DIP Episode 188 - Updated USMLE Step 1 GI Review Series 3

Okay, welcome. My name is Divine, I'm a resident. This is episode 180 of the Divine Intervention Podcast. In this podcast I'll be continuing the gastroenterology review for the US Emily Step 1. In today's episode I'll be focusing on all the diseases of the pancreas. So let's get going. So the theme is the pancreas, right? It's it's kind of like a mixed organ, right? It has endocrine functions, right? Like making like the insulin, blue organ and what not. And then it also has exocrine functions, right? Where it makes those enzymes that are necessary for digestion of food. Now it's very high yield to remember that people that have the pancreas, right? is located in the retroperitoneum. So because it's in the retroperitoneum that explains why people that have pancreatitis, classically have backpain on exams. And one of the thing is the fact that it's in the retroperitoneum also makes it very well hidden. This is why pancreatic cancer, right? Can grow, I mean this is why most cases of pancreatic cancer are like it has grown, it has widely invaded stuff before it comes becomes more apparent clinically. Now the pancreas, right? Big theme, right? Remember it's made up of three major parts. There's the head, there's the body, there's the tail. And like I said, the endocrine portion, right? That's basically the eyelids or longer hands. They have alpha cells that secrete local gond, they have beta cells that secrete insulin. And then they have delta cells that secrete somatosetatin.

That's the endocrine portion. The exocrine portion is kind of different, right? So it has asinar cells, whether the primary cells that secrete digestive enzymes, right? And then when those asinar cells secrete those digestive enzymes, we have like a bunch of dots that move those enzymes ultimately to the doodnam, the second part of the doodnam. And the thing is many of these digestive enzymes when they are made, they are made in a zymogen form, right? So in an inactive form, right? So and then they ultimately get activated by certain enzymes that I'll talk about in a second for them to be active and actually eating the digestion of food. And the thing is, like I said, remember I said the asinar cells they make these digestive whatever's and then you have the epithelial, you have like these dots that get them to the doodnam. The thing is these doctal cells, they actually line by epithelial cells. Sometimes it's cuboidal, sometimes it's but it's actually very high you'll remember that these epithelial cells that line those dots, right? They secrete like fluid that's like very rich in bicarb, they secrete new sin, right? So the reason I'm mentioning this is that if you think about a patient that has cystic fibrosis, right? The thing is those epithelial cells that line the dots of the pancreas, right? They contain that CFTR transporter. So the thing is if again you have a person has cystic fibrosis, that CFTR transporter doesn't work very well.

People that have CF can ultimately have like in specific pancreatic secretions. That is what ultimately leads to the like the pancreas and sufficiency that underlies cystic fibrosis classically will present as a as a fat malabsorption. And the thing is pancreate, I mean the pancreas, right? Many of the diseases, I mean obviously there's the pancreatic cancers, but the thing is ultimately if you're thinking in the big pancreatic pathology, you probably want to remember for your exams is just pancreatitis. And pancreatitis usually it arises when you have like auto digestion of the pancreas from early activation of pancreatic enzymes. Our discuss mechanisms behind these things are in a couple of minutes. And just again some quick like pancreatic physiology remember, like I said, these pancreatic enzymes they emit as zymogens, right? The thing is for them to be activated, you require trips in. And for that trips in to work, it actually needs to be converted from tripcynogen. And for that tripcynogen to be converted to trips in, you need an enzyme that's known as enterocainis. Okay? And the thing is you may say, okay divine, why do we need all these things? The thing is the pancreas actually almost has like some failed-sift mechanisms to almost like self protect itself from pancreatitis, right?

So this enterocainis sometimes on nbim exams you may see it referred to as enteropeptidis, but the enterocainis mechanism helps a lot because the thing that happens is that enterocainis is made solely in the Diwadnam, right? So the thing is most of these pancreatic enzymes need to make their reach to the Diwadnam to be activated. That is one example of a failed-sift mechanism. It's better to activate those pancreatic enzymes with your naked than in the pancreas, with it can auto digest the pancreas and cause pancreatitis. So the thing is enterocainis again like I said also called enteropeptidis, it will convert trips in to tripsin and then tripcyn go back and activate all the pancreatic zymogin enzymes. Now one of the things you should keep in mind is tripsin also kind of works through like a negative feedback mechanism. Tripsin can actually go back and inactivate itself. And then there is this gene product known as a spink one. Basically there is this gene known as spink one. It quotes for protein known as a tripcin inhibitor. It's actually made by like the cells of the duct of the pancreas and also those as in our cells and those serve to go ahead and inactivate tripsin. And I'll just go ahead and say something here. So there is one theme. So for those of you that listen to my podcast, there's one theme you'll begin to notice in many of my podcasts going forward. I will have a big cell biology focus. The thing is if you look at the more recent NBM Es, right?

