Crohn’s Disease: Etiology, Pathophysiology, Clinical Features, Diagnosis, Treatment

what's up ninja nerds in this video we're going to be talking about crohn's disease if you guys like this video you learn from it it makes sense please support us by hitting that like button commenting on the comment section and please subscribe also if you guys want to follow along with some awesome notes some illustrations go down the description box below it'll take you to our website check that out all right engineers but before we get started on crohn's disease we actually teamed up with an awesome online resource called chegg chegg is great it's going to be able to help you with a lot of your undergraduate and your graduate needs let's take a look and see what chegg has to offer for you all right ninja so the first thing i want to show you guys is go down in the description box below there's going to be a link there which is going to be having a promotion code for this chegg website so let's go ahead and check that out so whenever you click on that link it'll take you here and again the great thing that this offers for you guys is this coupon code for five dollars off for your first month of chegg study pack and you guys can go ahead and check this out all right so here on this home website we're going to go ahead and check out this really cool thing here on the side called the study tools tab it's going to take you to this kind of other menu where you're going to want to click on this one called check my writing and what i really think is cool about this is i'm not the greatest writer and i have mistakes in my grammar so it's really cool what you can do is you can take any of you you know your papers anything that you guys are writing for any course and go ahead and paste all of that in here or if it's somewhere on your computer on your google drive you can obviously click and upload that onto this link here also if you guys need some help there's actually like people who will read your paper they're experts in proofreading and they'll provide you a summary give you a bunch of different comments and help you guys out in the best way possible so i urge you guys to check this out go to this website make sure you again down in the description box below we'll have a link we'll give you guys that coupon code and check this stuff out it has a lot to offer for you guys all right let's get to our video all right so let's talk a little bit about crohn's disease crohn's disease is actually a category under the the what's called inflammatory bowel disease inflammatory bowel disease actually consists of crohn's disease and also consists of ulcerative colitis so what i want you to know is crohn's disease is an inflammation of the entire gi tract this inflammation that we're going to talk about can occur anywhere along the length of the gi tract usually it's most common particularly within the ilium and in the parts of the colon but nonetheless it can occur anywhere along the gi tract now this inflammation or kind of an autoimmune type of behavior what's it really due to believe it or not we don't have a completely beautiful underlying idea but there's some thoughts that we've seen with this one of the big things is that there may be some type of immune involvement and there may also be some type of genetics that are involved here and what do i mean here so our immune system is obviously targeting the gi tract right so we have different types of cells like macrophages we have our t helper cells which are also attacking the gi tract and then we'll also kind of infiltrate some neutrophils via the chemotaxis process to come there and also cause some damage what's kind of causing all of these cells to kind of really become very significantly going into the area and causing all this inflammation there may be some kind of underlying immune dysregulation why is there this immune dysregulation not completely sure but to give you kind of an idea here our gi tract is very very good at being able to especially the epithelial cells that line the gi tract wall they're very good at maintaining a nice barrier between what's in the lumen and what goes into the blood behind the actual epithelial tissue and so you know with inside of our lumen we have bacteria we have drugs we have different types of things that are moving with inside of this lumen here and normally the epithelial cells are very very good at maintaining an intact barium preventing things from just shifting right into the tissue right so what we've noticed is in crohn's disease this pathway may be somewhat altered where the barrier may be lost you know what happens you know epithelial cells they're good at sometimes sampling some of the bacteria and when they sample the bacteria they say oh this bacteria ain't no good man i don't like some of these bacteria let me destroy some of these so they don't overgrow in the lumen and they release very specific types of proteins called defensins one of the things that we see in these patients is that they may have a decrease in defenses there may be some type of decrease in the alpha defenses you know alpha defenses are made by these very special cells within the epithelial tract called the panth cells so penicillins are responsible for secreting defensins and crow's disease there may be a reduction in this the other thing you know goblet cells they make mucin mucin is also important because it provides a nice barrier a thick barrier between the bacterial this commensalistic bacteria which is in the lumen and the intestinal cells and underneath and patients with crohn's disease we also see that there is a reduction in mucin by the goblet cells you know what else there's certain types of bacteria especially like myco bacteria impaired tuberculosis it can get into our epithelial cells when it gets into the epithelial cells it kind of forms like these little vesicles inside so let's say here's the bacteria here's the mycobacterium tuberculosis gets inside of these cells normally what happens is we have very special types of vesicles in here containing lysosomes and what happens is these lysosomes will actually fuse with this vesicle containing the bacteria and destroy it what's that called autophagy and patients with crohn's disease what we see is a reduction in the autophagy process so there's also a reduction in now there's one very specific type of genetic thing that i want you guys to be aware of right there's a gene that's really important i want you to think about it like the intestinal sampler think about it like it's one of those guys that goes around and tastes wine everywhere it's running anything that's kind of running through the gi lumen it's just like tasting it's like all right let me see what's going on in here okay i gotcha i see what's in there this guy this gene there's a there's a gene in here that actually makes a very specific type of protein it's right here it's called the nod two nod two is this very specific sampler of bacteria and what happens is in crohn's disease there's some type of mutation in the nod2 gene where it's not really good at sampling the bacteria and when it samples the bacteria it's supposed to tell our immune system cells for example let's say that this bacteria the nod 2 will take very specific types of receptors it's an intracellular one let's say that there's a very specific antigen on that bacteria activates the nod too the nod two will then stimulate something called nuclear factor kappa beta and this will release very specific types of cytokines and what these cytokines will do is they'll tell our macrophages you know we have these cells called macrophages they'll be on high alert it'll stimulate them and when they're stimulated they'll come here and play a role with an immune surveillance on the back hey ain't nothing getting through here boy and so they play this very important role in immune surveillance now another thing is macrophages when they're kind of activated to play their role within this immune surveillance they also tell very specific types of cells called t helper cells you know these are very interesting cells probably not very talked about too often they're called th17 cells th17 cells release a very specific type of cytokine called interleukin 22 and interleukin 22 will tell some of these cells that are actually a part of the intestinal cells to make defensins to make mucins to increase the autophagy process and the reason why is is trying to prevent any kind of excessive growth of bacteria or really nasty bacteria with inside of the lumen but guess what in a patient with crohn's disease guess what's all jacked up that nod to be all jacked up and so because of that nod to mutation you affect the normal release of nuclear factor kappa beta this is still the debate and this is why it's so confusing is that some articles say that that's some of the literature says that it's a loss of function of the nuclear factor kappa beta some say it's a gain of function we truly have no idea but what we know is is that whenever there's this nod to mutation there's a loss of stimulation of macrophages and so the immune surveillance process is decreased now some of the bacteria that's inside here can actually grow and pass through and translocate right into the area here that's not good so now i lose some of the surveillance and the ability to control bacteria from moving to this area on top of that if i inhibit the macrophages then i inhibit the release of interleukin-22 i inhibit these cells from being able to do what to release defensins and mucin there's a reduction in that then i'm not able to break down particular bacteria with this protein called defensin i'm not able to make enough mucin to maintain a good thick barrier and guess what the autophagy process is also decreased you know what leads to this this leads to tons the bacteria just say hey man ain't nothing standing by the door now i'm just going to keep on growing and growing and growing and so then you get all of these bacteria that just overgrow here and this leads to excessive growth of bacteria especially really nasty bacteria this is called dysbiosis what is this called disbiosis and this can become somewhat problematic because you increase the number of bacteria and you increase the number of nasty bacteria that can actually cause problematic issues okay that's one of the the flavors of this that's why it's so confusing the other aspect of this oh let's actually put down here so what else do we say here not just these things but we also said another thing that really reinforces a lot of this is that nod to mutation very very important okay it's one of the big genetics the big genetic factors here that's really been kind of linked with this process and the last thing that maybe is related here is that there may be very specific cytokines we're not going to get into it right now we'll talk about in just a little bit but there may be an increase an over exaggerated increase in very specific types of cytokines that are produced and we'll talk about these interleukin-6 tnf alpha and interleukin-17 seem to be the ones that are very problematic and we'll talk about them a little bit later okay so these are the things that we've kind of seen associated with crohn's disease on the immune genetic end the environmental end is what we're still not really sure about so what do we know about this on the environmental end so we have immune composition here that's involved so there's three things it's kind of like they usually use like a circle sometimes like a three part circle so we have immune involvement some type of dysregulation some type of genetic predisposition and then the third thing that i want you guys