what's up Ninja nerds in this video today we're going to be talking about macro ciic anemia again this is part of our clinical medicine section if you guys like these videos they make sense to you please support it you can do that a couple different ways you can hit the like button you can comment down the comment section or you can also subscribe also please do yourself a favor go down the description box below there's a link to our website on our website we have a lot of great things to offer notes illustrations quiz questions so go check that out without further Ado let's get into macro anemia all right my friends so we're going to start with the pathophysiology of macro anemia now when we talk about anemia what is anemia anemia is when the hemoglobin is low right for a male it's less than 13 for females it's less than 12 so that's how we would basically Define anemia from there we say okay what's the MCV the mean corpuscular volume that gives us an idea of the type of anemia that we have if it's less than 80 it's going to be your micro ciic if it's 80 to 100 it's normic and if it's greater than 10050 lers it's your macro citic anemia when we talk about macro anemias we know those red blood cells are really really big but we have to understand why because I think it'll give us an understanding as to again the causes the mechanisms and that can really guide us along the way of our discussion here so I Want to Break these two macro ciic anemas up into megaloblastic and non-meal blastic and the way that we do that is a little bit further so really what I want to talk about here is you'll see later as we get into the diagnostic steps is that one of these has the presence right of what's called hyp segmented neutrophils so hyper segmented pmn we're going to call these and we'll dis describe what that means a little bit later I just want you to trust me for now and then the other one is you do not have a presence so there is an absence of hypers segmented neutrophils all right so basically whenever you have a patient who you describe as having a macro ciic anemia the first thing that you need to determine is okay if they have a macro ciic anemia is it megaloblastic or non- megaloblastic and the way you determine that is the presence of uh either multi mobed and so I'll give you a basic definition now polymorphonuclear lucaites those are your nutrifil usually they should have anywhere from three to five loes but it has greater than five loes it's a hypers segmented nutrifil that's due to impaired DNA synthesis so presence of them megal blasia no presence of them non- megaloblastic anemia all right so megaloblastic anemia what really happens here is you have your red bone miror right it's responsible for synthesizing what all of your blood cells right so hematopoesis is where this actually occurs right in the red bone marrow so it makes your white blood cells it makes your platelets it makes your red blood cells what happens is let's say in this potential patient here they're making these white blood cells and they're making these red blood cells and again in this definition here we we have macro ciic red blood cells so macro ciic rbc's and here we have the hyper segmented pmns so if you have hypers segmented polymorphonuclear lucsy and you have these macro ciic red blood cells this is how we would Define a patient having what a megaloblastic anemia now usually the reason for this type of process occurring is is that somewhere in this there is a decrease in DNA synthesis right so there is a decrease in DNA synthesis and that's leading to an immatures right not a mature pathway you're not allowing for the nuclear material to be able to completely mature so this impaired DNA synthesis is what's responsible for this potential process now whenever a patient has this DNA synthesis Turing inside of the red bone it's heavily dependent upon B12 and it's also heavily dependent upon folate so if a patient has a deficiency in B12 or deficiency in folate this is going to impair their DNA synthesis process which we'll talk about and that's going to lead to this process where you make these macrotics really really big red blood cells and you make these hypers segmented neutrophils where they didn't have the chance to completely mature and make normalized nuclei now what happens here is these macrotics they're sometimes too big and so they get chewed up a little bit and so they get chewed up by the red bone marrow right so your bone marrow will chew up some of these actual macro citic red blood cells this is the primary one and then your spleen right right so these red blood cells they get to the Bone Mar they get to the spleen and they get chewed up right and so now you're end up with these chewed up red blood cells right and this is usually going to be killed by process called apoptosis so so they're going to undergo an apoptosis process and so if you have this apoptotic process that occurs where you kill these red blood cells primarily in the red bone marrow and a little bit in the spleen then what's going to happen to your number of red blood cells if you just you chew these things up right you're going to end up actually doing what if you kill these red blood cells right so now we're going to have these red blood cells they're going to be destroyed if I destroy these red blood cells now I'm going to end up with less red blood cells in the circulation and so you're going to end up with a decreased number of red blood cells in the circulation all right so here we go in a patient who has megaloblastic macro cdic anemia they have the presence of hypers segmented nutrifil this is usually due to a deficiency in these two potential micronutrients and pairs DNA synthesis you don't allow for the nuclear material to properly mature and condense so you get big red blood cells and you get multi- lobated nuclei more than normal they can get chewed up in the actual bone marrow or chewed up in the spleen where they go on an apoptotic process you have less of them now and that's going to lead to less rub blood cells in the circulation that's going to contribute to the anemic process now with non- megaloblastic anemia something is occurring here where you're making macro ciic red blood cells so you still have these really really large macrotics but you have normal normal pmns or in this case the you know polymorphonuclear lucites they're not hypers segmented and so in this case this has nothing to do with an impairment and DNA synthesis something's either inhibiting the bone marrow from making these properly shaped red blood cells or something is altering the lipid metabolism we often times don't have really really great reasons but when we think about a non-meal blastic anemia it often comes down to a couple different causes one is alcohol use that's one all right a second one that I would definitely be on the consideration of is it kind of goes hand inand with alcohol use especially in a patient whose's chronic alcohol use and it's causing liver disease like curosis another one could be hypothyroidism so hypothyroidism should also be considered in these potential patients and then another one could be myod dysplastic syndrome so myod dysplastic syndrome is kind of an abnormal within the stem cells in the bone marrow so we often times abbreviate this what's called MDS so myo plastic syndrome and there can be one other one I'd say it's not as common but something to consider is a reticulo cytosis which we can see often times in patients with chronic homolysis or blood loss all right but in these scenario something is altering the actual stem cells or something is altering the lipid metabolism so this scenario here there's some type of either destruction of the red bone marrow or there's an altered lipid metabolism so altered lipid metabolism you know that lipids are pretty much what's responsible for the complete formation of the cell membrane and so if you have an alteration in this lipid metabolism process what's going to happen you're going to lead to these weird shaped red blood cell membranes and so this is going to lead to an altered lipid metabolism that leads to an altered shape in the red blood cell so altered red blood cell membrane all right now the problem with this is that if you have these big red blood cells again they're not not nice to be having you know roaming through your circulation and so what happens is is often times same thing they go to the red bone marrow they go to the spleen and if they go to the red bone marrow a lot of the times they'll get chewed up in the red bone marrow all right a little bit they may get chewed up in the spleen but the big thing here is that we're going to kill these macro citic red blood cells they're just abnormal and so what happens is when you chew these puppies up what do you do to the number of red blood cells moving through your circulation you end up with a decreased number of red blood cells in your circulation and the reason why is because you're going to undergo a apoptotic process and kill so you're going to have a apoptosis of these red blood cells in the bone marrow and to some degree in the spleen and that's going to chew these puppies up and as a result you're going to have less red blood cells moving through your circulation so when it comes down to this really between megaloblastic and