Like NBME 20 going forward. And you just hear like this general sense, right? The NBM is beginning to focus quite heavily on cell biology and it's related to pathophysiology of disease. So I am going to spend time emphasizing those things. Again, I won't go berserk on emphasizing them but the things that are very high yield need to know for exams. I am going to discuss them. So that's just something you should prepare your mind for. So some of you listen to this podcast me say oh divine that's low yield not important. I promise you it's not low yield. Again, I've been and thankfully been an educator for a pretty long time and I've worked with like thousands and thousands of met students from many met schools all over the country all over the world. So I promise you I'm not kidding why I say that cell biology and the context of disease pathophysiology is very high yield for the US Emily step one exam. So now that we've kind of lead the background for the pancreas, let's talk about some congenital problems that can arise with the pancreas. The first thing is just some very basic embryology. The thing you want to remember is that the pancreas ultimately forms from the fusion of like a ventral pancreatic bar and a doso pancreatic bud. So what are some problems that can happen with this pancreatica development? Well, one simple thing that can happen is you just don't have a pancreas. Okay, that's what's known as pancreatic agenesis.

Pancreatic agenesis it is super super rare but the big thing you want to remember is it's associated with mutation in an gene known as PDX1. Okay, a PDX1 gene mutation is associated with pancreatic agenesis. That's all you need to know about that. Now, the next pancreatic congenital thing you want to keep in mind is something called pancreas divisum. Right? In fact, of all the pancreatic anomalies, this is actually the most common. And basically, I mean look at the term pancreas divisum. Right? So it's almost like something is divided into. Basically, it arises when like the ventral and doso pancreatic buds don't fuse. So the thing that happens with that is that the mean pancreatic duct ends up draining like a very small portion of the pancreas. And then the bulk of the pancreas, right? From like the doso pancreatic bud, drinks like through like something called like a minus finger, right? And the thing is that minus finger has a very small opening, right? So the thing is because you have these drainage problems, ultimately, people that have pancreas divisum, the pressures in their pancreatic ducts are very elevated, right? And with those chronically elevated in traductive pressures, those people can have chronic pancreatitis. And then the next pancreas related congenital thing I want to talk about is anola pancreas.

Basically, it's a thing that happens where like the ventral and doso pancreatic buds, they kind of fuse in a weird way with pancreas ultimately like encircles the dwoadna. The thing is, it can cause like signs and symptoms of a small bowel obstruction. And that's pretty much or you should keep in mind with that. Although don't forget that anola pancreas has an association with Down syndrome, okay? Anola pancreas has an association with Down syndrome. And then I think the last thing I will mention with regards to the pancreas, actually two two quick things. One thing I will say is that people that have a pancreatitis, I mean, sorry, one congenital thing you can see with pancreas is just having pancreatic tissue in weird spots. Probably the classic one most medicine is used is like mecos diverticulum. Remember, mecos diverticulum is a true diverticulum. It has all three layers of a mucosa. I mean of of the like the lining of the GI tract, like it has like mecosa, sub mucosa, and muscularis external, right? But people can actually have a topic that pancreatic tissue like in many other locations, besides the pancreas, right? So, I mean besides like a mecos diverticulum. So you actually the most common location of a topic pancreatic tissue in the GI tract is the stomach, right? Flute by the doormum, okay? And then the genoma mecos diverticulum, like ilium, they're kind of like ticking the back seat. But for the most part really stomach, doormum, and all that stuff.

This kind of explains why if a person has like a pancreatic neuroendocrine tumor, many people say, oh, divine, why do some of these pancreatic neuroendocrine tumors not arising the pancreas? Well, that's why because you can have a topic pancreatic tissue elsewhere in the GI tract. And then one last thing I will also go ahead and say is remember that people that have polycystic kidney disease either like ARPKD, that's like autosomal recessive polycystic kidney disease, that's like in kids, or ADPKD, like autosomal dominant polycystic kidney disease, that's an adult. Those people tend to have cysts, right? Remember, those who tend to have cysts like in the liver, they tend to have cysts in the kidneys, right? And then they also tend to have cysts in the pancreas, okay? So that's something that's actually very high yield to know for purposes of the USMLA exams. So now let me go ahead and talk about pancreatitis, right? So obviously what are the two kinds of pancreatitis? There is acute pancreatitis and there is chronic pancreatitis, right? And really acute pancreatitis, if you're asking you, what are the most common causes in the US? You want to think more along the lines of like alcoholism and gallstones? Alcohol and gallstones are the two most common causes of pancreatitis in the US, probably like 80% of cases of pancreatitis in the US, arise from alcoholism and gallstones.