to remember here is environmental now there's some factors here that i want you guys to think about so what are some of the environmental factors so what we have seen is maybe there are certain types of infections remember i told you one of them was the mycobacterium tuberculosis pair tuberculosis listeria certain types of infectious species like that may be linked to it also antibiotics so antibiotics actually have been linked to it nsaids believe it or not have been linked to it you know it's a really interesting one it seems to be the only really reversible risk factor associated particularly with those patients with crohn's disease is you know what it is it's very interesting smoking smoking seems to be a very very interesting type of risk factor so don't forget this one okay because this is one of those that you can actually somewhat modify in patients with crohn's disease there's other things as well that may be associated with this like diet but any of these things are what's linked to crohn's disease it's a kind of a multifactorial type of component there's some type of immune genetic and environmental involvement that is producing this disease now let's come back for a second we know that if there's a problem with all of these defensins the mucin the autophagy the nod two what starts happening well all of this you lose the ability to break down the bacteria you start losing the barrier and you start losing the ability to maintain a nice intact barrier what starts happening as the barrier becomes lost these bacteria start translocating across the epithelial tissue what is this called this is called bacterial translocation because of all these problematic issues with crohn's disease you have an increase in bacterial translocation okay here's where things get a little bit heated and intense once these bacteria get in here they activate some very special cells any kind of antigen presenting cell really so let's say here you get an increase in the bacterial translocation so here's some nice bacteria they get into this area once they get into the area the macrophages will become exposed to them once the macrophages are exposed to them you know what the macrophages do with these bacteria they phagocytose the bacteria when they phagocytosis they process it they take a piece of the antigen on the bacteria and present it on itself you know they present it on what they presented on a very special molecule called mhc2 molecules so here's going to be a piece on that mhc2 complex i'm going to have a piece of that bacteria right there now what happens is this macrophage now that it's been primed with all of these bacteria they're going to have tons of them because lots of bacterial translocation are occurring it's going to take this and present it to a very special cell and this is called a t cell and it's a naive one right and so the naive t cell has a very special type of protein that recognizes the antigen and then it is another protein that recognizes the mhc2 protein this right here is called the t cell receptor and this is called the cd4 positive protein okay now once this interaction occurs something really interesting happens this macrophage will become activated from this interaction here and it'll start secreting some cytokines which includes interleukin 1 and tnf alpha so this is some of the things that it'll start releasing and this is a nasty and phlegm pro-inflammatory cytokines now you know what else happens the macrophage depending upon kind of the the inflammatory process here not only release these cytokines which we're going to talk about it causes a lot of inflammation but it also releases something else it can release a molecule called interleukin 12. now interleukin-12 when it acts on these t cells it converts some of these t cells into a very special type of t cell you know interleukin-12 is a very strong stimulator and converting these naive t cells into what's called t helper 1 cells and t helper 1 cells when they're stimulated they release a massive amount of interleukin 1. interleukin 6 tumor necrotic factor alpha and these are massive inflammatory cytokines so now you have all of these massive inflammatory cytokines of interleukin-1 interleukin-6 two-minute chronic factor alpha what the heck do these things do they do so much unfortunately what they're going to start doing is these cytokines is they're going to start activating other nearby immune system cells to come to the area right so you're going to start activating what kind of cells well first off they're going to get over here to the area of the bloodstream so let's kind of like bring these guys down here they're going to act on the actual blood vessels within the vicinity okay so they're going to act on the blood vessels within the vicinity here when they do first thing they're going to do is going to cause these blood vessels to become very leaky so they're going to cause the blood vessels to become super leaky as the blood vessels become super leaky what happens well the whole purpose of making a leaky is so that any white blood cells or any kind of complement proteins that are moving through this area can leak out so it's going to cause a lot of capillary permeability so that's the first thing that happens the first thing that happens with this is that you'll have an increase in capillary permeability and that can lead to a lot of edema within the gut wall right so as you have lots of fluid leaking out into this area within the again this is within the actual intestinal wall this is going to cause a lot of edema so you're going to get a lot of edema associated with this increase in capillary permeability all right if you go back to our immunology not only do these kind of cytokines cause increase in capillary permeability but you know other white blood cells that are moving through this area you'll have t cells moving through this area you'll have other macrophages that are moving through this area you'll have neutrophils that are coming through this area you're going to want to let them know where all of this inflammation is these are like little cookie crumbs for the macrophages and the neutrophils and the t cells to follow and so another thing that it'll do is it'll stimulate these guys to come to the area of the gut wall where there's a lot of this inflammatory cytokine production what's this called positive chemotax so it'll try to bring these actual white blood cells towards that area now in order to do that what we need to happen is it's going to have to make some of these molecules on the vascular endothelial cells really sticky because what we want is we want the white blood cells to come faster the area but we want them to stick to the area where there's the most inflammation so that when they stick here they're like oh this is where i gotta go all right cool i'm gonna go into this area so the next thing that it's going to do is it's going to increase the expression let's make it another color let's do purple it's going to increase the expression of a ton of different cell adhesion molecules within this vicinity so in this vicinity there's going to be tons of these cell adhesion molecules now naturally what happens is on these white blood cells they have very specific proteins called integrins that bind with these cell adhesion molecules so what's going to happen is you're going to increase the expression of these cams and whenever you increase the expression of the cams the white blood cells have integrands that stick with it and cause the white blood cell to stick and roll along the actual blood vessel what is that called margination so not only would cause kind of a chemotactic response but it also cause margination okay and i want you to remember here cams okay that's where the cell adhesion molecules are produced so you're having a lot of interaction here so let's draw kind of that macrophage or neutrophil or whatever it's kind of sticking with this area here and believe it or not i know this seems like like why the heck am i talking about this it's actually a very important process especially when we get into the pharmacology this will stick here now that it sticks here it'll come to this area and move via the diapedesis process into this area and start causing more cytokine and more inflammatory damage so this will bring more white blood cells to the area there's one more thing though guess what all these cytokines they get into the blood interleukin 6 tnf alpha seem to be the big predators and even a little bit of interleukin one these go throughout the bloodstream and start causing systemic complications so you're gonna get a ton of these molecules and they're gonna start rolling out into the peripheral tissues affecting the brain affecting the skin affecting the joints affecting multiple different areas and causing systemic complications what we're talking about now is just local now not only do you get this kind of effect here okay but these cytokines not only do they cause lots of edema not only do they cause a lot of neutrophil migration a lot of macrophage migration but you know what else lots of these neutrophils so let's say that we get lots of neutrophils coming to the area lots of neutrophils and lots of macrophages coming into the area from all of these cytokines what's the problematic issue here well you know what else the macrophages do and the neutrophils do they release very special types of molecules that are the whole point is that there's some type of infectious pathogen or something that's crossing over causing this whole reaction i don't want it here so i'm going to release some nasty molecules to kind of destroy it and so unfortunately this leads to the production of reactive oxygen species the production of proteases and you know what this does it tries to destroy some of the actual pathogens or whatever that form of invader is but it starts leading to destruction of nearby tissue within the gi wall and so this increase in reactive oxygen species and increase in proteases inadvertently leads to a lot more damage to the actual gastrointestinal tract wall it's a problematic issue believe it or not i wish we were done but that's not it so we got this interlugan-12 there's another cytokine that the macrophage releases it releases another cytokine and believe it or not this is a it's kind of a it's it's it's not a super well-known process we talked about a little bit called the th17 cells it releases a cytokine called interleukin 23 and what interleukin 23 does is it takes this actual naive t cell and converts this into another type of t cell called a t helper 17 cell t helper 17 cells have been shown that when they're stimulated normally these maintain a good regulation kind of a helping to maintain a good balance kind of a regulatory function if you will of the gi tract wall within that kind of an immune system area but whenever it's hyperstimulated by this interleukin-23 it causes this mass production of interleukin 17. you know what interleukin-17 does it gets into the bloodstream and it stimulates a very very specific type of white blood cell to come to the area via the chemotaxis and migration process you know what that's called neutrophils and the neutrophils in this vicinity will start secreting lots of reactive oxygen species and lots of proteases you know what these things start doing they start causing damage to the actual gi tract wall damaging the pan cells damaging the goblet cells damaging the intestinal epithelial cells damaging some of the submucosa the muscularis external damaging all of the tissue within the gi tract wall and this is problematic okay now that's kind of the basic thing that i want you guys to remember about this okay now the only