non- megaloblastic one is there's either an impairment to the bone marrow being able to synthesize red blood cells or there's an altered lipid metabolism that leads to a weird shaped membrane all right for megaloblastic it's something that's impairing DNA synthesis the nucleus doesn't get the proper time to mature so you end up with hypers segmented neutrophils and big large red blood cells and both of these scenarios they usually undergo a little bit of apoptosis in the bone on the spleen which kind of reduces the amount of red cells moving through their circulation all right so we now understand that whenever you have a megaloblastic macro ciic anemia your problem is an impairment in DNA synthesis right and so because of that the nuclear material in these cells is not maturing and usually what happens is as nuclear material matures in these kind of proliferation and differentiation phases the nucleus should get smaller and smaller and smaller right but that's not occurring in this megaloblastic process right and that's why you get big red blood cells in these multilobated nuclei particularly for the nutrifil so it's a better understanding of how this occurs so we know that it's impaired so let's say here I have a stem cell that's going to make my red blood cells and that usually is the same Stem Cell It's a myoid stem cell that will also make your white blood cells right especially the um granul acidic ones like neutrophils now what happens is and the abundance or the presence of B12 and fate you'll notice this normal pathway and then you'll notice this abnormal path way and the deficiency or absence of an appropriate amount of B12 and folley and what we've already been able to surmise from that is that you got normal red blood cells and you got big hunky red blood cells right so you got your normal red blood cells that are occurring from a normal kind of like differentiation and pathway from whenever these stem cells eventually make red blood cells and here you got big country red blood cells these are well cornfed puppies here right and now what's really the difference well in one of these you have a proper amount of B12 and you have a proper amount of folate whereas in this one you have a decrease in B12 and you have a decrease in folate right now how does this actually kind of work out to cause these changes in red blood cell size right because we we talked about non- megaloblastic you still get big red blood cells but it's probably due to an impairment of the bone marrow the stem cells being able to properly properly differentiate or an alteration in lipid metabolism that causes a change in the cell membrane right that was the non- megaloblastic for megaloblastic how does this actually occur well if you look at this normal pathway take a look and just look at the nucleus for a second what do you notice a difference in the nucleus as it goes through the blast stages right in the normal pathway versus what happens to the nucleus as you go through the maccro acidic red blood cell pathway what do you what do you notice a difference in the nucleus size it gets smaller and the cytoplasm gets smaller right what do you notice here the nucleus it's not really getting as small as I would like it to be throughout this differentiation process and so you end up with these big red blood cells so really what happens here is that the nucleus get smaller and smaller and smaller and so the cytoplasm shrinks appropriately and you get a small red blood cell so here we have a nucleus size that is decreasing appropriately and you have a cytoplasm size that is decreasing appropriately because of the presence of B12 in folate allowing good DNA synthesis and good DNA maturation so this is a normal process these should you know decrease in tandem so you get a normal size red blood cell but in this one I don't notice that process so I unfortunately don't see the nucleus size decreasing as well as the cytoplasm size is and so because the nucleus does not does not decrease in size appropriately that's really the best way of saying it it doesn't decrease in size appropriately as compared to the cytoplasm size now you're probably wondering okay how does that cause a how does that cause a big red blood cell remember the nucleus makes up most of the size all right of this red blood cell when it's going through the blast stage so because it's not getting smaller in size it's taking up a good amount of space so the cytoplasm will shrink and shrink and Shrink but the nucleus is taking up a lot of space eventually that blast will turn into a reticul site and it'll spit out that nucleus but it's going to spit out a big nucleus and that's going to leave behind a pretty large red blood cell because it was taking up so much of the Space by the time you spit it out you're left with all the space that it was occupying that's the difference here same thing if I were to take that same same stem cell and I were go through the differentiation process to where it finally matures and when it does mature it makes a let's say a neutr here and that neutr has an appropriate number of loes and then compared to this one where this one has a crazy amount of loes this one's got like you know what eight nine loes this one's got like maybe three so because in a patient who has a normal B12 and a normal folate versus those who have a decrease in B12 and a decrease in folate we notice a difference in the amount of loes for the pmn or the neutrophils so a decrease in B12 and a decrease in folate will cause this change now neutrophils should normally normally have about three to five loes that's about normal right so here we'll have a normal pmn and then here we'll have a hyper segmented pmn if a patient doesn't have an adequate amount of B12 and folate you'll notice that the nucleus doesn't condense and make the proper number of loes and so in this one you end up with how many this one you make three normal is about three to five loes but if you don't have be 12 and folate you won't allow for that proper condensation process and the condensing of the nuclear material will unfortunately not occur and you'll end up with tons and tons of lobes and so for this one you'll end up with greater than five loes that's often times how we'll Define these hypers segmented neutrophils so we know now that really when it comes down to this megaloblastic macroy anemia it's an impairment of hom mopis due to a impaired DNA synthesis which is leading to a improper nucleus size decrease in tandem with the cytoplasm size decrease or it's leading to less condensation leading to less lobes and unfortunately end up with multiple and multiple loes in the white blood cells in order for us to understand how B12 and fley really you know impair himat poesis we got to kind of dig into a little bit just a little bit of the biochemistry so here we have DNA right here's our DNA molecule now what's really crucial to re realize is that DNA makes up the nuclear material within our stem cells so here I'm going to take a piece of the bone marrow and I'm going to zoom in on that so here is our stem cell now within this stem cell we have the nuclear material and again that's made up of this DNA so we need the DNA to allow for the presence of the nuclear material so that this stem cell can allow for it to properly differentiate and make normal-shaped red blood cells or normal-shaped polymorphonuclear lucites if I have some type of process where there's a deficiency in B12 and a deficiency in foli it actually will impair the DNA synthesis and so you'll end up with less of this DNA you'll end up with an impairment of this nuclear material where it matures properly and because of this you'll make these big red blood cells and you'll make these multi-lobulated nuclei within the neutri s we have to understand though how folate and B12 do this so let's start off here what we actually need to know is that fate is crucial because when it actually gets taken into our cells it actually should be converted into what's called di hydrolate then it should be converted into Tetra hydrolate then it should be converted into what's called 510 uh methylene tetrahydrofolate so methylene tetrahydrofolate and then it should actually be converted to what's called five methyl tetrahydrofolate and then in this process if there is a deficiency in folate there'll be a deficiency in dihydrofolate which will lead to a deficiency in tetrahydrofolate which will lead to a deficiency in this guy here and then also a deficiency in this one here now now how is this kind of problematic to the DNA synthesis well there's a molecule that actually utilizes methylene tetrahydrofolate to be able to convert itself into what's called thymidine right so we actually take um d u MP which is your uh uracil right so it's one of those uracil derivatives and we want to make or urine and we want to make thymidine and so thymidine is basically one of those potential nucleotides that is essential to making DNA but in order for this process to occur I need to actually utilize methylene tetr hydrolate in order to make dtmp and then dtmp will then be utilized to make DNA whenever that happens though it actually takes this methylene tetrahydrofolate and converts it back into dihydrofolate so if I have a deficiency in folate I'll have a decrease in this guy a decrease in him a