And of those two, alcohol, it kind of depends on the resource you read though, but I'll say for purposes of the USMLA exams, just remember that alcoholism is probably the most common cause of acute pancreatitis in the US. If you are going down the line of chronic pancreatitis, chronic pancreatitis is most commonly caused by alcoholism. Alcoholism is far and away the most common cause of acute pancreatitis in the US. So what are some things that cause acute pancreatitis? I already talked about the alcohol and gallstones. If you have basically the gallstones, they can obstruct the pancreatic ducts, that can cause problems. Remember, if people have infection, especially in the developing world, infection with ascarus lumbaricoides or chronicis synences, that can also obstruct the biliary tree or the pancreatic ducts and cause trouble. And then there are certain drugs that tend to cause pancreatitis. Many of these are anti-segeometric medications. Some of the HIV drugs like stavidine and didenocene. There is another drug known as zalcidabine. Those drugs can all cause pancreatitis. Then, phyazides can also cause pancreatitis as well. Phyazides can cause pancreatitis. That's very high up to no. They don't forget mumps, mumps, coxaccyvirus, those can all cause pancreatitis.

Then, if a person has high levels of triglycerides, high levels of triglycerides, or those people have primary hyperparthia, I already said, if how hypercalcymated in general can all cause pancreatitis because they can activate pancreatic enzymes. Then, if you see candle-bindering in a child or a person is in a motor vehicle accident and they have severe pigastric pain radiating to the back, think about pancreatitis as well. Then, if a person also has a bwardenal ulcer that can also cause ulcer, then it can also cause pancreatitis. Then, if you are going down the cell biology land, then, again, those listen to this podcast. Pay attention, it is floorily high yield. So, no, for the USML exams. If you have a mutation in an enzyme known as press one, prss one, or mutation in another enzyme known as spink one. So, prss one spink one mutations, those are associated with something known as hereditary pancreatitis. Hereditary pancreatitis can cause acute pancreatitis. So, it may say, okay, define, how do these things cling to the etiology of a kid pancreatitis? Well, the thing is, when a person has like a pred, let me give you some examples, right? If a person has like a prss one mutation, the thing is prss one, quotes for tripsinojin, right? So, if you have a mutation in prss one, the thing is, remember I said that, tripsin goes back to turnoff itself in like a negative feedback mechanism. The thing is, when you have this mutation, tripsin will not be able to turn itself off.

So, if you cannot turn off tripsin, then that tripsin will be constitutively like in an active form, and that can go ahead and activate all that pancreatic enzymes, and that can cause an auto digestion of the pancreas. Although one other thing I guess I should go ahead and see is that for about one in five cases of pancreatitis, we have absolutely no idea why those people have pancreatitis, right? So, just I mean, guess you can see if you're pathachy, right? But yeah, there is like one in five cases of pancreatitis, we're like, I don't know what's causing this person's pancreatitis. And again, like I said, the primary thing that happens in people that have pancreatitis is, they have auto digestion of the pancreas. Like, if you ask your boy like a mechanism on a test, right? Think about auto digestion of the pancreas by just enough appropriately, activating many of the pancreatic enzymes. And remember that people that have pancreatitis, right? I mean, if you activate it again, if you activate your lipis early, that lipis can go ahead and essentially like destroy like adipose cells, right? You can almost, you can have like this fat necrosis. And those fatty acids can actually bind up a presence calcium, okay? And that can actually cause a hypocalcemia. So, hypocalcemia, there actually be a finding in pancreatitis on the USMLE exams. So, that's something you definitely want to keep at the back of your mind.

And then, the thing is you may see a divine, how do some of these drugs and some of these viruses and what not, cause pancreatitis. The thing is those drugs and what not, they cause like direct injury to the asinar cells. If you directly injure those asinar cells, that can increase the presence risk for, again, premature activation of pancreatic enzymes. And that can ultimately lead to pancreatitis. Even alcohol, right? You may see all white, those alcohol cause problems. The thing is alcohol, right? Remember, it can create oxidative stress. And if you create a lot of oxidative stress, again, that can cause direct injury to the asinar cells. And if you cause direct injury to the asinar cells, that can ultimately lead to pancreatitis. Now, how does pancreatitis classically present on NV Me exams, right? You'll present in a person that has, you know, like severe pigastric pain, it's radiating to the back. And typically, if you want to do your diagnostic testing, right? You know, you, you, you check the lipase, right? Lipase is a lot more sensitive and specific for pancreatitis compared with amylase, right? Because amylase, if you have vomited atone, if you have mumps and all that stuff, that can elevate your amylase, right? So lipase is more sensitive and specific. In fact, like clinically, at least as an intern, when I was taking care of patients like, like, in the ICU or whatever pancreatitis, I never ordered amylase on those people.