other thing that i want you guys to think about here is that not only is all of this kind of inflammation occurring and it's really damaging all of this tissue area again this is the local effect so this is that local effect don't forget a lot of these cytokines get into the bloodstream and spread to multiple different areas within the body and when they do they cause a systemic effect and this is some of the things that you can see that are really really negative okay so i think this kind of gives us at least the basic idea of crohn's disease and how all of these causes and pathophysiology are related here and the reason why i went into a lot of this detail i know it seems crazy is because a lot of the actual medications that we utilize particularly work in certain steps here and we'll talk about that all right so this covers all of the aspects of particularly like the causes and some of the pathophysiology let's see how all of this damage the gi tract wall and systemic effect leads to the clinical features that we can actually see present to us in the clinic or in the hospital or wherever it may be all right so we have an understanding now about the some of the causes and some of the pathophysiology behind crohn's disease right we notice this massive inflammatory reaction characterized by a massive increase in t what is the big ones two minor chronic factor alpha interleukin-6 interleukin-17 are some of those big big big ones and they cause lots of inflammation now it could be local and it could be systemic now the local effects within the git is very interesting now remember what i told you crohn's disease can occur where anywhere along the gi tract it can hit the esophagus it can hit the oral cavity it can hit the stomach the small intestine large intestine it typically spares the rectum or the anus but it still can involve the anus okay so big thing i need you to know is that this can involve anywhere along gi tract okay anywhere along the git now how does this actually occur well you know what actually happens is let's say that you get some inflammation here in the stomach and you get some destruction some inflammatory release some a lot of cytokines a lot of edema a lot of reactive oxygen species and proteases and you start causing destruction of the gi wall tissue you can get these ulcers okay you can start getting these ulcers that occur at kind of like normal like intervals of normal tissue then destructive tissue and then you have normal tissue then you have destructive tissue this is really important okay so you can get these ulcerations that can occur along the gi tract wall and usually the most common location that i really want you guys to remember tends to be the ilium so the most common locations is the ilium and the colon in general but for the most part for the most part it usually spares the anus okay now what's the issue with having all of these ulcerative lesions of the gi tract wall because you know it actually involves what's called transmural you know within the gi tract we'll talk about a little bit later you have the mucosa submucosa muscularis externa and then depending upon the organ adventitia or serosa crohn's disease can involve all of those layers it can lead to an ulcerative or destructive lesions of the mucosa submucosa musculus external all the way down to the serosa adventitia if that happens let's say that i destroy parts of the small intestine because again it can occur anywhere along the gi tract i get some lesions here of the small intestine and our small intestine is super super important for absorption if i have loss of epithelial cells that are needed to be able to absorb specific types of amino acids and carbohydrates and fats and vitamins i lose that so i may have a decrease in absorption and the problem with that is if it's a decreased absorption of nutrients right fats proteins carbohydrates what's that going to lead to it's going to lead to weight loss failure to thrive cacti kind of appearance right so this can lead to weight loss and worst case scenario at a baby or a younger individual a failure to thrive okay that's one thing the other thing is it's important for absorbing very specific like micronutrients you know things like iron or things like b12 are very important if we lose the ability to absorb these things right so we have a decrease in iron absorption a decrease in b12 absorption this can lead to what is what is iron really needed for for being incorporated with hemoglobin within our red blood cells if you have a reduction in iron absorption you have a reduction in the amount of iron within the hemoglobin and this causes the red blood cells to be smaller what is this called this can lead to a micro cytic anemia if you have a reduction in b12 and there's another vitamin that gets absorbed within the ilium called b9 folate these are important for the maturation of the red blood cells and if there's a decrease in these you can have what's called big red blood cells called macrocytic anemia here's where it's a really important thing if you have destructions let's extend this down here if you have destruction of the actual small intestine particularly near the ilium the ilium is really important for absorbing fats and for absorbing bile salts okay if there is a decrease in fat absorption that means that you have less free fatty acids in the bloodstream right less free fatty acids within the bloodstream then because you're not absorbing as much fat all right so what's the problematic issue with having less fat being absorbed and having like less free fatty acids in the bloodstream that may sound like a good thing right well not necessarily when it comes to this next problematic issue with these fats right so let's say that we have kind of some fat molecules here so here's our fat molecules normally these are not bound to anything specific normally you have something else you know with inside our git we may have this molecule called oxalate all right this is called oxalate and oxalate is normally bound to a molecule is called calcium so normally calcium will be bound with the oxalate okay what happens though is because you absorb less of this fat more of the fat stays within the git lumen and what happens is instead of the calcium binding with the oxalate it goes and it binds with the fat molecules and as you bind lots of these calcium molecules with the fat you lose some of the calcium with the oxalate and so you absorb tons and tons of oxalate instead of having calcium combined with it what's the problematic issue with that let me explain less free fatty acids within the gi lumen you absorb less calcium is absorbed but as kind of a problematic kind of side effect from this because the calcium is no longer binding with the oxalate you absorb a ton of oxalate that oxalate believe it or not can precipitate and form nasty crystals you know where these crystals can really kind of precipitate and get stuck they can get stuck in a very very special organ that helps us to make you pee-pee called the kidney and as a result you can get these oxalate stones and so what's a result of this the result of this is that you can increase the risk of what's called kidney stones okay so there's an increased risk of kidney stones also known as urolothiasis in this case what else do we have less absorption of so not only is there malabsorption of like nutrients not malabsorption micronutrients and malabsorption of fat which plays a role within formation of kidney stones but also less bile salts so you have less bile salts you know bile salts are very important with within our gallbladder with making bile it's obviously one of the most important components of bile is the bile salts the colic acid the deoxycolic acid whenever you have less bile salts right this becomes a problematic issue with the bile now the bile is going to be rich in what less bile salts what's the other main component of the the actual bile cholesterol and fat but cholesterol seems to be the big one so now in this bio composition you're going to have less bio salts because you know these bile salts they get actually absorbed across the ileum taken back to the liver recycled and get put back into the bile if you have less of them getting absorbed you have less bile salts to put into the bile instead you have high cholesterol this high cholesterol in low bile salts leads to what's called gallstones so then you start getting what's called gull stones and if we were to kind of show that here what is this called what's the actual technical name for gallstones this is called cholelithiasis so this is called cholethiasis so again it's going to increase the risk of what's forming gallstones via cholethiasis due to less bile salts being absorbed or lead to the increased risk of kidney stones due to increase in oxalate absorption and also anemias due to less b12 less b9 less iron and also weight loss and failure to thrive due to just decreased in macronutrient absorption in general all right let's now talk about diarrhea all right so now if we have the next thing which is diarrhea again you're going back here to like let's say large intestines so small intestinal is very specific for the malabsorption but again crohn's disease can involve anywhere along the gi tract let's say that you get some ulcerative lesions along the actual large intestine if you get this what's the large intestine really good for don't say absolutely nothing the large intestine is good for absorbing some electrolytes but primarily water so it's primarily involved in water absorption within the large intestine so again let's kind of annotate here this is within the large intestine okay if there's all sort of lesions within the large intestine you have less epithelial cells there less of these simple columnar cells to be able to absorb the water because they've been damaged there's a loss within that normal barrier you have less water absorption if you're like you're absorbing less water that means all that water is going to stay within the git and when you go ahead and you go ahead and you know restock the lake with brown trout you go ahead and drop the deuce what are you going to be dropping out with it tons of water and so this can lead to a lot of water being lost within the stool and if you get your you know you're got the hershey squirts your peanut your butthole this would be diarrhea as a result of destruction for ulcerative lesions of the large intestine leading to less water absorption so let's say that you get a lot of these ulcerative lesions of the intestines whether it be large intestine small intestine doesn't really matter you get these ulcerative lesions right now naturally what happens is we know that not only do you get these alternative lesions but you get tons of inflammation within that wall right there's going to be lots of interleukin 1 interleukin-6 tnf-alpha lots of white blood cells lots of fluid there should just be naturally a ton of edema so there's going to be like a thickening a thickening and edema of the actual walls so what could i see here not just what i see some ulcerative lesions but you know what else i could see i may also see a lot of edema and bow wall thickening so now i'm going to have some bow wall thickening and within that ball wall thickening i'm going to have lots of fluid and white blood cells inflammatory products there and you know what else can start happening you can also start activating fibroblasts in the more chronic stages of the disease so then you start getting a little bit of fibrosis some scarring of these actual areas of bowel wall thickening and edema and where the actual ulcerations are but if you look here what happens if you've got to try to move poop