decrease in him will he be able to react with the DP to make thymidine to make DNA no so this process becomes inhibited which then that means I'm making less of the thymidine decrease in thymidine synthesis leads to a decrease in D synthesis that impaires the stem cell from maturing so you inhibit the maturation process and as a result you end up making these big honky siiz red blood cells and multi-lobulated nuclei within the neutrophils that's folate now what about B12 well B12 is essential in being able to convert this five methyl tetrahydrofolate into tetrahydrofolate there's another molecule and it's called homo cysteine and homocysteine should be converted into a molecule called methine now b12 is crucial for this process to make homosysteine into methionine and in order for that process to occur we need five methyl tetr hydropi to make tetr hydropi to go back to this guy to help us to make what thymidine if there is a decrease in B12 then this process C won't occur this will be inhibited which means you'll make less of the tetr hydrolate less of the 510 methylene tetrahydrofolate less of this will be able to be converted back into dihydrofolate which means you'll make less thymidine and then less DNA so that's really the importance here is that in the absence or deficiency of B12 and folley you will impair the synthesis of thymidine which will impair the synthesis of DNA you won't be able to have the adequate DNA for the stem cell to mature and to condense and so you'll end up with these honky red blood cells and the hypers segmented neutrophils so this how you get your megaloblast right and you'll get your hyper segmented pmn all right now that we understand this process we should have a good idea of really how do we differentiate megaloblastic macro anemia from non- megaloblastic macro an macro anemia and it comes down to the presence or absence of hypers segmented neutrophils but then taking it a step further it also one is an impairment in DNA synthesis which is dependent upon B12 and fully the others are not a DNA synthesis impairment there's either some type of alteration lipid metabolism such as in curosis and alcohol use or hypothyroidism or there's some type of impairment in the hematopoetic stem cell being able to differentiate into the properly shaped re blood cells maybe this is MDS right or there's another process like reticul cytosis that's at at Bay now that we know that let's kind of dig in a little bit more into talking about B12 deficiency what's causing that and fley deficiency and what's causing that we Now understand that if a patient has megaloblastic macro anemia they have a anemia low hemoglobin MCV greater than 100 and the presence of hyp segmented nutrifil on peripheral blood smears right and we know it's du to an impairment and DNA synthesis that's the basic concept here what I need you guys to understand is what causes of a deficiency in B12 really that's the big thing right because we if we can recognize that we could potentially address that and treat that so let's kind of do this off of this diagram here I think this mind map will really help us so let's say here we're talking about the git and we're going to have different levels the oral cavity here above the dotted Blue Line the stomach and then the small intestin and then from here there's an absorption into the systemic circulation where it takes it to our tissue cells if a patient has a inadequate intake of B12 so in other words they're not consuming enough B12 that'll lead to a deficiency in this B12 molecule right right so now we have a deficiency here of B12 what would be a cause of that strict vegan diet diets that's really the primary way that you can think about that from a oral cavity at this part here where there's a decreased intake if you will and that usually would be very strict vegans all right now generally you can find B12 in a lot of things you know meat eggs dairy products so if you're kind of staying away from those things in the scenario of strict vegans you may not be able to get an adequate amount of that B12 into the git that means less of it moves through the git less of that B12 gets into the systemic circulation and less of it gets taken to the tissue cells where your bone marrow is to make the actual proper red blood cells what if the patient is not a strict vegan though takes in an adequate amount of B12 but the problem now here is that the B12 usually it kind of moves down from the oral cavity the esophagus and it gets down here into the stomach right gets down here into the stomach there's another molecule though made by our salivary glands and this is supposed to help to protect B12 right because when it's you get into the stomach there's all the hydrochloric acid and the pepsin uh which are going to you know break down some of the actual B12 components or the food B12 and so this this protein that is really important from the salivary glands is called hapto Corin now haptic Corin is a transport protein essentially for the B12 and what it'll do is it'll bind with the B12 and you'll end up with this kind of complex if you will all right so now you'll have a complex and let's kind of represent this with this blue color here here's our B12 and we're going to have it bound with our beautiful little hapto Corin all right so here's the complex that we have of these two now once these get into the stomach right hapor is supposed to protect it from a lot of different nasty enzymes but there is a really important molecule that we need from our stomach uh and these are these cells here these are called your parietal cells and your parietal cells are cool because not only do they make hydrochloric acid right so they do make hydrochloric acid but they also make a molecule called intrinsic factor all right so they make a molecule called intrinsic factor so they should make hydrochloric acid and they should also make this molecule called intrinsic factor now intrinsic factor is super crucial because eventually it'll want to bind to B12 but it doesn't happen immediately in the stomach it happens further down in the intestines and so intrinsic factor is crucial and you'll see why a little bit later why intrinsic factor is really really necessary because the B12 inhorn complex will just continue down and they'll get into the small intestine eventually right and we'll talk about how that's relevant but what if a patient doesn't have an adequate amount of intrinsic factor so in this scenario we said their problem could be what if it is what if it is a problem where there is a deficiency in B12 intake so this could be the problem there and that was due to a strict vegan what if there wasn't an adequate amount of intrinsic factor this process wasn't occurring then I wouldn't eventually be able to bind to the B12 and help it to get absorbed we'll see how in a second I want you to trust me for now but intrinsic VOR is crucial what would cause a deficiency in intrinsic factor a lot of things one is you cut out the cells that are responsible for making intrinsic factor what's that called a gastrectomy so sometimes a gastrectomy or any kind of like bariatric surgery I'd definitely be thinking about that right ruin why gastric bypass the vertical SE gastrectomies definitely think about that another one is what if I destroy these cells what if there's inflammation or there's destruction or decrease in the size of the stomach so we call this atrophic gastritis so atrophic gastritis could also cause this and this is basically you're not making enough of the intrinsic factor what else another really really important one is called pernicious anemia so it's called pernicious anemia now here's the big thing to remember with pernicious anemia this is due to particular antibodies so you're actually making antibodies represented here with these blue color here you're making antibodies that are usually directed against the parietal cells or directed against the intrinsic factor so if I have a patient here who I have these antibodies directed against the intrinsic factor that'd be called anti intrinsic factor antibodies if I have another antibody that's directed against the parietal cells that make the intrinsic factor these are called anti parietal cell antibodies and so these will bind with the actual intrinsic factor or damage this guy damage the parietal cells and so you can't make intrinsic factor right and so this process would be impaired so it's either these are directed against and destroy the parietal cells which then impairs the synthesis of intrinsic factor all right so these antibodies are called what again let's actually list these These are called either anti-parietal or anti-intrinsic factor antibodies so anti intrinsic factor antibodies are anti parietal cell cell antibodies now for pernicious anemia is an auto disease so you see this in patients who maybe have um Vitiligo or Hashimoto thyroiditis so definitely be thinking about that in the clinical vignette but again to think about this like in a in a simple mindmap way if it's an the orchadia esophagus and there's not enough B12 there it's because you're not taking in enough strict vegans if it's a process in the stomach it's because you're not making intrinsic factor that eventually will bind to B12 and help to get it absorbed you're either cutting out the stomach the