It was just basically a waste of, waste of clinical resources, right? Lipase is more sensitive and more specific. Now, one thing I want to keep in, I want you to keep in mind is that, so remember, I said that when a person has pancreatitis, they can get, like, saponification, right? Where they essentially have like calcium ions binding to freely release fatty acids because lipases on board. Remember, lipases job is to break down triglycerides into monoysilosterone and two free fatty acids, right? So those free fatty acids, they combined up calcium, right? The thing is, it's actually very high doctor. Remember this factoid. If a person that has pancreatitis has persistent hypo calcium, that is actually one of the worst prognostic factors in the setting of, uh, in the setting of acute pancreatitis. So you may say, oh, divine, why is it important to know this thing? The thing is, the NBME in recent times has been known to write questions where they ask about, like, the best prognostic factor for a disease or the worst prognostic factor for a disease. So that's something you absolutely, positively want to commit to memory for your exams. So you may say, okay, divine. So how do we manage acute pancreatitis? Well, the way you manage acute pancreatitis is kind of easy. Just remember the mnemonic pin PIN, okay, PIN, PIN. So the P is for pain control, okay? You, uh, basically you can use essentially every form of pain control, but morphine, right?

Remember morphine can cause spasim of this finger of OD, which is bad for pancreatitis. And then the eye stands for IV fluids. You give these people a crap ton of fluids, like sometimes I've given some of these people like four, five, six liters of fluid in a very short amount of, very short amount of time. And then the N is for MPO, right? You don't want to put any foot down the GI tract so that you don't encourage the pancreas to contract or whatever and then cause trouble. So PIN, pain control with usually with opioids because this thing is like super painful. The eye is for IV fluids and then the N is for MPO, right? So Neopurus, keep the patient, uh, MPO, they just don't eat. I mean, I've had patients where, um, they had pancreatitis and essentially had them not eat for like a week because they just had like pancreatitis and like some pretty severe complications. Now, one quick thing I guess I want you to keep at the back of your mind with pancreatitis is so people can actually have a sequelae of pancreatitis known as a pancreatic pseudo-sist. A pancreatic pseudo-sist is basically it's just, um, where you have like pancreatic tissue that kind of like liquefies and then it's like ward off by fibro-stitio, right? So it's actually important to remember that it's not ward off by epithelial tissue, it's ward off by fibro-stitio. That's why it's known as a pseudo-sist. And the thing is, most times these are pancreatic pseudo-sists. They're pretty rich in pancreatic fluid.

Um, and typically, uh, if they're like less than 5 to 6 centimeters, you don't need to do anything for them. You just kind of let them go, um, they will kind of like resolve on their own. Although if they kind of like hang out for like six weeks or more, then you can do something, you can do like a percutaneous drainage. But if a person has pancreatitis for greater than, I mean like a pancreatic pseudo-sist that's more than like 5 to 6 centimeters, typically you want to go ahead and drainage on that those are circumstances. So we've kind of talked about acute pancreatitis. I guess it makes sense to talk about chronic pancreatitis. Well, the thing with chronic pancreatitis, again, like I said, the most common cause, right? Very high yield to notice, for example, the most common cause of chronic pancreatitis is chronic alcoholism, right? Chronic alcoholism. And then if you see like pancreatitis in a kid, like chronic pancreatitis in a kid, one thing I really want you to think about is a CFTR mutation, right? Again, with cystic fibro-stits, right? Because again, those people have like inspecithid, pancreatic doctor's equations. And so what do I mean by inspecidid? Just I just mean like very viscous pancreatic secretions, right? Those things can all cause a pancreatitis. So you may say, okay, chronic pancreatitis, why does it matter?

Well, the reason it matters is that if you destroy the exocrine function of the pancreas, right, you're not able to make things like light peas, right? So those people tend to get like a phatma lapse option, right? And phat's typically, if you check like the fickle elastis, right? The fickle elastis will be decreased, right? And a person that has chronic pancreatitis because again, they just have no ability to make pancreatitis because the exocrine function of the pancreas is gone. And then people that have chronic pancreatitis, right? They almost get like a type one diabetes presentation because again, because you've destroyed the pancreas, then you no longer have, you no longer have like the endocrine function of the pancreas available, right? So those people, again, they don't make insulin, they don't make local gone, right? So they just have dysregulation of their glucose, like, like their blood glucose levels and things like that, right? So those people generally get placed on insulin, right? Because think about it, right? Those people can, it doesn't make sense to put them on an oral hypochalicymic agent because they have literally no pancreas, right? So any drug you give them is pretty much not going to work other than insulin, right? Because essentially giving them what they are lacking. Now, one other thing I want to mention with chronic pancreatitis is actually two quick things I want to mention is don't forget this thing known as autoimmune pancreatitis.

It's just something that has started making like, you know, kind of making its way to the USMLE exams. Basically, if they tell you that a person on, you know, tends to keep having these recurrent episodes of pancreatitis, right? And then the like, recurrent episodes of like acute pancreatitis and then they tell you that on imaging, you see like a sausage shape to the pancreas or they may even say that all like they did like a biopsy of some part of the pancreas and they notice that you see like an infiltrate of like lymphocytes, plasma cells and you notice that many of them are positive for IgG4. It's very important to remember IgG4, okay? If you see that think about autoimmune pancreatitis and really the treatment for autoimmune pancreatitis is steroids, right? So it's actually kind of treatable, right? And the thing is, autoimmune pancreatitis just represents one of many IgG4 related diseases. The IgG4 related diseases are floridly high, you know, for the USMLE exams. So they include things like autoimmune pancreatitis, they include things like autoimmune colisestitis, they include things like radials, thyroiditis, that's something you'll learn about when I make the endocrine podcast for step one, right? But those IgG4 related diseases they can cause like retroperitoneal fibrosis and all that stuff, right? So that's one big thing I want you to keep in mind with chronic pancreatitis.