through this area if i try to move poopoo right through this area it's narrowed then there's a little bit of an area of kind of like some ulcerative lesions but then i gotta go through another narrowed area this narrowed area due to the bow wall thickening and inflammation and maybe even some type of fibrosis is called strictures and these strictures can reduce the passage of fecal matter through the actual bowels and what can happen as a result of that what happens if i'm not able to push a big enough turd through that area it gets stuck proximal to that and so then what happens to that all that poop starts getting stuck and stuck and it starts expanding the bowel wall is proximal to this it kind of mimics somewhat of a bowel obstruction so strictures increase the risk of bowel obstructions okay all right so so far at this point we've already i understood that crohn's disease can involve any any part of the gi tract right ilium colon can't even involve the oral cavity aptus ulcers is sometimes a common manifestation we've talked about how it can cause malabsorptic symptoms it can cause watery diarrhea it can cause strictures leading to increased risk of bowel obstructions what else can it do though another thing i want you guys to remember is because you can get these again what kind of inflammation a trans mural right which means it goes through almost all the layers of the gi tract wall so it'll involve the mucosa the submucosa the muscular sector and maybe even extend down to the serosa and organs that have serosa which means it's a it's an intraperitoneal organ it's inside of the peritoneum it has a visceral and a parietal peritoneal layer in these sometimes what can happen is the ulcer can actually extend through the serosa and then epithelial cells can actually migrate and form somewhat of this like epithelial tube if you will and this epithelial tube can connect to nearby organs this connection between the gi tract and a nearby organ is called a fistula okay so it's basically whenever the inflammation of the ulcers have eroded all the way down to the serosa and some of the epithelial cells migrate and make an epithelial tube that connects two organs what organs can it connect to one of the big ones is it connects to the skin and you can literally have like gi material coming out from the gi tract that connects to a fistula and drains fecal material onto the skin this is called a enterocutaneous fistula you can also have this you know especially with the rectum near the rectal areas near two structures the bladder and the vagina so nearby you can actually fistulize and have some of those structures connect to the actual bladder and what is this called you know another word for the bladder is the vesicle so we have what's called entero vesicle fistula then if it actually connects to the vagina which is usually the rectum kind of facializing with the vagina this is called a recto vaginal fistula and so if someone has intercutaneous fissiles obviously there's going to be fecal material that's escaping onto the skin in pterovesicle you know what this causes this causes fecal matter to present inside of the actual urine so there can be tons of bacteriuria and fecally area but also sometimes there's lots of gas that can present within the vagina i'm sorry within the urethra and within the urine and so this can cause pneumaturia pneumoturia but this definitely increased the risk of them developing urinary tract infections so you can have lots of bacteria that show up within the urine within the bladder as well as new material which is kind of gas with inside of the urine then again rectovaginal you'd obviously have fecal material coming up into the vagina that sounds absolutely disgusting but it's possible right the next one is that you can fistulize between one part of the intestine to another part of the intestine and if you do that that's called a entero enteric fistula okay now these fistulas one of the problematic issues with these is think about this if you have an erosion it extends all the way down right it extends all the way down to the serosa layer and then you start developing this epithelial kind of tube nearby the bacteria that is present with inside of the gi tract can then do what can just invade through that fistula into nearby tissues and cause infections or it can accumulate in this area and become walled off what's that called i'm glad you asked it can become an abscess and so again sometimes what can happen is whether it just be due to the transmural inflammation or whether we do the fistulas you can develop pyogenic complications where let's say here you have a opening up there's this transmural inflammation ulceration of the gi tract wall and now bacteria can just completely invade right into this little area here so now you have an opportunity for infectious pathogens to extend into this area where the transmural inflammation and ulcers were and lead to an infection what is this called an abscess and usually these abscesses occur commonly near the perianal area so perianal abscess is a relatively common type of abscess as you can see within crohn's disease so we have git involvement anywhere along the gi tract usually it spares the anus but it can happen in the anus obviously in perianal diseases again we can get malabsorptive syndromes we can get diarrhea we can get strictures with increased risk of bowel obstruction fistulas what kind intercutaneous enteroenteric enterovesicular and rectovaginal and then also you can develop pyogenic complications cause called abscesses and these abscesses what kind of pathogens would be kind of invading into the area anything within our git right so you're going to see kind of anaerobes and lots of gram negative bacteria that is going to be infiltrating into this area and that's important to remember the other thing i want you guys to remember going along with diarrhea is that if you actually have ulcerations if you actually do have ulcerations of this kind of like bowel wall where the small blood vessels that are moving through the actual vessel within the gi tract wall if there's enough inflammation and ulceration it actually hits one of those small little vessels you can lead to small amounts of blood to end up with inside of the stool and so sometimes there can be red blood cells that show up within the stool but it's not an overt kind of gi bleed it's something that may come up positive when you do like a fecal occult blood test or it shows up kind of insidiously with someone having signs of anemia so that's another thing to remember is that again with the diarrhea i wanted you guys to make sure it's primarily watery diarrhea but there could be red blood cells that leak into it in cases where it actually erodes into the small vessels within the gi tract wall okay good so we have malabsorption involving small intestine diarrhea involving large intestine with possible red blood cells we've got strictures with increased risk of bowel obstruction fistulas abscesses what's another complication gi wise locally well think about this if i have the epithelial cells and all the other tissue cells that here's the ulceration right generally what's going to happen you have tissue destruction normally your gi tract cells they have the ability to replicate they have the ability to undergo mitosis they're not a mitotic and so what will happen is if you salvage some of the cells which are nearby the basement membrane they'll try to go and repair this area and replicate but then let's say that you destroy it again you have another flare up so then let's say on top of that you have another flare so there's another flare you destroy more tissue cells after you destroy those tissue cells more cells try to come in and replicate and try to fix that area up and you just have this continuous type of process so with multiple flares and increased replication and healing what happens if you have tons and tons and tons of dna replication there's always the risk of having a mutation there's always a chance of having some type of problematic issue with the dna replication process that increase the risk of mutations therefore leading to cancer so there is an increased risk of mutation risk with multiple replication cycles and that can increase the risk of colorectal cancer so that's a big big thing to be able to think about okay all right so we cover the local complications of someone with crohn's disease now let's cover some of the systemic involvements of crohn's disease all right so now let's talk about the systemic complications of someone the crohn's disease again this is a massive kind of inflammatory condition right so not only is involving the gi tract wall but it can extend outwards and involve multiple systemic areas so what if you have this massive cytokine release remember interleukin-1 interleukin-6 tumor chronic factor alpha interleukin-17 all of those guys are released interleukin-17 kind of has its effect mainly within the gi crack wall but interleukin-6 interleukin-1 tnf alpha they cause this cytokine storm if you will that kind of affects the hypothalamus so if you cause the hypothalamus to become stimulating it increases the riddles release of what's called pg e2 and this increases your body temperature what can this lead to this can lead to fever so that could be one obvious sign is that a patient may have fever that's not indicative of an infection it's just indicative of the giant inflammatory process that they have going on now the other thing that you definitely have to remember we'll take a picture we'll take actually take a look at these is it can involve the actual eye in particular parts of the eye so you know you have the choroid which is this red part here and then you have this this is the iris this is the choroid and then you also have the retina there now you also have another tissue here called the sclera okay now what happens is this inflammatory process you lead to lots of cytokines and inflammatory cells that infiltrate these areas of the choroid the iris the retina and the sclera if it involves kind of the episcler so it's a tissue just on top of the sclera with a lot of vascular supply to it it can cause episcleritis okay episcleritis if it involves the anterior aspect you know the uvia the uv is kind of there's a two parts of it the anterior aspect of the uv which primarily is made up of the iris and the post here which is kind of the choroid and the retina if you involve that portion just of the iris that's kind of the anterior aspect of it we call that iritis or anterior uveitis we'll just put i rightis and then the next thing is if you involve the posterior aspect of the uvula which is the choroid or the retina this is called posterior uveitis so you may see anterior uveitis are also known as iritis or you may see posterior uveitis which is involving the chloride and the retina or episcleritis we'll take a picture of those and i'll take a look at them all right the next thing is if there's a mass of inflammatory cytokines that involve the skin it can lead to some really nasty lesions so you know within the skin there's one condition called erythema nodosum and one more which you definitely have to remember which is called pioderma gangrenosum this is a really interesting type of lesion and you really want to remember this to be kind of on extensor surfaces so if you see this on this particular extensor surfaces this is a big thing to remember the next thing that i want you guys to remember is that if the inflammation extends and it starts causing inflammation of particular areas of the bones and the joints especially near the sacroiliac area and near the spine if you cause inflammation of the actual vertebral