stomach is really really atrophied and it's inflamed or you're having antibodies directed against the intrinsic factor or the cells that make the intrinsic factor all right what if I get down here to the small intestine so now at the small intestine level I'll have that complex right I'll have my complex here of the B12 and the hapor now I'm getting to the intestines where I need to absorb I need to absorb this B12 so what should I do now well the pancreas is really cool and it makes some enzymes and these are called pancreatic proteases and guess what hapto Corin is it's a protein and so these pancreatic proteases will eventually go and break down what they'll break down the hapto Corin and so what will happen is you'll have these pancreatic proteases and they will chew up this guy here so they're going to come over here and they're going to actually help to take and chew up the haptic Corin and then what are you going to be left with so it's going to stimulate this step here and we're going to spit off the haptic Corin so we're going to spit off that haptic corn which is that Protein that's binding to the B12 so now that's going to be free and what are you going to have free now and roaming around now you're going to have the B12 free from the haptic corn that intrinsic factor that was moving down here is going to get involved in this process he's going to come in and he's going to combine with this dude so now I'm actually going to bring this guy here I'm going to bring him down and what I'm going to do is I'm going to have these pancreatic proteases they're going to be involved in this step here right they're driving that process but then you free up the B12 and you're going to bind this guy the intrinsic factor with the B12 so when these two guys bind you end up with a what intrinsic factor and B12 complex that's what I have there so I have a B12 an intrinsic factor complex guess what these do they bind with little receptors on the small intestine in the ilium and so here they're going to go and bind onto these receptors when they bind onto the receptors they'll go undergo a receptor Meed endocytosis process and eventually they'll get absorbed into the bloodstream and then here I'm going to have that B12 get pushed into the bloodstream so this is the process here so you have to remember that if a patient has some type of deficiency and intrinsic factor from these scenarios here what will happen you have less intrinsic factor binding with the free B12 that got liberated from the haptor if it's not going to allow for thus complex to form you won't be able to absorb it so less of this guy leads to less of this reaction less of this complex and less of the B12 getting absorbed that's important to remember now what if what if there's something wrong with the pancreas the pancreas was inflamed if the pancreas is inflamed could you make pancreatic proteases no if I can't make him could I stimulate this process to liberate haptic corn from B12 no and so if I don't have enough of these this process could be inhibited and I could have less free B12 to combine with the intrinsic factor to make this complex to get absorbed so you see in a patient who has what's called pancreatic insufficiency so this is called exocrine pancreatic insufficiency so exocrine pancreatic insufficiency they don't make enough of the pancreatic proteases they don't Liberate the complex that contains what B12 and haptic Corin if you can't Liberate the hapor you don't get free B12 to bind with the intrinsic factor if I don't have him I don't bind with him to make this complex which is needed to get absorbed that is crucial here's another thing let's say that you have the adequate amount of pancreatic proteases you have intrinsic factor you're taking enough of the B12 but whenever the B12 gets to this part when it gets liberated there's a lot of bacteria or there's a tapeworm and what happens is that B12 gets metabolized heavily so you end up with a heavy metabolism and you chew up the B12 right so there's a heavy metabolism of the B12 what could that be due to if you heavily metabolize this process you're going to chew up that B12 this could be due to a bacterial overgrowth so if I have lots of bacteria if I have lots of bacteria that'll drive this process which will further further lower my B12 and I won't have enough of it to bind with the intrinsic factor to get absorbed so in situations of bacterial overgrowth another one is if you have a tapeworm it's called a fish tapeworm that can also chew up and eat all that free B12 so fish tapeworm is another one to think about all right we come to the last scenario here for the intestines let's say there's no problem with bacteria or fish tapeworms there's no issues where you're you don't have the pancreatic protasis there's no issues where you don't have enough intrinsic factor there's no issues where you're not taking in enough B12 in your diet the problem is is that you have a normal amount of intrinsic factor in B12 but the process where you want to absorb the B12 the tissue is destroyed so there's inflammation or destruction of the epithelial tissue that's supposed to transport that B12 ah even if all these pathways are intact you don't have the tissue that's needed for you to absorb because you've destroyed the anas sites or you've destroyed the surface area the little micro that are important for absorption what could that be due to Crohn's disease or silc disease so if a patient has Crohn's disease or celiacs disease you should definitely be considering something like that as well so Crohn's disease or celiac disease okay what do we know about this to take away from this again you either don't take enough B12 in into your your mouth right and so you don't have enough of it going down this pathway or you don't make enough intrinsic factor whether because you cut the stomach out and you got rid of a lot of cells that make it or you have atrophy and inflammation of the cells that make it or you have an antibodies directed against the cells that make it you don't have it and therefore you can't make this complex or you make haptic Corum but you don't have the enzymes from the pancreas to liberate the hapto Corin from the B12 so therefore it never combines with the intrinsic factor to absorb across the intestines that could be in pancreatic insufficiency or you have all of these enzymes and proteins and you're taking enough in but you have too much bacteria or tapeworms that are just consuming the B12 that are free inside of your intestines and now you have less of it available to bind with intrinsic Factory to get absorbed or you have all these enzymes not enough no bacteria no fish tapeworm but even though you have an adequate amount of intrinsic factor in B12 that get to the ilum the ilium isn't capable of being able to absorb it because it's injured or damaged and the surface is messed up and that could be in Crohn's disease or celiac disease now once this guy gets out once this B12 gets into the circulation it will eventually bind with another a protein called transcobalamin so it's called trans cobalamin and this transcobalamin will then transport the B12 so here would be our B12 he'll be transported around with this transcobalamin to all the different tissues that it needs to go to and when it goes to these tissues especially where especially the tissues of like the liver or the bone marrow it'll be utilized in order for us to make proper red blood cells but if you have a deficiency in this B12 what's going to happen you're not going to allow for the synthesis of red blood cells properly so that's a really really important thing to think about okay now we've hit B12 deficiency pretty hard sometimes if it's not due to a decrease in intake or a problem with like malabsorption of sorts there is sometimes where let's say that you're taking in B12 but your tissue's demand is so much higher so sometimes in pregnant patients um we can see their tissue Demand Being a little bit higher that they require more B12 to be absorbed and even though maybe you're absorbing an adequate amount of B12 your tissues are consuming it and so theoretically if your tissue demand is higher than what you're able to give it it could cause a mismatch and a B2 deficiency so watch out for patients who are pregnant as well with that being said what I want to talk about now is complication a that can arise and B12 deficiency and the reason why is when you get a patient who has megaloblastic macro anemia it's crucial for you to be able to realize if it's B12 deficiency or folley deficiency and there is some clinical cues that can make you think about that so the first one is neurological complications this is really the Crux of it all and patients who have B12 deficiency they often have neurological symptoms which is not present in patients with fully deficiency anemia but they do have a degree of overlap which will'll see so whenever we kind of get closer to this side you'll see that there is a little bit of overlap between the two now for B12 deficiency these neurological complications what does it do to well inside of the mitochondria of especially lots of different cells but I'd say neurons are the big one you have a molecule which is called methyl malal COA right so it's called methyl malinal COA and what's supposed to happen with this