DIP Episode 319 - NBME Gastroenterology Series 6 (for all USMLEs)

Okay, welcome. My name is Divine. This is episode 319 of the Divine intervention podcast. And in this podcast I'm going to be continuing the MBME Castron Arrogi review. This is going to be series 6. Again, this is for all the USMLX apps. And again, as a reminder, if you're a ticket and step 2, CK Step 3. This month I do have two comprehensive review classes taking place. One is going to be on the, I guess I hold him in conjunction on MBME Test Taking Strategy's course. So the first series will be like on the 17th of this month. We'll be having the MBME Test Taking Strategy's course. And then on the 18th and the 19th of this month we'll be having the comprehensive step 2 CK, step 3 courses. There will be 10 hours each day. I just designed that specific session just to help people schedule. People that cannot take so many days off from rotations. And then at the end of the month I have the MBME Test Taking Strategy's course on the 20th of June from 2 to 4 30 PM Pacific Standard Time. And then the 20 hour comprehensive review course is going to be taking place on from the 29th of June to the 2nd of July. And there's going to be like five hours each day. So it's going to be from 11 PM to 4 PM Pacific Standard Time. Each of those days. Again, many people have taken these courses and they've done really well on the exams.

In fact, I've had people, they took the course like right before their test and they, it really bummed them up from like their last practice exam by 10 points, 20 points, things like that. So again, if that's something you're interested in just shooting an email through the website and I'll be happy to give you some more information. Okay. So let's jump right into it. So what is the disease that, and I also have a step one course as well for those of you that are taking step one is going to be a 48 hour very comprehensive review course. It's going to be taking place next month from the 19th to the 24th of July. It's a 48 hour course. We'll cover about 4,000 different scenarios as to the information that's tested on step one. And then for the step to CK course, we cover about 1500 scenarios as to what the MBME routinely goes after on step to CK and step three, you know, Peds, surgery, I am Neuro, Psych, Obigain, Biostats, FX, and then the November 2020 changes from last year. Okay. So I'm just going to jump right into it. So what if they give you a question and they give you all these pieces of information, right? So you have like a 45-year-old female, they tell you that she has lots of HN, she has yellow eyes, she has yellow skin. If you see that, what are you thinking about? Well, I hope you're saying old wine, this is actually primary bilayery serosis. Remember the name of that has changed recently. It's now called primary bilayery colonjitis, right?

So remembering PBC, essentially the thing that happens is you have CD positive T cells, right? They actually attract that to an antigen that you find on the surface of the mitochondrial membrane. And then they attack, they attack those those cells, right? And they ultimately end up getting getting a lot of problems, right? So it's actually very high yield. Even if because I know many people will screw this up, right? It's actually CD positive T cells that are mediating the damage and it's the intra-lopula bowel ducts that are being destroyed. And because the reason I think I'm saying people may screw this up is, yes, they have those positive anti-mide or contra-lanty bodies, right? And in fact, some of these people actually have positive RNA, right? Those are things you'll find in people that have lupus. But believe it or not, it's CD positive T cells that actually mediated the damage, right? Of course, you know your friends at the MbMe will know that stuff, right? And they'll try to see if they can mess people up with that. So please don't be one of those people, right? So it's CD positive T cells that actually, again, damage the mitochondrial membrane, right? But again, the way you diagnose this is sort of typically is first you'll find the positive anti-mide or contra-lanty bodies in the serum. And then usually you're going to do some kind of liver biopsia and you'll see the damage to those cells.

Now remember that this is something you should really consider in a woman that's like in a 40s and a 50s and she's like intensely paritic, she's jaundiced, right? And she'll have like direct type of interbenemia. So a direct bilirubin will be elevated, right? So that's what ultimately puts these patients in trouble. So how do we treat these people on exams? So we're going to treat them on exams because we're going to treat them with also dial, right? Remember, also dial is also deoxycolicacid, right? It actually does in per survival in people that have PBC. But if you ultimately want to cure the disorder, you need to go ahead and perform some kind of liver transplant. That's the thing that would ultimately achieve these patients. And this podcast, by the way, I'll try to make it somewhat short because I'm going to go into some deep pathophysiology on like three disorders and I'm going to talk about a short key. So what if they give you like the amalgamus question, right? Of a guy that has like a histro-cronic bloody diarrhea and they tell you that he has been having a redocardial pain for the last few weeks and he's directly rebelling his elevated and then you notice that he's a elk-force. His alkaline phosphatise is also elevated. What should you be thinking about in those circumstances? Well, I hope you're saying, oh, divine. This person likely has PSC, right? Premiers Claruse in colonjitis. Remember, Premiers Claruse in colonjitis is associated with P-enca, right?

Zero P-enca. Although that's not entirely true, but that's accurate enough for the USM in the exams, but it's associated with P-enca. And when people have a PSC, usually you find it in people that have a histro-force redocardial pain, so they'll have like this histro-like chronic diarrhea. Usually it's going to be bloody, bloody diarrhea. And remember, unlike PBC, where it's just the intralopular bowel docks that are affected, right? The intralipartic bowel docks that are affected. In people that have PSC, it's the intra and the extra-hypatic bowel docks that are typically affected. And unlike PBC that occurs in women, PSC tends to occur in men. PSC tends to occur in men. And typically, given or so dial doesn't do squat for patients that have PSC. Given or so dial only helps people that have PBC, the only way you can cure PSC is by getting the person a liver transplant. It's by getting the person a liver transplant. I mean, if you're having a lot of itching and let's say a liver is not immediately available, one thing you can do is you can do an ERCP and then try to install like some stints in some of the ability-arid dots to help with drainage. But again, that's just that temporizing measure. It doesn't really improve survival. It doesn't really do squat for those patients. So that's something you want to keep at the back of your mind, for example. Now, what if they give you a question about a 17-year-old male? They tell you that he has diabetes, right?