column in that area it's called spondylitis so you may see signs of what's called spondylitis or you involve the sacroiliac joint and cause inflammation of the sacroiliac joint this is called sacroiliitis and you know what's interesting about this you can have also peripheral joints can be involved as well but whenever you see these like spondylitis and you see sacroiliitis this should make you think of hla b27 positive types of conditions these are called your seronegative spondyloarthropathies so this will make you think of like ankylosing spondylitis reactive arthritis and ibd or enterohepatic arthritis so in conditions like ibd they can present within these hla b27 or seronegative spondyloarthropathy so they may have pain within the vertebral column or pain around the sacroiliac joint decrease kind of mobility around that area and also maybe some peripheral joint involvement okay that's a big thing to remember the next one here as if we come down it also can lead to involvement of the parts of the liver you know there's inflammation and this inflammation starts extending to the biliary ducts so you can actually kind of get inflammation around the biliary ducts with inside the liver called intraopatic or the biliary ducts outside the liver called extrahepatic biliary ducts this inflammation of these biliary ducts due to the cytokines is called primary sclerosing cholangitis okay now big thing to remember here with the primary sclerosing cholangitis is it is an inflammatory type of reaction particularly of the intraopatic and extrapatic biliary ducts you know what's really important i want you to remember because again we're going to talk about uc ulcerative colitis this seems to be more common in ulcerative colitis than it is in crohn's it's an important thing to remember okay now the next thing that i want you guys to think about is because of this massive inflammatory cytokine storm you know we have different types of proteins that are present with inside of our blood vessels that are running through that are involved in helping to make clots so you have what's called the pro coagulants right and what happens is there's a very specific type of protein a very very specific type of protein you know there's a protein called von wilder bronze factor von what bronze factor basically is this protein that kind of gets deposited let's say that there's like a micro tear within the blood vessel you get a little micro tear generally there's this like little protein here called von wild bronze factor and it activates platelets and the platelets want to come there and stick so if i had a ton of like little platelets the platelets would come here and stick to this area and cause a big old clot and this can occur with an artery or can occur within a vein what happens in these patients do these like increased cytokines is it may increase the activity of some of the pro-coagulant enzymes but also increase the activity of the von wildebrand factor if you increase the activity of some of these pro-coagulant enzymes you increase the formation of clots easier but also you increase the initiation of clots easier and so this can lead to arterial thrombi or you may jack up them veins man and if you jack up them veins and you get clots within them that may lead to venus thrown by so these are big things to remember as well it's more commonly that you'll see the involvement of the venous thrombi than you will of the arterial thrombus so you may see patients with dvts or pes as a complication of the crohn's disease okay so we got all of these systemic involvements in crohn's disease now let's go ahead and move ourselves over to the diagnosis of crohn's disease all right so let's talk about the diagnosis of crohn's disease right so we've gone through we've talked about the causes we talked about the pathophys we went through some of the actual clinical features that may be presented within the gi tract wall like the local effects the systemic effects if you suspect someone has crohn's disease right one of the other things that we didn't really talk about with the gi tract involvement with all those ulcerations it may produce abdominal pain and if they do have abdominal pain what was the most common locations that i told you guys to remember for crohn's the ilium and then the colon so usually that's going to be on that right side so they may present with more of a right lower quadrant abdominal pain if you suspect that they have crohn's disease what are some labs that may help point me in the direction of crohn's well first thing is let's say that we think oh man maybe there's some small intestinal involvement because they have weight loss they have cachecactic kind of appearance they have a decreased amount of protein with on their cmp they just look like they're having a difficulty being able to you know thrive they have anemia something like that i'm suspecting a malabsorptive type of problem we'll go back think about that if there's a decrease in the absorption of what type of things let's say there was a decreased absorption of proteins if you check their actual cmp so you know on a cmp it gives you their total protein and these patients they might not have as much proteins that they're actually absorbing across their livers being able to utilize to make things like albumin and globulins and things like that so if you check they may have a decrease in their total protein that's present on there cmp so get a cmp if you see that they have a decreased number of albumin a decreased number of proteins total protein that may be one of the things that you can think about sometimes also if someone's cachecactic or having weight loss they don't they're actually utilizing or damaging their muscles or they're not having as much protein incorporated into the muscles so another thing that you may see besides having a decrease in proteins for malabsorption is there may be a decrease in their creatinine okay and that may also be something that you can pick up off the cmp particularly the bmp okay so if you get a cnp you may see that they have a decrease in the creatinine or also a decrease in their total protein that may kind of key in about a malabsorptive syndrome now another thing that may be a problematic issue here is that there may be a decreased absorption of iron and a decreased absorption of b12 and b9 what did i tell you about these if there's less iron that's being absorbed you can check iron but more likely than not you'll actually see someone with if you get a cbc they're going to have less red blood cells but the red blood cells are going to be small and we utilize a very particular red blood cell indices to determine if they're small red blood cells it's called mcv mean corpuscular volume so if they have low red blood cells and a low mcv you may be thinking that they have iron deficiency anemia and you can pick that up off of their cbc so you can get a cbc and maybe some iron studies if you really wanted to go that extra mile so the thing i could check for this is a cbc so i could check a cmp i could check a cbc also b12 b9 i could check those levels but guess what if i have a b12 and b9 deficiency because i'm not absorbing these properly then i'm going to also result in these kind of less red blood cells and less hemoglobin but guess what their mean corpuscular volume goes up and so they have a high mcv and that may clue you into what's called a macrocytic anemia and again what can i get that off of i could get that off of a cbc okay and again these are some of the things that you want to be thinking about with these kinds of patients right so we could be checking a lot of these things checking to look for any kind of malabsorptive issues now what else could i do the other thing i want to be thinking about here is that sometimes with the liver the liver is important because whenever there's kind of a massive inflammatory cytokines remember those cytokines that were released again interleukin 6 is a big one tumor necrotic factor alpha interleukin-1 these love to tell the liver hey man lots of inflammation going on buddy you better start releasing some very specific types of molecules to let people know and this is called crp or there may be an increase in the crp the c-reactive peptide or an increase in the erythrocyte sedimentation rate and so these may be other things that you can see on a patient particularly with celiac disease okay so there may be an increase in crp there may be an increase in the esr because of the acute phase type of reaction because of the inflammation okay what else now another thing that we could look at is that you know whenever they have these acute phase reactive proteins it's kind of indicative of like a systemic inflammation we may be able to kind of narrow down the inflammation to the gi tract wall specifically so you know whenever those neutrophils were coming to the area because they were being stimulated by different types of cytokines they were being stimulated by interleukin 1. they were being stimulated by tnf alpha they were being stimulated by interleukin-17 and when they were activated they were releasing tons of reactive oxygen species and proteases and damaging the bowel wall well you know what else they release they release very specific types of proteins that can show up within the poopoo and what are these proteins that can show up within the poo these are called fecal cal protectant this will be positive and elevated and another one which is called fecal lactoferrin so you got to get your hands in that poop send out a stool sample and check for these particular types of inflammatory markers that are actually a little bit better than a crp and esr telling us about the gi tract wall inflammation okay so we can check for malabsorptive types of processes we can check for acute phase reactive proteins of systemic inflammation more specific inflammation of the gi tract wall what else could i do now the next thing that you could also check is you know those antibodies that are sometimes you know lymphocytes can get involved in this process and they can release antibodies we didn't talk about it too much over there within that kind of immune response and the reason why is it's more particularly an ulcerative colitis that we see these very specific antibodies one of the specific antibodies that i want you guys to remember is called p anchors okay these are specifically like anti-neutrophilic cytoplasmic antibodies okay and these are released and they attack neutrophils so generally what they'll do is they'll attack neutrophils and the theory behind this will talk more about it when we get into ulcerative colitis but p anchors are more specific to ulcerative colitis you should always check because sometimes it's tough to you know determine is this uc or is this crohn's disease so what happens is you check a p anchor and in crohn's disease the pianka should be negative this should be positive only in ulcerative colitis now there is another test you should know for your exam but the sensitivity of the test is not very good you can check what's called the saccharomyces cerevisiae antibodies which is like these antibodies against like the yeast like a cell wall and these asco antibodies are positive but remember they have a low sensitivity and kind of like determining you know patient having crohn's disease it's easier just to check to see if the p ankles are negative if you check these ask antibodies it's kind of a more of a test kind of exam question that you want to remember okay all right so we've gone through these particular tests that are more of the lab things that you'd want to do the other things that you want to do is if i'm thinking that a person has