is It's supposed to be converted to another molecule called suon COA in order for this process to occur it's heavily dependent upon an enzyme and this enzyme is called methyl malinoa mutase but what's more important is that B12 is essential for that enzyme to work so if a patient has a deficiency and B12 what will happen is this process will be inhibited the enzyme won't be able to work properly and so what happens is methyl malan COA will build up in the mitochondria of these neurons the problem with methyl malan COA is that this bad boy this elevated we're going to actually abbreviate it methyl malal COA we like to call it MMA so we're going to abbreviate it methyl malinal COA so increas in me methyl malonic acid so MMA whenever there's lots of MMA right what can happen is it can it can cause a specific process where here we have let's say normal milin sheaths so here's your milin sheath and then here is some other milin sheets MMA is crucial For the myin synthesis within our neurons the axons right and so if there's a high chunk of this methyl maloa what happens is is it leads to deyin right so it can stimulate unfortunately demyelination now when I demate these axons then what am I going to have here I'm going to have these neurons that are all chewed up right especially on their axons now look at the myin are you going to be able to conduct impulses properly here on these no you won't so this chewed up axons here will lead to decrease signaling of the neurons so this will lead to decrease neuron conduction and unfortunately this will cause a lot of pathological types of presentations like what well if I demate some of these neurons that are present in the spinal cord it can lead to a condition called SCD so it's called Subacute combined degeneration of the spinal cord now what it tends to affect is the dorsal column and the lateral column but I'd like to remember a little trick here so there's a little trick here and you can remember s c d so s c d so s is there's spino cerebellar tracts that are injured and the spino Cabell tracts are usually on the outer side of the lateral white columns so usually on the edge of the lateral white columns is your spino cerebella tracts those will be demyelinated so spino cerebellar tracks will undergo demyelination so you'll have damage to these right so spino cerebella tracks will be damaged now if these are damaged what would this kind of present with well well this is sending information to your cerebellum your cerebellum is crucial for balance and coordination and so often times a taxia is a very common presentation here so a taxia that's something I would watch out for so sometimes you can even cause a positive Romberg sign within Subacute combined degeneration so watch out for a positive Romberg sign all right so the other component here of SCD is going to be again the corticospinal tracts so the corticospinal tracks are going to be damaged or deyin now these are again in the lateral column as well and usually what happens is you get the decoation of the pyramids they come down and so they'll actually eventually end up synapsing on the anterior uh motor neurons right in the anterior gray Horn of the spinal cord and that'll go out to the muscles and so if you end up causing deamination of those you alter the signals to your skeletal muscles right and so this will lead to weakness and so because of that you want to watch out for paresis but especially it can be kind of a type of appearance this I'd say is a little bit later in the disease but definitely be careful and cautious for what's called paresis and a worst case scenario sometimes it can cause paralysis the last one here is the D for the Subacute combined degeneration so this is going to be the dorsal column right so watch out for demyelination potentially of the dorsal column now you have to again go back to some of your basic function here and your physiology that the dorsal column here is responsible for carrying signals that do what they carry Sensations particularly related to propri reception and vibration and fine and discriminative touch and so whenever there is a destruction of these it can lead to an alteration in that and so you may have Sensations where there is decreased vibration and decreased proprioception with all of this being said a patient may have again Subacute combined degeneration of their spinal cord where they have demolation of the spinal Cabell tracts cortical spinal tracts or the dorsal white column if this exists they could have these Sensations plus they may even have a positive Romberg sign so watch out sometimes for a positive rberg sign here in these patients as well all right now another thing that you want to watch out for in patients with B12 deficiency is not only can it cause this Subacute combined degeneration but it can alter some of the higher cognitive functions in patients and so sometimes they can have neuros psychiatric disturbances so you want to watch out for neuro psychiatric disturbances sometimes this can even cause patients to kind of look like they have dementia it's really really important to always be able to recognize that so if a patient has delirium or dementia always check a B12 level and the last thing is you may also get some involvement of the peripheral um neurons and so you can get neuropathy right so you want to watch out for any kind of neuropathy here now the big thing with neuropathy especially for this patients is it often times involves the lower extremities more than does the upper extremities and it's usually going to be symmetrical so you'll get symmetrical paresthesias and that's really really important to remember as well so watch out for symmetrical so you'll end up with symmetrical paresthesias and again it's going to be more distal in these potential patients all right so subq combined degeneration of the spinal cord is a big feature of B12 deficiency as well as Neuropsychiatric disturbances and symmetrical distal parasthesia from neuropathy now the other thing that can happen in patients to have B12 deficiency it has a pretty significant effect on another pathway so we talked about methyl malal COA right how if we don't convert that into what the sucin COA you end up with a buildup of that it's the same kind of concept there's another molecule and we talked about this back in the beginning where you have what's called homosysteine right and what we know is that homosysteine is eventually supposed to be converted into another molecule right so here we'll say this is homo here in blue it's supposed to be converted all right so here's our homo cysteine it should be converted into what methionine if a patient has some type of process where they have a deficiency in B12 again we have to remember that B12 was really critical for methionine synthes which converts homosysteine into methionine if you have a deficiency in B12 what will happen you won't be able to convert homosysteine into to methionine so this process will be inhibited as a result what will happen to the amount of methionine it'll go down what will happen to the amount of homocysteine well you can't convert him so he will start to build up when homosysteine levels build up it has a really nasty effect on our vasculature one of the things that homosysteine can do is it can actually kind of cause platelets to want to get aggregated so it can actually cause platelets to maybe want to get a little aggregated so they want to stick together at the blood vessel but also it may signal the endothelium and the endothelium can kind of cause a lot of cyto kindes to be released there'll be lots and lots of cytokines and these cyto kindes will cause what kind of a lot of dysfunction it'll cause a lot of inflammation so that's one thing it'll cause inflammation so it kind of cause some inflammation but the other thing here is that it'll cause endothelial to be dysfunctional so one when you get a lot of these cyto are going to cause inflammation but on top of that this inflammation it's going to cause a lot of dysfunction or injury to the endothelial cells when you injure the endothelial cells do they have the capacity to release nitric oxide and procyclin which inhibits platelets no so because of that you end up causing platelet to want to stick and so the plets are going to love to stick to this injured endothelium so whenever you have inflammation that's going to cause plaques to build up because it's going to cause endothelial dysfunction but on top of that it's also going to cause pus to want to Aggregate and so these patients can get as a result from this process they can get converted into this they can go from a normal vessel to this and this is going to be atherosclerotic cardiovascular disease and in some scenarios they may end up with thrombi that form on top of that and that's what you get worried about right is getting a thrombus on top of an already existing plaque why because if they have a plaque they may have a decrease in Supply but not so much that it's completely blocking off the oxygen so they can end up with a lot of vascular diseases things like CAD maybe they block off the the vascular supply to the brain for a little bit they end up with a Tia or they block off some blood flow to the muscles of the legs and they end up with this called p a but if they get a clot there what do