Another big thing I want you to keep in mind with chronic pancreatitis is you may say, oh, divine, well why those chronic pancreatitis happen? Well, the thing is as you keep having like these recurring bolts of inflammation, inflammation, inflammation, the thing that can ultimately happen is you can fibro-stap pancreas and when you fibro-stap pancreas it loses all its function. So you may say, okay, what causes fibrosis of the pancreas? Well, this is another cell biology query for the exam. You want to remember that one of the things that causes fibrosis of the pancreas, right, is activation of TGF beta, right? So trans-framing growth factor beta, right? And then another one is like PDGF, right? So like pleclyde derived growth factor. The thing is those cytokines, right? They essentially like tell the fib- the myofibroblasts that hang around the external cells to satisfy the secretive a ton of collagen and that's very, very important in the pathogenesis behind the fibrosis. Now we see that constitutes a chronic pancreatitis and then it's chronic pancreatitis to be honest. You can actually make the diagnosis pretty well by getting imaging of the abdomen like a CT scan. Classically on MBME exams you'll see calcifications within the wall of the pancreas. If you see calcifications within the wall of the pancreas, think about think about chronic pancreatitis, okay? Think about chronic pancreatitis. So again, calcifications within the walls of the pancreas.

And one of the things I'll go ahead and mention is that people that have chronic pancreatitis don't necessarily expect their amylase and lipase or whatever to be elevated. In fact, typically those people's amylase and lipase levels, they're just basically not reliable, right? Typically they actually lower normal because you've essentially burned out the pancreas so you're not able to make those things anymore. So with that said, I guess we can go ahead and jump to the pancreatic cancers, right? The thing is let me talk about some of the B9 stuff and then I'll go to the more, you know, nasty nasty nasty stuff. I mean pancreatic cancer is awful, the terrible disease. Don't wish it on anyone. I mean, it's very rapidly progressive. Like many people have seen where pancreatic cancer, right? They go from they're doing fine and then they're dead within a couple of months. I think like this person known as, I mean, it's claimed many famous people in history, right? Like Steve Jobs, I'm fairly certain he died of a pancreatic cancer or there is this person that right now is actually dealing with pancreatic cancer. I think his name is like Alex Trebek. He's like a big time show host here in the US. He has pancreatic cancer. He's been fighting, fighting, fighting. But pancreatic cancer is just bad, right? It's not something you wish on even your worst enemy. So let's talk about some of the pancreatic cancers, right?

And I think, I think probably a nice way to delineate these pancreatic cancers is to discuss them as like the cystic neoplasms, right? And then to discuss them as the full blown like pancreatic adenocarcinoma, okay? So let me talk about the cystic neoplasms first. And then I'll talk about the pancreatic adenocarcinomas. The cystic neoplasms, the first big one you probably want to keep in mind is like the serocyst adenoma, serocyst, cyst adenoma, right? Notice I said cyst adenoma. I did not say cyst adenocarcinoma, right? So the thing is these serocyst adenomas, they have been for the most part, right? They very, really progress to something that's like, like frankly, malignant, right? And the thing is one, again, cell biology, currently, to want to keep in the back of your mind here is that people that have serocyst adenomas, they tend to have like mutations in like the VHL tumor suppressor gene, right? Remember VHL, right? When he pulling down, remember when he pulling down, has an association with like human geoblastomas in the brain. It has an association with cysts in the pancreas, right? Like these are serocyst adenomas and those are serocyst adenomas, like bilateral renal cell carcinomas, right? And remember that those human geoblastomas can produce EPO in a perinoplastic fashion, okay? So again, serocyst adenomas, big thing one, to keep in mind is they tend to have mutations in the VHL tumor suppressor gene.

And then the next pancreatic like cystic neoplasms, like the musinos cystic pancreatic can neoplasm, basically, on like the serocyst adenomas that tend to arise, actually, let me not make a mistake there. Let me continue with this so I don't confuse you. I'll kind of like separate some things. In fact, I think maybe one thing that will be probably be helpful here is to talk about, yeah, let me talk about each first and then I'll talk about one key difference. So the musinos cystic neoplasm that you can find in the pancreas, the big thing one to remember is that it tends to arise in the body or tail of the pancreas, okay? And typically, this is something you may not necessarily use on step one is more for like a surgery shelf or like a 30-a-shelf exam. But the way you treat this musinos cystic neoplasms, you actually do something called a distal pancreatic to me, right? So because they arise like in the body and tail, you can just resect the distal portion of the pancreas and those patients should be fine. Although remember that on like the serocyst adenomas that have almost no potential for progressing to like a frank pancreatic malignancy, this musinos cystic neoplasms, they actually bona fide precursors to pancreatic cancer, okay? So they can become bad, right? They do have a like a higher malignant potential compared with the serocyst adenomas. And then another kind of pancreatic like cystic neoplasm I want to talk about is the IPMN, right?