crohn's disease and they have diarrhea what else would i want to do rule out infectious causes so i definitely would want to send off maybe a stool sample to rule out any kind of infectious diarrhea because that also may be something that might be going on there so also think about that when you're ruling out trying to figure out is it crohn's disease rule out other causes by sending out some stool sample analysis and checking to make sure that there is no kind of infectious diarrhea present okay let's come down now we're getting into the imaging if we talk about the imaging that we really want to know for a patient with crohn's disease there's two types of imaging well there's actually three imaging modalities that you could do the first one that you could do which is the gold standard is what's called a ilio colonoscopy and biopsy this would be kind of the best test this is your gold standard okay and what could this tell me if i do an iliocolonoscopy with biopsy i'm going to be taking kind of this camera running it up through their butt up through their colon looking at the colon looking all the way around here and even getting down here into the area of the ilium and looking to see what's going on i could see a bunch of things i could see ulcerations and crohn's disease what else could i see i may also see strictures i may see abscesses i may see fistulas but you know what is the characteristic thing that you need to remember that you can pick up of an ileal colonoscopy is you may see these lesions that pop up where you have normal tissue damaged tissue normal tissue damage tissue it's like you're skipping from areas of damage to normal damage to normal these are called skip lesions this is a very important kind of like buzzword term that you guys need to be able to remember is that you may have areas of like edema bowel wall thickening and then areas of like ulceration and so it kind of looks like a cobblestoning type of appearance if you look at that on the uh the ilio colonoscopy on the camera so it may also have what's called a cobble stone appearance these are big buzzword terms that you need to think about for crohn's disease skip lesions areas of damage normal damage normal and areas of bowel wall thickening and ulcerations in between indicative of cobblestoning of the actual mucosa the next test that you could do this is the ilio colonoscopy it's the gold standard kind of the best test that you could do an alternative to that is you could do what's called a mre an mri enterography or you could do a cte which is a ct enterography the mre is actually the preferred test okay because it's way more sensitive the only reason you would get a cte is if a person's like unstable they have some type of contraindication of getting an mri but mra should be the preferred over cte way more sensitive and what this can do is it can still tell you is there any kind of like structures it can tell you if there's any bowel wall thickening it can tell you if there's any kinds of like complications like fistulas abscesses strictures anything like that it's really good at that but it also picks up one other thing sometimes you can get like this mesenteric fat that you get a ton of and it's like this excessive mesenteric fat that can occur around the actual bowel wall and you know what they call this it's called the creeping fat sign it's called the creeping fat sign and this is when they have excessive mesenteric fat stranding that occurs around this inflamed gi tract wall and that can be easily picked up on a mre or cte so illegal colonoscopy to get a good camera visual look inside of the lumen you can pick up skip lesions and cobblestone you can actually look at the mucosa with an mre you can't visibly see the mucosa but you can pick up some subtle signs of some of the same things complications like abscesses strictures maybe some areas of bowel wall thickening maybe even um certain types of like abscesses or strictures and things like that but another big thing that you can see is this what's called excessive mesenteric fat stranding around the bowel wall edema and that's called creeping fat sign the last test that you could do and it's actually kind of working its way out in efficacy and they don't use it too much anymore but this last test that you could perform is called a small bowel follow-through so the next one is called a small bowel follow-through and what you do is it's an x-ray you have them swallow contrast and you take pictures as the contrast is moving through their actual gi tract okay and what happens is if you have an area let's say right here let's say right here you have some contrast that should be flowing through this area right here it will flow through this portion that's maybe a lot thicker but it'll be really thin through this area and so it looks like a string is like moving through that area of that stricture and so it's really good at picking up a very specific type of buzzword term called a string sign which is kind of an area of significant stenosis or structuring of the actual bowel wall due to the crohn's disease and having a lot of that inflammation so these are the big things that i need you guys to remember so first test gold standard iliocolonoscopy get a biopsy because if you biopsy these areas of ulcerations or cobblestoning all that stuff you want to look at it underneath the microscope for the pathology of it then if you can't get that mre is the second test good at picking up a lot of the same things but doesn't get a visual look at the colonic mucosa and then the last test which is probably the least effective test and not commonly utilized anymore which is the small bowel follow-through other tests that you could do is you could do like the pill camera very expensive and it takes a long time but that's another option that you could go to for these imaging okay nonetheless we do these tests we think that they have crohn's disease we see the cobblestone and we see the skip lesions let's say we get the mre we see the same kind of thing process here ulcerations bowel wall thickening complications we see the creeping fat sign we get the small bath all through we see the string sun when we get the biopsy there's an important thing that i want you guys to remember now go back to your histology right you have the mucosa and what's the mucosa made up of you have your epithelial cells you have your purple layer here called the laminopropria and then you have that little muscle layer there called the muscularis mucosa that's part of mucosal layer right then underneath that you have this blue layer and this is called the sub mucosa right that's called the submucosa and then you have another layer here which is just this red layer that red layer there we're going to abbreviate it is called the muscularis externa and then the last layer is this pink layer which can actually be two things it can either be adventitia or it could be serosa so it's either one of those and depends upon which part of the organ you're in if you're in a retroperitoneal organ it'll be adventitia if you're within an intraperitoneal or going to be serosa either way when someone has crohn's disease they get all that inflammation all those cytokines all that kind of cellular damage and reactive oxygen species and proteases it destroys all the way down here it destroys through the mucosa the submucosa the muscularis externa and extends down here into even the serosa adventitia this right here is called trans mural inflammation or transmural ulceration this is a microscopic finding that you would see so if you took and biopsied this area of ulceration and you looked at it underneath the microscope this is another big big thing to look at microscopic scopic examination right so you're looking at this under the the microscope you would see transmural inflammation or ulcerations involving all of these layers here you know what else do you see you know within the bowel wall because of all those inflammatory cells that are kind of aggregating to the area remember i told you that whenever there was all those immune system cells that were coming to the area what were those immune system cells that we had what were these blue cells here these were called your macrophages and there was tons of these right and then what were the other cells that they were interacting with and pulling lots of those cells into the area t cells right so you had your t cells your different types of lymphocytes then after that you may have also these like necrotic and not necrotic area but all these like proteins and giant cells that accumulate here in the center so that may be what's called these giant cells which are kind of like some of the macrophages that are fusing together and some of the proteins within there you know the asteroid bodies the shaman bodies we talked about that in the video called sarcoidosis similar thing here but there's another thing which is some of these fibroblasts come to the area and form some of this fibrotic tissue around there so you're also going to have some like fibroblasts and some connective tissue surrounding that this structure here is called a granuloma it's kind of an accumulation of proteins and giant cells then macrophages then lymphocytes then fibroblasts with connective tissue but the center of this granuloma does not contain necrotic or dead tissue so this is very very specific finding that you want to remember called a non caseiating granuloma so what would happen is if you were to kind of take an actual um a biopsy of this area of the gi tract wall where there's like ulcerations and inflammation and bowel wall thickening and you looked it under the microscope not only would you be able to see these areas of transmural inflammation ulceration but you may see nearby these non-caseiating granulomas and that's another very very important finding here that you want to be thinking about is these non-caseiating granulomas that can appear upon the microscopic imaging we've covered all the aspects of the diagnostics of crohn's disease now let's talk about the treatment of crohn's disease all right so let's talk about the treatment of crohn's disease when we talk about treating crohn's disease one of the big things that you want to be thinking about is what are we trying to target so primarily crohn's disease is medically mediated all right there's specific types of medications that we're going to try to be able to kind of suppress their immune system a lot of immunosuppressive therapy but when we're doing immunosuppressive therapy one of the big things is you have to understand what you're trying to accomplish so crohn's disease usually occurs in like flares right so you can have a flare-up where you have more of this kind of problematic issues that we talked about and then they may go into a period of remission where they have none of these autoimmune kind of inflammatory attacks when someone has a flare-up you want to be able to induce remission stop the flare-up but then you also have to have other medications that come through the back door and prevent any kind of relapse in the future maintain the remission so we have to understand that if someone has a flare like a crohn's flare we're going to want to prescribe particular medications that are going to induce remission and the main ones that i want you guys to think about for inducing remission is corticosteroids but also biologics okay and then for maintaining once we've kind of induced remission we want to maintain remission and this is where we maybe continue on with the biologics or we try other different types of things like immuno other types of immunosuppressive medications that maybe take a little bit longer to work but