they run the risk of completely including that vessel they can get an MI so they can end up with an infar here they can actually block all the blood flow off to the brain end up with a stroke a CVA or they can completely olude the actual limb and lead to a critical limb ischemia right and so you want to watch out for that because these are the big things that can actually start to develop as a result so one of the things that's really interesting is working in the hospital is when we have patients who have strokes they're younger don't really have a lot of cardiovascular risk factors check a B12 because B12 can actually increase their risk for cardiovascular complications and increase the risk of Strokes really really important to remember all right that's B12 deficiency let's now talk about Foley deficiency all right so let let's talk about the causes of fley deficiency so in a patient has fully deficiency it's kind of somewhat similar to B12 deficiency in the sense that we're going to kind of use this mind map here to guide us so what if a patient doesn't get enough foli in their diet now it's kind of hard because foli is kind of fortified in so many different foods Within you know our food groups so to get it from like you know being a vegan or vegetarian or things like that it's not too common really the only way that you can see this if a patient is like a severe chronic alcoholic that may cause a Foley deficiency U but it's not super super common as a problem of deficiency they may not just get enough of the actual Foley in their diet especially all of they're doing is just drinking and drinking tons and tons of beer liquor because that's not really rich in a lot of the micronutrients so if there's a decrease in the intake of folate really the only thing that you can really chalk that up to is severe alcoholism folate whenever it gets you know moved from the oral cavity eventually it'll get through the stomach and it'll get to the small intestine right so when we get it into the small intestine it actually exhibits uh kind of two forms this is called the polyglutamate form so it's called the poly glutamate form and then this is our mono glutamate form of folley now in order for the polyglutamate form to be converted into the monoglutamate form we need an enzyme and this enzyme is called intestinal conjugase so it's called intestinal conjugase now intestinal conjugates will actually break down the polyglutamate form into the monoglutamate form now what if a patient has uh for some reason they have things that could inhibit the intestinal conjugates so what if I inhibited this enzyme right and if I inhibit this enzyme I can't allow for this process to occur so I get decreased amounts of the monoglutamate form the problem here is that the monoglutamate form is supposed to get absorbed from the small intestine into the bloodstream right and so that's how you get your folate here so that's how you're going to get your folate here into the bloodstream well there's a couple different reasons this could happen but the main thing is that it could be due to something that's inhibiting this enzyme and that usually is a drug called photoin so this is one of our anti-epileptic drugs and phenin has been known to inhibit the intestinal conjugates the other thing here is that alcohol has been really shown to heavily inhibit not just the amount of folate coming into our diet but it can also directly inhibit the absorption of the monoglutamate form so this can inhibit the absorption of the monoglutamate form so we'll get less folate being absorbed across the intestines into the lerum so again a patient who has alcoholism this could be a pretty common cause the next thing what if a patient has proper intestinal conjugates activity they're not taking in a lot of alcohol into their diet but the problem really here is is that the intestinal epithelium is damaged and you don't have the anas sites that are capable of being able to do what absorb that foliate across the git this would be whenever there is some type of destruction of the intestinal epithelium over those two diseases I told you one that's causing significant inflammation like transal ulcers and the other one's causing loss of the little microvilli the absorptive surface area decreases that could be Crohn's disease and P celiac disease so watch out for Crohn's and celiac disease we know that it's a patient who either either has severe alcoholism that the most of their diet is beer and liquor that they're not getting enough the micronutrients in their diet second is you inhibit the polyglutamate form to monoglutamate form photoin you don't absorb the monoglutamate form alcoholism or you have a damaged epithelium that won't allow for you to absorb that monoglutamate form and that would be celiacs disease or what else this could also be due to Crohn's disease now let's say that you have a problem here with these right that would explain these potential issues but what if you have a you know no issue where you're getting an foliate in your diet right you're not having any issu with alcoholism you don't have any inhibition of the intestinal conjugates you have no damage to the intestinal epithelium so the amount of foliate that's getting absorbed across the bloodstream is appropriate but what happens here is that when the folley gets out here to the tissues some kind of weird things happen you got to kind of go back here and remember what happens right so we know that folate is converted into what's called dihydrofolate and then the tetrahydrofolate and then we know further down it's the 510 methylene tetrahydrofolate and then we got the five methyl tetrahydrofolate right and then again we kind of know this whole process that kind of goes back right what's really important here is we want to convert dihydrofolate into a molecule called tetrahydrofolate right in order for that to happen you need Folly to get converted to dihydrofolate and then eventually into tetr hydrolate then these guys and then this one right here right and what we know is is that in order for us to make what the thyadine we know that this guy has to go back to him and then in that process we take the what DP and then we make the dtmp which helps us to make DNA right we know that process what you need to know is that folate right in order for us to get dihydrofolate converted to tetrahydrofolate we actually have an enzyme here and this is called [Music] dihydrofolate reductase now dihydrofolate reduce is supposed to help to drive this step dihydrofolate to tetrahydrofolate but what if I inhibit this enzyme right so I inhibit this enzyme so I inhibit this step even though I have maybe an adequate amount of folate it won't matter because that folate isn't able to going to be able isn't going to be able to be utilized to synthesize the actual what 510 methylene tetrahydrofolate so then I won't be able to allow for this process to occur so I won't make thymidine and I won't be able to synthesize DNA there's certain things that actually inhibit this dihydrofolate reduce do you guys know what that is this is usually going to be two big drugs one of them is going to be methotraxate and the second one is going to be trimethoprim sulfamethoxazol so this is going to be one of those immunosuppressive agents that we can use in things like rheumatoid arthritis or SL and then this is going to be something that an antibiotic that we give now trith suf oxol is supposed to inhibit dihydrofolate reductase that's involved in bacteria but it can actually affect some of the eukariotic cells as well which is in our normal host human cells so it is something that actually consider the last thing that I would also want to consider here is that in this scenario right the folate is actually maybe normal so maybe a patient has a normal amount of folate the problem though that exists here is that they just don't have enough of it being utilized by the cells because it's being inhibited from being able to kind of go to make the precursors that are needed to make DNA often times what we'll do in these potential scenarios when we have a patient who's on methy trexate or trimeth suam myth oxol more wored about them developing a flei deficiency will actually sometimes give these patients fenic acid and so sometimes a kind of alter a therapy to consider is we can actually give something called fenic acid and that may actually help to prevent this process from occurring in these scenarios because you can have an adequate amount of folate but the foli doesn't being utilized to its maximum capacity other scenarios that I would also be considering is if ther kind of demand issue so sometimes in patients who have um homolysis chronic homolysis their demand for foliate is super high or in pregnancy their demand for foliate is super high so if the tissue demand let's say that this tissue that's utilizing the folate if there is a massively increased demand for folate so maybe you're getting enough folate in your diet maybe you're absorbing enough of the folate but the problem that exists here is that your tissues are demanding so much more foli than you're able to give it that could be in situations of pregnancy and chronic homolysis so again we say pregnancy will kind of cause such a strong desire for Folly that you're going to need to get more in your diet