So like the intra-doctor, papillary musinos neoplasm, okay? The thing is on like the musinos cystic neoplasm that I said primarily arises in the body and tail of the pancreas, the IPMN, right? Classically arises in the head of the pancreas. That's a key difference you want to be able to recognize for purposes of the USM Ls. And the thing is most people that have IPM Ns, the primary cell biology correlate you want to keep at the back of your mind for purposes of the USM Ls is that this is actually associated with mutations in a protein known as GNAS, like Gmas, so GNAS mutation. The thing is when you have this gen, this is a GNAS, GN mutation. Remember GNAS actually encodes for like the alpha subunit of like GS, right? Like the stimulatory, G protein coupled receptor. So the thing is if this, if you have this mutation, you have like a constitutively active like stimulatory, stimulatory, G protein coupled receptor and that can promote cell proliferation and again can lead to malignancy and remember. These IPM Ns, right? They also again have bona fide precursors to pancreatic adenocarcinoma, right? And again, most pancreas, so I guess with that said, let me just jump to, you know, just straight up pancreatic cancer. So pancreatic cancer, it's almost always an adenocarcinoma on MBM exams, right?

And the thing is the biggest risk factor because again, your friends at the MBME, they've started caring again, like I know some people may say, oh, Devon, I don't believe what you're saying. I promise you these things, I'm saying are true, right? Again, like you don't have to believe me, just take the more recent MBM Es, right? And again, just look at the, because this is one thing I feel for whatever is in people just completely ignore when studying for the USML exams. There is actually like a USML outline, there's like an actual like guide that the MBME puts out for topics that he tests on these USM Ls. Go and look at that topic list and tell me that cell biology and correlates with pathophysiology of disease is not important. So again, I promise you like risk factors, cell biology correlates, they have very, very high yield, not just for step one, but also for step two CK in fact. One thing people don't realize is that the outline that the MBME uses for USM Ls step one is actually the exact same outline that he used for USM Ls step two CK. That is why when people ask me, oh Devon, what is the biggest, what is the best way to set myself to do well on step two CK? I tell them is actually to do well on step one, like it's extremely unusual for president to do well on step one and not do well or even better on step two CK. At least that was certainly the case for me. So the biggest risk factor, very high yield, is the biggest risk factor for pancreatic cancer.

Or at least you can say like environmental risk factor for pancreatic cancer is smoking, okay? Smoking plays a very big role in the pathogenesis of pancreatic adnocarsinoma. Now, the thing is if you are looking at pancreatic cancers, if you are going by section of the pancreas, remember I said the pancreas is divided into like a head, a body and a tail. Most pancreatic cancers are rising the head of the pancreas, about 60% of pancreatic adnocarsinomas they are rising the head about 15% are rising the body and then about 5% are rising the tail. So just remember 60, 15, 5 and they're going in order of head, body and tail, okay? You'll keep that straight. Now, if you remember, when I talked about when I gave, I think it was either the first, yeah, I think it was like the first of the LGI USMLE Step One podcast. I talked about how we have this sequence that ultimately leads to the development of a colon cancer, where I think the pneumonia gave was like AK53, where you have like an APC gene mutation and then you have a Keras mutation and then you have a P53 tumor suppressor gene mutation and then you get full bloom colon retoc cancer. Well, the thing is there is also, there is also like sequence, right? That's actually be identified in the pathogenesis of many pancreatic adnocarsinomas and really the way I remember it is, I remember it as KP53. So instead of AK53, like we had for colon cancer, we have KP53 for pancreatic cancer. So what does KP53 stand for?

Basically, the first thing that happens is that you have a mutation in something known as Keras, okay? Remember, Keras, so that's the Keras is an oncogene, right? The thing is, when you have that mutation in Keras, then you will essentially lose the GTP's activity of the Keras protein. So you will then become constitutively active, right? And the thing is Keras activates like, you have like an activation of many intracellular pathways that can ultimately lead to cancer like cell proliferation and things like that. And then the P stands for P16, right? Sometimes on MDM is instead of putting P16, then we put this name CDKN2 A, right? So CDKN2 A basically it's a tumor suppressor gene, right? And when you have a mutation in that tumor suppressor gene, remember if you go back to cell about cell physiology, I'm not gonna meet some podcasts of cell physiology, I still have a few more to make. But basically when you have a mutation in P16, remember P16 is a cell cycle regulator. It's like a checkpoint regulator in the cell cycle. So when you lose the ability of P16, you essentially lose a tumor suppressor gene, right? And that can cause problems and ultimately again, make basically big cells are complegine defects, but it still proceed through the cell cycle. And then the 53 stands for the P53 mutation. Remember P53 is a tumor suppressor gene. If you activate P53, then not ultimately leads to the development of like full blown invasive parcreditica agrocarcinoma.