once they kick in they're pretty strong okay so the big thing i want you to remember here is when we're trying having a flare of crohn's disease we want to induce remission corticosteroids seem to be the best for that and then maintaining the remission is where you're going to want to be able to utilize some of your biologics and other types of immunosuppressive therapies okay so let's talk about some of these medications the first one that i want you guys to understand or know about is what's called sulfasalazine sulfasalazine so this is kind of almost like a like a nsaid in a way okay what happens is you take sulfasalazine as like a pill you can also give it like rectally but you take this and when it you take sulfasalazine it gets broken down into two different parts the main part that i want you to know that it gets broken down into is what's called five asa okay this five amino salicylic acid that it gets broken down into is going to act somewhat like aspirin and so since it acts like that you know what it does whenever there's like lots of tissue damage you know there's like lots of tissue damage here of the gi tract wall because of crohn's disease there's lots of damage here lots of damage of tissue cells you know there's a molecule called arachidonic acid it's a part of the cell membrane it gets broken down and when it gets broken down it goes through this process where let's say you have some tissue damage here when you have this tissue damage you release out some arachidonic acid and then arachidonic acid will get converted into what's called prostaglandins and leukotrienes you know those prostaglandins and leukotrienes you know what these sons of guns like to do they like to tell the macrophages hey man lots of inflammation going on around this area bro you got to take care of it bro you need to start stopping this kind of what are you going to do man so he starts releasing things like interleukin-1 tumor chronic factor alpha and interleukin-6 which kind of induces that massive kind of inflammatory response right and whenever this is released this is going to induce that massive inflammation which pulls more macrophages into the area more neutrophils to the area more lymphocytes causes more edema more reactive oxygen species proteases and tissue destruction so what sulfasalazine does is it gets broken down into two components one is like the sulfur pyridine which is the side effect portion and then the five asa five asa will work specifically on a very special enzyme that triggers this process of going like from arachidonic acid into prostaglandins you know what this enzyme is called keep your minds clear it's called cox right it's cox cyclooxygenase cyclooxygenase works in this step here to be able to drive this process 5asa is a cyclooxygenase kind of inhibitor and what it'll do is it'll inhibit this enzyme if you inhibit this cox enzyme it can't convert the arachidonic acid into the prostaglandins that results in a decrease in the prostaglandin leukotrienes that results in a decrease in the activation of these macrophages and results in a decrease in these massive cytokine storm that reduces a lot of the edema the inflammation of that bowel wall area so this is one of the medications that we can prescribe usually sulfasalazine is more for the mild cases okay and we prefer it maybe in a patient that we're trying to limit corticosteroids for it's one of those drugs that may be helpful in inducing remission and maintaining remission but it's not super super effective so we kind of go to other medications and as an option but more in the mild states sulfasalazine may be utilized okay the next thing that i want to talk about here before we actually keep going on with all these other medications for immunosuppression is remember i told you this is kind of an interesting thing here with with crohn's disease crohn's disease is definitely a lot of inflammation right lots of bacteria that may be either translocating or accumulating with inside of the gi tract lumen but there's also complications you know how they can get fistulas and the fistulas can maybe lead to some pyogenic complications so they may end up having what's called fistulas which can maybe lead to some pyogenic complications or they have things like abscesses due to the transmural inflammation ulcers and the bacteria just infiltrating into these areas right when that happens these are pyogenic complications this is an infectious process on top of their already pro problematic crohn's disease and these types of pyogenic complications you would actually treat these with antibiotics okay so we would do antibiotics you know what kind of antibiotics we'd have to target well think about it i talked about over there we had what kind of bacteria gram-negative bacteria but what were the other big ones anaerobes anaerobic bacteria we want to target with metronidazole okay so metronidazole we also can use another drug another oral drug you know another oral drug that actually targets anaerobes augmentin what's uh the actual generic name for augmentin though if we were to be specific it's amoxicillin and clavillonic acid right so if we were to really be specific it's amoxicillin and clavillonic acid but we're going to just say augmentin and another time that you can use this because it's a really broad spectrum that covers some anaerobes and also gram-negative bacteria is fluoroquinolones augmenting can also cover gram-negative bacteria as well metronidazole is more specific though for the anaerobes your augmenting can give you some anaerobes and cram negative coverage but the fluoroquinolones is a very kind of a broad spectrum type of antibiotic as well now the other thing that's really interesting and there's still not enough research on it but they're saying that maybe these antibiotics not only are they good for the pyogenic complications but these antibiotics may be maybe have some anti inflammatory effect in crohn's disease and in some way shape or form they may be helpful in being able to reduce some of the inflammation associated with crohn's disease but this is still questionable so stick primarily with this upper part here that if they develop pyogenic complications that's when you give antibiotics don't go straight away with some of the research still not being known yet if they have the anti-inflammatory effect okay so we've covered sulfasalazine we covered the pyogenic complications like abscesses and fistulas and things of that nature with antibiotics what are other medications that we can prescribe okay another one this is this is the big mama the big mama here that i want you guys to think about here is corticosteroids corticosteroids are kind of like the backbone for a patient with crohn's disease you don't know why this thing covers everything this is why it's such a powerful drug it's really good at being able to induce remission during those acute flares and so there's many different types you can give what's called budesinite i think this one's a really cool one imagine like you get a drug right so here's the drug and you take the drug you you're swallowing a po and here's this area let's say here's the area of the most inflammation when it gets to this area of the most inflammation it releases some of the particles from the drug into this area so it's kind of like a controlled release drug really interesting but budesinite is a steroid that you can give another one that you can give po is prednisone prednisone is another one and then another one you can give kind of iv if you have to is methyl prednisolone all right so either way you give some of these corticosteroids they're good for kind of inducing kind of the remission they're more for more like the mild to moderate kind of cases or even severe cases this is just a general all-around good drug now how do they work exactly corticosteroids are very interesting kind of medication so let's say here i have a corticosteroid drug here that you get into the body what they do is they first love to act on these macrophages and they also love to act on these dendritic cells when they act on these cells here the dendritic cells and the macrophages you know the macrophages and the dendritic cells are antigen presenting cells so they're the ones that interact with those bacteria that translocate and they release what kind of cytokines interleukin 1 and tnf alpha which cause a lot of inflammation right so what these corticosteroids do is is they inhibit the macrophages and inhibit the antigen presenting cells from releasing these cytokines so it results in a reduction in these cytokines which cause a lot of the edema and neutrophil migration and a lot of chemotaxis and a lot of inflammatory processes the other thing this is really interesting is remember the macrophages and the dendritic cells they release very special types of cytokines like interleukin-12 and interleukin 23. corticosteroids also inhibit these macrophages and dendritic cells from releasing interleukin-12 and interleukin-23 if you inhibit these cytokines what is the problematic issue with that there's less of these cytokines to stimulate very specific t cells you know the t cells that respond to interleukin-12 they become th 1 cells and the th1 cells are the ones that release that interleukin-6 the tumor necrotic factor alpha which cause tons of inflammation if we give them this drug corticosteroids they reduce the interleukin-12 reduce the th1 cell differentiation and reduce this cytokine release which reduces a lot of the edema the inflammation all those processes if you reduce the interleukin-23 you reduce the conversion of the th cells into what's called th 17 cells do you remember why we just went over all that kind of like pathophyllic physiology over there if i decrease the conversion of the th17 cells i result in less interleukin 17 which causes all that neutrophil chemotaxis if i reduce that i reduce a lot of the inflammation and devastating inflammatory effects all right so another thing that the glucocorticoids can do we didn't mention this mechanism over there but it kind of kind of gets in a little bit of too much detail but what happens is these glucocorticoids also act on macrophages you know macrophages they sometimes can release another cytokine called interleukin-10 and what interleukin-10 does is it's supposed to be able to shut down it kind of acts on itself and shuts down these macrophages and dendritic cells from releasing more of these nasty cytokines like interleukin-1 tumor necrotic factor alpha inhibits the release of interleukin-12 interleukin-23 all of this process so this is kind of like an anti-inflammatory function you know what the corticoids do the glucocorticoids kind of stimulate this process they increase the drive of this process to increase interleukin-10 production which kind of has an anti-inflammatory type of action that's a really cool process there all right corticosteroids generally just reduce significant amount of inflammation particularly inhibiting antigen presenting cells inhibiting the t helper 1 and t helper 17 cells function as well all right the next thing we can utilize other drugs here there's a drug uh it's called azathioprine or six mercaptopurim what is this drug called you're like what the heck it's called as a thioprin also known as 6 mercaptopurine this is also another type of immunosuppressive agent you usually utilize this one when you're getting more to like the moderate cases of you know someone with crohn's disease so if you're getting more to the moderate cases of crohn's disease this would be a drug that you would go with now this one is definitely not going to be one to induce remission it takes a long time to work so because of