because your tissues are consuming a lot of it or homolysis so you're breaking down red blood cells and if you're breaking down tons and tons of red blood cells chronically guess what your bone marrow is going to need a lot of foli to make more red blood cells and so that's another situation where the demand for folate will go up often times in patients who have chronic hemolysis will actually treat them with folate supplement a so with this being said if a patient has foli deficiency think is it alcoholism because they're not getting enough nutrients is it due to inhibition of the intestinal conjugates phenin is it due to me not absorbing the foliate across the git because of alcohol or celiacs or Crohn's is it a problem where the foliate is actually an adequate amount getting taken into the system but it's being inhibited from being able to be converted into the metabolites it needs to make DNA such such as in inhibition of dihydrofolate reductases such as in Methotrexate or trimeth suth oxol use and then lastly what if it's your demand for foliate is so high that it's consuming so much of the folate from these tissues that it's lowering the amount of folate that we have available that can also cause a functional foli deficiency such as in pregnancy and chronic homolysis with this being said it's important to understand what are the classic presentations that can occur in fley deficiency and help us to differentiate that from B12 so in fley deficiency you don't see these neurological symptoms like the Subacute combined degeneration you don't see a taxia positive Romberg signs weakness uh paresthesias numbness and tingling in the lower extremities bilaterally you don't see the loss of prop perception and vibration problems in this you actually see the same thing so in patients who have Foley deficiency they also have this issue where they can inhibit this process the homocysteine into the methionine so if you have a deficiency in B12 and you have a deficiency in folate both of these pathways are heavily dependent so this pathway is heavily dependent on B12 and fley so it decrease in fley you're not going to make methionine you're going to build up homocysteine so patients who have a B12 deficiency or a fley deficiency have higher risk of cardiovascular complications such as atherosclerotic cardiovascular disease what's also interesting is that these patients have high risk of obstetrical complications so if a patient is pregnant then you want to consider these potential complications such as neural tube defects Now foliate is really needed in order for us to close up the neural tube right so you have what's called a neural tube that you want to make and it's there's a little pore here called the neuropore and there's the anterior neuropore and the posterior neuropore and in order for those to close you need the presence of foliate all right so in order for this to completely close off that neural tube you're going to want an adequate amount of folate but if you have a decrease in folate this process will not occur and because of that you'll end up with neural tube defects that neural tube won't completely close what could that look like one way is it could look like spinabifida for the child right in other words they don't completely close off their lamina so you know how you have your transverse processes and you're going to have your lamina which helps to combine with the spinus process that won't occur and so they actually get this little TFT of hair and cause a little dimple area and they're usually in their back it can also cause a meningo seal and this is sometimes because they don't close off their lamina some of their Duram matter or their meninges kind of Bulge out into this little pocket outside of their body and that's called a meningo seal and then worst case scenarios sometimes you can have this pocket holding into it what meninges and spinal cord and that's called a maningo Milo seal the worst case scenario for a patient with a neural tube defect is something called anany where a good chunk of their skull uh doesn't actually form and it looks a little bit like this with that being said having a deficiency in folate in a patient who is pregnant can cause significant obstetrical complications such as neural tube defects and you don't want to have these happening so often times we'll make sure that if a patient has a pre either pregnant we maintain a really good Folly level and sometimes if we are scared that they're developing these things we can check things like maternal serum Al fetal protein levels we can do ultrasounds as well but again we want to try to prevent this and so making sure that they get an adequate amount of folate is super super crucial all right so with this being said we've really hit a lot of information about macro citic anemia and defi deciding if it's megaloblastic or non- megaloblastic and then we really spend a lot of time talking about megaloblastic macro sitic anemia really understanding how that impairs hematopoesis how it impairs DNA synthesis and then focusing on what are those issues it's due to B12 efficiency and Folly deficiency what causes those things and then lastly we discuss what are some specific complications or clinical features that can help us to distinguish those between the two which will help you to destroy those vignettes so now that we've done that let's take the time to actually go through and approach this in a really nice systematic way we talked a lot about macro anemia but now we got to put into practice everything that we've really discussed so if a patient comes in you get a CBC because they're presenting maybe they're presenting with fatigue poar disia maybe they have a hyper dnamic State you want to check a CBC you get a reticulite index because you're really really good you do that the retic index comes up less than 2% what does that usually mean again means the bone marrow is not working right that's usually for most of the cases almost all macro ciic anemas if the retic index is really really high though that would be something different and we'll talk about that but again what does a retic index less than 2% mean it tells me that the bone marrow is under producing that stem cell is not properly making enough of these reticul sides to convert into uh the matured red blood cells whereas if the we take index is greater than 2% it tells me that the bone marrow is overcompensating and this means because I'm losing a lot of blood or I'm humanizing a lot of my bread blood cells and this is just telling me that the bone marrow is really working hard to produce a lot of reticul sites to mature as much as it possibly can into some of these red blood cells that's the big difference here so for macrotics we're focusing on patients who are going to have a low reticulite index but what they're really going to be looking for is that hemoglobin you want to see the hemoglobin less than 13 in a male or less than 12 in a female to make it anemia then you need to look at the MCV the mean corpuscular volume if it's less than 80 that's microtic if it's 80 to 100 that's normal cic and if it's greater than 100 fol lers that is macro citic anemia so you found macro ciic anemia based upon three different things one is the presence of anemia based upon the hemoglobin right the next is the presence of an MCV gr to than 100 that supports macro siic and then lastly is the presence of a reticulite index less than 2% that helps to support that this is an under production all right now we need to really take a look and say okay is this megaloblastic or not megaloblastic what did I tell you was the real big difference it's the hypers segmented nutrifil if I take a look at that peripheral blood smear and I see the presence of hypers segmented neutrophils that's definitely more than five loes bro that is a megaloblastic macro ciic anemia and that comes down to B12 in fley deficiency so now I have to ask myself the question how do I determine this get a B12 and a foliate level if I get the B12 and it's low it's B12 deficiency if I get the flei and it's low it's folley deficiency where it might be a little bit more difficult is when the levels are like borderline like normal or they're like pretty much like the same right then you're like H I don't know I mean it's like borderline low it's just like near the lower limit but it's not really really bad and those scenarios or maybe they're equivocal that's another thing so how do you really determine which one's driving this if it's borderline low or uh you know in this kind of situation very equivocal then what I would do is I would go ahead and get what's called a MMA and homocysteine level the reason why is if a patient has like borderline like low it's kind of almost normal or they're both like equivocal and you don't know which one's driving it you can really differentiate these two that's only when you do it is when you're like man they're both kind of like normal or they're both about the same like low value and you're like I don't know which one's driving it get the MMA and the homosysteine level the reason why is the MMA was only affected by B12 homosysteine was affected by both of them because again remember the homoy emia was the thing that led to cardiovascular complications in both of them MMA was only leading to the neurological