are patients, it's impossible to do. They're testing fasting. Um So I think it's ok if they want to do a low um iron morning meal or a snack before getting this testing done, just be aware of this so that, you know, when you are interpreting these results, that will be in the setting of they eat something. So, you know, the iron numbers might be slightly high because they just ate. But let's say, you know, they have a low hemoglobin, they have a low M CV, they have elevated RDW and their iron numbers are just slightly normal or close to normal. Then I think it might still be iron deficiency and you should treat it as iron deficiency, at least for a couple of months. Give a trial of iron if they respond to it. Great. If they are not responding to it, that's maybe when I will do some more work up to understand what's the cause for this anemia? Perfect. That we're all six. Fantastic. Um, we do still have time if someone wants um, to answer or ask another question, we're here for just a few more minutes. So feel free to type. But um otherwise doctor Well, thank you so much for your time and to all of our guests today. Thank you so much for your time. Um Just a reminder that you do need to fill out the evaluation form, but we scan your QR code or as soon as we end this web browser, we can fill it out with a reminder also being sent tomorrow in order to reach your credit. Um um if you have any questions or any follow up needed uh with doctor ill or the liaison team, feel free to reach out to us at any time. Um And with that, I'll check one last time. I think we are clear on our questions. Thank you everyone for your time today. We look forward to seeing you next time and doctor. I thank you so much for your time. Thank you all. Take care. Bye. Created by