that's going to be one more for maintaining remission how does this drug work it's actually really freaking intense so let's say here's the area of inflammation within the gi tract wall right when you take this area of inflammation you zoom into it you obviously know that some of the culprit there is these t helper cells you know these t helper 1 cells they're kind of the culprit in this process because they're just blasting out interleukin 6 interleukin 1 and tnf alpha which is causing a lot of these problems well there's a protein that is actually involved in this this protein or enzyme is called rac one it's called rack one it's kind of imagine like kind of like a transcription factor if you will what happens is rac1 normally tries to stimulate particular genes to increase the production of these cytokines interleukin-6 interleukin-1 tnf alpha when you give a drug like as as a thioprint or 6-mercaptopurine these drugs particularly work by inhibiting this rac-1 so what does this drug do it works by inhibiting rac1 if you inhibit rac1 you won't be able to stimulate the particular genes that are needed to make these cytokines this results in a reduction in interleukin-6 interleukin-1 tnf-alpha you know what else is also really interesting about this it also inhibits these genes that are important also for the cell cycle and because it also affects the cell cycle guess what else this can do this can also induce this cell cycle process to cease so there's a decrease in the replication process and actually kind of induces apoptosis so then you result in a destruction of the th1 cells as well as a decrease in the amount of cytokines that these cells are releasing and so this can also be helpful in these patients with crohn's disease so as a thyropreneur 6 mercaptopurine is another drug that you can use more moderate cases of crohn's disease what else what's another drug another drug that you can utilize is called methotrexate so it's called methotrexate methotrexate again is more towards the moderate cases of crohn's disease and again this is going to be more for maintaining remission because it takes a decent amount of time to work its mechanism is a little bit more complicated so here we have these th1 cells right and these th1 cells are the ones that are the problematic ones that are releasing all these different cytokines right the tnf alpha the interleukin-6 the interleukin-1 these are the problematic suckers okay well you know in order for this to happen th cells need dna because dna is the code for all rna which is the code for all proteins it's basically what helps the cell to be able to survive when you give methotrexate what methotrexate does is is it actually inhibits some specific enzymes involved with making nucleotides you know folic acid it's actually a precursor to making a molecule called tetrahydrofolate and all i want you to know is tetrahydrofolate or folic acid eventually gets used to make purine nucleotides like thymine methotrexate actually inhibits this process it would inhibit the formation of thymine if you don't have thymine can you incorporate that into dna make more dna allow for the cell to be able to replicate no so then there's a decrease in the replication process another thing there's another pathway that is actually utilized i don't want you guys to remember too much about this but there's another substrate that can convert it into what's called another type of nucleotide called pyrimidines and your pyrimidines are your guanine and your adenine methotrexate works by inhibiting this formation the formation of pyrimidines you can't make guanine you can't make adenine so if you can't make guanine you can't make adenine you can't make purines like thymine what happens to the amount of dna a result results in a decrease in the dna and if that happens this decrease in dna reduces the replication process and may eventually lead to maybe some death of some of these cells because they're not able to pass on some of their actual genetic material to other cells so a decrease in this replication process may result in less th1 cells if there's less th1 cells there's less of these cytokines being released reducing the inflammatory process all right so what's another type of drug that i want you guys to remember these are the big ones okay so we talked about sulfasalazine for mild cases corticosteroids for kind of the mild to moderate and even in severe cases for inducing remission methyltraxate as a thioprin or six mercaptopurine more of the moderate cases to maintain remission other drugs are your biologics okay so you guys got to go back imagine again there's all that inflammation occurring here in the gi tract wall and it's obviously a response of these problematic issues remember that whenever there was all that inflammation your t cells those t helper one cells those t helper one cells were popping out what they're popping out things like interleukin one they were popping out things like interleukin six but what was the big one that i really want you guys to remember the big one here we'll kind of beef this sucker up here it's called tnf alpha the same thing when the macrophages were activated they were also releasing things like interleukin-1 and but they were releasing tons of tnf alpha all right so tnf-alpha is a big culprit in crohn's disease so what i want to do is i want to be able to give drugs that block the effect of tnf alpha on all of the tissues and all that massive inflammatory response and so what i'm going to do is i'm going to give a drug that acts as an antibody and binds to tnf alpha inhibits tnf alpha from exerting its effects on all these different types of cells and tissues and these are called t in f alpha inhibitors and these are more for your severe cases okay so more of the severe almost refractory cases of crohn's disease when you get to the point of biologics these are good at actually inducing remission but also maintaining remission now some of these they got crazy names one of them is called infliximab this is kind of the big one that i really want you to remember but there is other ones like adalimumab okay as well but remember these are monoclonal antibodies and these are drugs that are going to be inhibiting or reducing the effect of tumor necrotic factor alpha on the peripheral tissues and different types of cells within the body reducing the massive inflammatory reaction in crohn's okay the other one which is kind of the newer drug is remember the macrophages whenever it was kind of interacting with the t cells and it was stimulated it released things like interleukin 12 which act on the t cells to help to stimulate th1 cells and then they started releasing all of those cytokines like the tnf alpha right and all the interleukin-6 and all that stuff and then there was also interleukin-23 interleukin 23 act on t cells and converted them to what's called th 17 cells released a ton of interleukin 17 which was also problematic in crohn's disease there's a drug that's been shown to be able to inhibit interleukin-12 and interleukin-23 action on th cells and what are the names of these the drugs that actually work to particularly inhibit the interleukin-12 interleukin-23 these are called interleukin 12 interleukin 23 inhibitors and this is actually a very specific type of drug class that again these are used more in the severe cases even when patients have not really responded to the tnf alpha inhibitors this is a very specific type of drug we call it ustekinumab okay ustekinumab and again it's going to inhibit the interleukin-12 interleukin-23 activity all right the last one here for the medical therapies this is really interesting this is why i talked about that cell adhesion process remember we had these different molecules called cams the cell adhesion molecules that bound with these other things on the white blood cells what were these things on the white blood cells called they were called integrins the integrins that were bound to these white blood cells like the macrophages the neutrophils the lymphocytes that were coming into the area of inflammation there's actually very specific components called alpha 4 beta 7 integrins and we have drugs that actually can target these so they're monoclonal antibodies that actually target they specifically target these integrins and when they bind to these integrins they block the white blood cells from being able to come out of the blood into this area of where all the inflammation that will induce and exacerbate crohn's disease these are called your alpha 4 beta 7 integrin drugs and this drug that we utilize and again the severe refractory cases is called vedo lisumab this is an alpha 4 beta 7 and tegrin antibody blocker this is another drug that we can give to patients with crohn's disease more in the severe case all right last but not least if we've tried all the medical therapies and again again in a kind of a step up fashion if you really wanted to know the perfect step of fashion you should in in the guidelines start with sulfasalazine in the mild cases if that doesn't work then you go to corticosteroids generally you try things like budestinide the controlled release first if that doesn't work then you can go to the po prednisone or the iv methyl prednisolone try to induce remission after you've done that then you step up to trying things that will maintain remission like as a thioprin or six mercaptopurine or methotrexate if that's not working and you're still having a flare you're not able to maintain remission you go to the tnf alpha inhibitors like infliximab adalumab and then if that doesn't work you can try other drugs like ustekinumab which is the interleukin-1223 and an alternative to that is a vettelizimab which is an alpha 4 beta 7 integrin blocker all right so let's talk about the surgical therapy so if a patient has crohn's disease right and maybe they have some very diseased segments maybe they have like an area that's really really diseased and it's just not functional anymore we have to go and resect that portion that may be a surgical option for a patient so there may be the need for resection the other thing is especially with those strictures with strictures sometimes you can actually go in and actually dilate those areas and so sometimes dilation of a stricture may be another option for a surgical procedure here's the big thing what i really want you guys to take away from the surgical therapy and this is not curative this is not curative in comparison to something for ulcerative colitis it would be curative because if you remove that actual segment you it would actually be helpful but in a patient with crohn's disease this is not curative okay very very important to remember now the next thing is surveillance when we have a patient with crohn's disease they're at high risk of colorectal cancer that's because again they have that disease segment they're having continuous replication to repair that epithelial barrier there's obviously a risk of mutations with that and so because of that they need to get colonoscopies earlier than those individuals who do not have crohn's disease and so you should get a colonoscopy eight years after crohn's disease diagnosis or diagnosis of primary sclerosing cholangitis may also be another reason okay so these are the big things that i need you to remember all right engineers we covered so much on crohn's disease i hope it made sense i hope that you guys enjoyed it and as always until next time [Music] you

Channel: Ninja Nerd

Views: 95,465

Keywords: Ninja Nerd Lectures, Ninja Nerd, Ninja Nerd Science, education, whiteboard lectures, medicine, science

Id: UJw2WUtHLIk

Length: 95min 28sec (5728 seconds)

Published: Mon Nov 22 2021