manifestations which was present in B12 deficiency so if it's high for both of them it's B12 if it's high only for the homocysteine it's folate deficiency all right now if a patient has B12 deficiency is it a it is Paramount to really determine if it's pernicious anemia and so often times what you'll do is you'll get those antibodies get the a parietal cell antibodies and the anti-intrinsic factor antibodies to see if those come back positive if they do you got pernicious anemia but if it comes back negative that's sometimes where we may consider this additional test called the Schillings test it's an older school test and we don't really do this as much anymore but it can be tested on your exam all it is is you take and give a patient oral radio labeled B12 all right so we can tag this they ingest it and when they ingest it it gets absorbed across the actual git into the bloodstream and then what happens is from here you'll do another step so you'll give them the B12 and then you'll inject them intramuscularly with B12 to really load up their circulation when their circulation gets really overloaded with B12 what happens is some of that oral radial label B12 it'll just have to get excreted out something will have to get excreted out and so it'll go to the kidneys and the kidney will actually Force this out into the urine and so if there's really high B12 levels because of the combination of both of these getting into the circulation you'll pee out a lot of that oral B12 and it'll show a normal or elevated value here what this tells me is that there is no issue with absorption this is not a absorption issue it's a decreased intake or your body's in such a high demand but if I give the oral R label B12 and there's something wrong an absorption issue maybe it's a a part of the stomach it's a pancreas issue it's an intestinal issue it's a bacteria tapeworm issue whatever this will not get properly absorbed so you get less of this oral radial label B12 into the bloodstream you'll give them an injection to try to up their little levels of B12 but they're not going to have as high of a level of B12 in the circulation as they would in this scenario so what happens is less of this oral radial label B12 gets forced down to the urine that means their B12 and the urine will be low lower and that suggests more of a absorption issue and then from here you can kind of take a little bit step for forward forward with uh the Shillings test where once we determine oh it's likely an absorption issue what you can do is give them intrinsic factor and if the B12 level normalizes that's pernicious anemia you can give them pancreatic enzymes like the pancreatic proteases and if their B12 improves it's probably ex pancreatic and sufficiency if you give them antibiotics it will kill off all those bacteria that are overgrowing less of it will get metabolized and the B12 will increase in the urine so these are ways that we can try but we don't often do this but remember this for your exam at least all right if I don't have any hypers segmented neutrophils then I'm left with the non- megal blastic something is going on with the alteration in lipid metabolism again with this one you're really just kind of looking at their history uh if a patient has pancytopenia um I would consider myo plastic syndrome right you really got to get a bone biopsy to truly confirm this but it could be something to consider um if I see no pancytopenia then what I'm really looking for is is there other causes like alcohol use is there some type of liver disease is there a thyroid issue and so if they have an alcohol use history it's could be that if they have abnormal lfts it could be curosis and if they have abnormal thyroid function tests then I would think it's a hypothyroidism right so a low T3 T4 and depending upon if it's primary or secondary that would determine the TSA AG right but at least we know that this patient definitely has one of these disorders another one you could do is you could look at the reticular site count if the reticul site counts really really high that could suggest a reticular cytosis in this potential scenario all right all right so we got to treat this now and so generally any kind of anemia as we talked about in the blood transfusions you follow the same guideline that for every one unit of pack red cells it increase the hemoglobin by one gr but you need to know when you give a a unit of pack red cells if it's less than seven but they hemodynamically stable you can give them that just give them enough to get them above that seven um if that's less than eight and they have pre-existing coronary artery disease um sometimes we'll even say if they have like CHF if they're getting ready to get cardiac surgery then you can give them a unit of blood as well to get them just above eight um this one's extremely controversial and it kind of goes back and forth um I wouldn't Harvest this in your memory but at least kind of consider it that some will even say that this less than eight would be applied to a patient having an acute coronary syndrome but some go with a little bit more of a liberal strategy I'm sorry restrictive strategy where they kind of say less than 10 hey I'm going to go ahead and give um a unit of blood or however many units of blood that I need to get the hemoglobin above 10 if they're having an acute MI but a lot of um clinici is really clinician dependent a lot of them stick around here that if there is a really really high need for it there's an increasing demand from the body like a pre-existing CAD CHF cardiac surgery something where you need to get more blood to the actual tissue especially the heart or the brain then they may push a hemoglobin greater than eight for that this one is extremely controversial the last one is a patient is in hemorrhagic shock so a patient comes in they have an acute drop in their hemoglobin they're hemodynamically unstable you give them blood if they're in evidence of hemorrhagic shock you just give blood you don't aim for a specific uh hemoglobin Target you do that until they're a little bit more stable that you can get them to the o or stop the bleed whatever it is so the three primary indications is less than eight hemodynamically stable less than I'm sorry less than seven hemodynamically stable less than eight with a pre-existing uh underlying disease that's increasing the demand CAD CHF cardiac surgery maybe something neurologically going on that you need to increase the blood flow and oxygen delivery and then lastly is hemorrhagic shock all right now with that being said once we've done that again it's important to remember that if again I have indications for blood transfusion okay get the blood transfusion going but from there I need to determine how do I treat the underlying disease which is the B12 deficiency really it's just comes down to are they not taking enough in or is there an increase in demand like in pregnancy if that's the case just give them oral B12 encourage oral intake if the patient has an absorptive issue and they have symptomatic kind of anemias okay so let's say that a patient has like they have symptoms of anemia poar fatigue Etc but more specifically neurological symptoms that's what's really concerning if I see the presence of neurological symptoms with a B12 deficiency they're getting IM B12 all right the other scenario is if they have a malabsorptive issue so if they have a malabsorption if I give them oral B12 it may not even matter and I have to give them IM B12 so again I'm looking for symptomatic anemia but the most important symptom is neurological manifestations if you have malabsorption I got bypass the git and go straight into the circulation all right folley deficiency funny enough we don't follow that same concept oh if there's like a malabsorption issue you'll have a problem right funny enough you still get at least enough of the folate to get absorbed and so folate deficiency no matter what we just give right away even in malabsorptive issues we give them oral folate all right if they're not responding to that then we can maybe go to the IM folate or IV but often times more than not oral folate would be just fine now one thing to add here is that let's say that you have a patient who has macro cdic anemia and you don't know which one it is and so you just like start them on fate right alone without the B12 you may improve their macrocytosis and normalize their MCV and improve their hemoglobin but what you're doing is you man you kind of like hide their neurological problems for a little bit and so what will happen is you fix the anemia but the neurological manifestations continue to occur due to the deficiency in B12 and so that I'll keep allowing for the MMA to build up keep dementing and keep causing potentially irreversible neurological damage so whenever a patient has macro anemia don't treat them with foliate alone give them a combination of foliate or B12 or just wait until those levels come back and you determine that just don't treat it with foliate alone because you'll treat the anemia and fix that but you'll worse in the neurological manifestations if you don't give them the B12 all right my friends that was macro anemia I hope it made sense I hope that you guys enjoyed it and loved it as always thank you love you and until next time [Music]