And then one thing I'll just go ahead and throw out there is that some other genes like BRCA2, right? So because I know like when people think of BRCA1, BRCA2, they think about as like breast cancers, ovarian cancers, don't forget pancredit cancers. Pancredit cancers can also arise in the setting of a BRCA, especially like a BRCA2 gene mutation. And then there's this gene that occasionally you may see on the USMEL Es. It's known as like SM8 E4. It also plays a role in the pathogenesis of many pancredit cancers. And how does pancredit cancer present for the most part, right? Really for the most part it usually presents as like a, you know, like a painless, you know, like a person having like not painless actually. You have like jaundice, right? And you have like you know like severe weak loss. And then you have like severe pain. And you may see, okay divine, why do they get the jaundice? Well, the thing is when people have a tumor of the head of the pancreas, right? It can obstruct like the pancredit ducts and also the bilirid ducts. In fact, on imaginary biology, we call this the double duct sign. Okay. When you obstruct the pancredit duct and the the pancredit duct and the bilirid duct and both of them are dilated on imaging, that's the double duct sign. Again, obviously if you obstruct the bilirid, like the common bowel duct, right? You have an obstructive jaundice so you have like a direct or you can call it a conjugated hyperbilirid emia, right?

And that can cause that can ultimately cause a jaundice. So actually one high you thing to know, this is just a nice way that your friends at the MIMIC and test anatomy in the context of GI, right? Is that people that have adenocarcinomas at the head of the pancreas, they tend to have jaundice, people that have adenocarcinomas at the body and tail of the pancreas, they tend to not have jaundice, right? Because again, right, if you have a body or tail pancredit tumor and that would not cause that would not obstruct the bilirid tree, right? So typically, those people do not have jaundice, okay? Typically those people do not have jaundice. So again, very, very high, that's why usually body and tail pancredit cancers, they're like super big widely disseminated when they are ultimately diagnosed. And you may say, why do people that have pancredit cancer have a lot of pain? I mean, like, like when you see pancredit cancer patients, these people typically have like just nasty, nasty like unbearable pain. The reason behind that is that many times these tumors, they begin to entrap nerves that you'll find around the pancreas and by entraping those nerves, those people tend to have like severe pain. I mean, these people are like very high levels of very large amounts of opioids, like basically like in the terminal stage of the malignancies, you'll see it's just bad, bad, bad, bad, bad situation.

And then one thing I want you to keep in mind is I want you to know some tumor markers for pancredit cancer. You don't use them to diagnose pancredit cancer, but you can use them to trap the progression, right? Like you see like, oh, progression of disease or response to therapy. And those are things like CEA, right? Remember CEA is known as the Casino embryonic antigen. And then another one is known as CE199, okay? CE199. And then one of the things you'll see on your exam is something called a migratory thrombophlebitis. Some people call it like trussosendrum. Basically, it kind of happens in about 10% of patients that have pancredit cancer. And basically it's just these people, they just have like clodding and like inflammation of like different veins in their body. It kind of seems to travel all around the body. That's why it's called a migratory thrombophlebitis, okay? And the pathophysiology behind it is that many times these pancredit adenocarcinomas, they make like some like some factors that can encourage pleated aggregation and to be like secondary hemostasis, right? So you can begin to clod of these organs. That's why clod of these veins. That's why many times when people have amalgamancy, they are really placed on chronic anti-coagulation, because again, they have like a very high risk of like dvts and pts and stuff of that nature.

And then one thing I want you to keep in mind is when people have, I forgot to mention this with acute pancreditidus, when people have acute pancreditidus, there are some physical exam findings. You may actually see on the USMLE exams, one is known as the great Turner sign, right? Where you have like almost like a blue red discoloration of the persons like flank and they're back. It's something you can see in that acute pancreditidus and then there's something called the colon sign, like CU, double L, E, N, where people have like again like a red blue discoloration of like the area around the ombillicus. One nice thing to remember the colon sign is ombillicolens, right? So colon sign around the ombillicus and then great Turner sign you turn to see your flank. That's a nice way to keep that straight. You may see all the divine walkos is that basically, it's just like hemorrhagic pancredit tissue that's kind of tracking around the retro peritoneum, right? That's why you then see those dermatological findings in people with acute pancreditidus. And then since I've talked about like the pancredit exocrinoplasms, let me just talk about the pancredit endocrinoplasms, right? So pancredit endocrinoplasms, you want to think about things like insulinomas, right? Insulinomas, classically on imbim exams, they present with whipols triad, right?

So those people have, and I'll probably talk about this when I also get to the endocrine podcast, but you know, they typically have whipols triad where they have hypoglycemia and then they have signs of hypoglycemia and then they have relief of those symptoms with the administration of glucose. That's like one of the most obvious triads in all of medicine, but basically whipols triad is pathonomonic on imbim exams for insulinomas amongst other things. The other things I'll talk about them in my endocrinoplasms review podcast. And then insulinomas, right? Typically you try, you know, try surgery for those. One of the things you can do is you can give a drug known as a diazoxide. Diazoxide opens up that opens up the potassium channel that we find in a pancredit cells and that can, I mean, in pancredit like beta cells that's secreted in insulin and that can short down the release of insulin. And then another one you may see is glucagonoma, right? So people glucagonoma, again, they have like a pancredit tumor, secreted acryptone of glucagon. So they have like diabetes, right? So if you see a person that you know is having like diabetes, shopping like in their 60s is kind of weird, right? So like diabetes and then they have like a rash, the classic buzzword for that rash is necrolitic migratory erythema.

If you see that think about a glucagonoma, you can try to treat with octriotide, you can try to reset it, but glucagonomas, they're typically pretty bad, they have like a pretty awful prognosis actually. And then you might also see like soma-statinomas, you might see a vipermus, right? Vipermus, remember the secret, visual active intestinal peptide, they are classically associated with the WDHC syndrome where people have like watery diarrhea, and they have low potassium, so like hypochylemia, and then they have echlohedria. So they are chloride levels in their bloodstream, very very low like in the 80s, 90s, kind of deal. And remember that these pancredit nerve endocrine tumors, they tend to have an association with the MEN1 syndrome. Remember in MEN1, people have like the pneumonia care member is para-panfit, these people tend to have like primary hyperparthyroidism, and then they tend to have pancredit nerve endocrine tumors, and then they tend to have like pitotary adenomas usually a prolactinoma. So I think I'm gonna go ahead and stop here. I think that's all I have, I think at least that is, in my mind I feel is high to note regards for the pancreas of the USMELIS. As I do at the end of every podcast, I do offer like multiple kinds of tutoring and teaching for the USMELIS exams.

So like if you need tutoring for step one, step two CK, step two CSTEP 3, or your medicine resident and new student for the internal medicine treatment exam, or the ABI and board exams, or you need, you know, tutoring for your pre-clinical medical exam, 30th year of exams, I do offer one or one tutoring, I do offer booster courses that's typically at the end of people's dedicated periods, or when they want to put everything together in a short period of time. And I also do like just large group teaching sessions, right? But I need a minimum group of five. If you need details on any of these things, just reach out to me directly through the website so you can send me an email at divineinterventionpodcasts with an sdn.gmail.com. And then if you're a medicine plant to residency, so like an irisap or a cholesterol plant to med school, so like an amcasap, I do offer again one or one like coaching, or I guess consulting for like reclaterous personal statements, editing applications, mock interviews, and mean I've worked with tons of people on this, many of the people I've worked with have been very successful, and I've actually have admissions community experience. I've actually been on the admissions committee of a top two med school for like a year, right? So I've reviewed thousands of very high quality applications. And then if you're college student and you need to learn from like Genkame, OKM, Physics, Bio-Kame, Histology, Physiology, Alpha-Turum for all those things.

So have a wonderful rest of your day. I wish you a very successful December. I'm praying that this is a great month for everyone of us and people that are you know waiting on the iris process, I'm really praying that you get more interviews, you match at the program of your choice, and for those of you taking the USMD exams, I'm wishing I'm praying that you have good success, and you excel on those exams so that you can move forward with your life. So have a wonderful month. God bless you. I'll see you in the next podcast. Thank you.

Alcoholism and gallstones.

Entero-peptidase (also called entero-kinase).

Hypoglycemia, symptoms of hypoglycemia, and relief of symptoms upon glucose administration (Whipple's triad).

Intraductal papillary mucinous neoplasm (IPMN).

Cullen sign (periumbilical ecchymosis) and Grey Turner sign (flank ecchymosis).

VHL gene.

Head, Body, Tail (Anatomy); Endocrine function (Islets/Hormones) and Exocrine function (Enzymes).

Saponification of free fatty acids (FF As), which bind calcium ions.

Diabetes mellitus, and a rash known as necrolytic migratory erythema.

Pancreas divisum.

Keras $\rightarrow$ CDKN2 A (P16) $\rightarrow$ P53.

MCN typically arises in the body or tail; IPMN classically arises in the head of the pancreas.

Head, Body, Tail (Anatomy); Endocrine function (Islets/Hormones) and Exocrine function (Enzymes).

Saponification of free fatty acids (FF As), which bind calcium ions.

Diabetes mellitus, and a rash known as necrolytic migratory erythema.

Pancreas divisum.

Keras $\rightarrow$ CDKN2 A (P16) $\rightarrow$ P53.

MCN typically arises in the body or tail; IPMN classically arises in the head of the pancreas.