And then they tell you that he also has like a shiny complexion to his skin, right? Like he has skin hyperpigmentation. If you see this, I really hope you're saying, oh, divine. This person has hated trigemochromatosis, right? And also, I'm hoping it'd be like, why are we talking about hemochromatosis? The thing is, again, this, that's why this GI series, I'm going to make sure that I really break things down, right? Your friends at the MBMD love this stuff where they just again make tons of integrations, right? And again, people don't necessarily study that way, for exams, right? But hemochromatosis is a well-defined GI disorder that your friends at the MBMD love to after, right? So why do these people have diabetes? Well, the reason they have diabetes is because their pancreas has been messed up significantly, right? So remember, people that have hemochromatosis, that again, I'll talk about the pathophase. Whenever people have hemochromatosis, typically those people's pancreas have been destroyed by the fentine reaction, right? And when it's destroyed by the fentine reaction, you then notice that, oh, wow, the presence pancreas is dead, when your pancreas is dead, unfortunately, you're not going to be able to make insulin, right? So you're going to get like an insulin-dependent diabetes from that. And then in addition to that, you're not going to be making your pancreatic enzymes, right?

So these people can have fat malabsorption, so they can give you like a vitamin A, D, E, or K deficiency on the exam with that. And then remember, these people can also destroy their testing, right? So again, many times they tend to be infertile, right? And remember that this is also associated with people getting restrictive cardiomyopathy, right? Yes, don't get me wrong. Hemochromatosis can also cause dilithic cardiomyopathy. But many times on MBME exams, whatever bizarre reason, they're a little more selective about going with that restrictive cardiomyopathy. Again, if you remember from my, I think it's episode 129. It's a very good, um, um, um, um, analogy podcast. I talk about like the rosis role for things that cause restrictive cardiomyopathy or restrictive long disease. Anything that ends in ulces, whatever bizarre reason tends to cause restrictive disease of the involved organ. That's like a relatively reliable role for the USM in the exams. Again, I'll talk about the pathophys behind hemochromatosis. But one other thing I want to say is that remember, if they give you a question about a person that has hemochromatosis, don't forget that he can affect the joints, so CPPD, the calcium pyrophosphate, the hydrate deposition disease, has a very strong association on hereditary hemochromatosis on MBME exams.

Now, what if they give you a question about a 17-year-old male and they tell you that he has all these Parkinsonian symptoms, so he has like, he has very small hand writing, has a echinnesia and all those things. He has a pyrus pneumagony, right? And then they tell you that you see some corneal abnormalities on from the scopic exam. If you see this, I want you to think about well-sense disease, I want you to think about well-sense disease. Basically, it will present in a young person and the person will have neuropsych problems and liver problems. That's the classic thing you want to keep in mind, right? You'll have neuropsych problems, you'll have liver problems, right? If you see that, I really want you to think about well-sense disease. Remember, another name that your friends at the MBME could use for well-sense diseases, they can call it hepato lenticular degeneration, I'll say that again, hepato lenticular degeneration. Remember, one thing our friends at the MBME is love doing these days. They love taking things you know and then putting like different words that people are not used to, like neuro tube defects. Instead of calling it a neuro tube defect on the exam, they'll call it a spinal dysrophysm, right? A spinal dysrophysm, right? So it's just something I want to keep at the back of your mind for for these tests, right? And remember that people that have well-sense disease, you definitely don't want to give them the copper IUD, right?

The copper I'm traitering device, if it's a woman that has well-sense disease because they already have copper excess, right? So why would you want to give them extra copper? That doesn't make any sense, right? So just something to keep in mind, that's a nice way to get integrated that would OB-GYN on MBME exams. And then what if they give you a question about a 17-year-old nail? They tell you that he presents with hepato splenomegaly and they tell you that you know multiple family members have died from respiratory problems in their 50s. And then they tell you that, you know, the performer liver biopsy and the fine PES positive intrahepatic inclusions, right? So you see these PES positive inclusions within hepato sites. If you see that, I want you to think about alpha-1-antitripsin deficiency, right? Alpha-1-antitripsin deficiency, remember? Alpha-1-antitripsin deficiency is a search-doh panasinar and fizema, right? So I think the thing I'm going to devote the rest of this podcast too. So again, I'll try to keep this podcast short. Is describing the path of physiology these three just disorders because many people tend to mix them up or just not really understand them, right? So let's talk about the pathophys behind hemochromatosis, behind well-sense disease, and behind alpha-1-antitripsin deficiency. So hemochromatosis, right? So what's the pathophysiology there, right? So the thing is in hemochromatosis, yes, let me establish a few things.

Remember, here the true hemochromatosis is an autosumorescensive disease, right? And it tends to shop early in men, much earlier in life in men, compared with women, right? Because if you're a woman, think about it, you're essentially blood-led in every month. Because remember, one of the ways we treat hemochromatosis is at the bottom, right? So by being a woman because you're having your period, you're literally blood-led in every month. So people, women that have heritage of hemochromatosis, they tend to not have problems until later, right? And again, it arises typically from like a C2 H2 Y or H63 D gene mutation. I'll say that again from a C2 H2 Y or from a H63 D gene mutation, right? Now, one usual thing that your friends at the MD may love to do with heritage for hemochromatosis is they love to give you these iron labs that you classically see in anemias, and then they'll try to see if you can deduce what the iron labs will look like in a person that has hemochromatosis. Well, again, if you understand the fact that hemochromatosis is an iron overload disorder, then you can easily make these integrations, right? So if you think about it, people that have heritage of hemochromatosis, it's an iron overload disorder, right? So that means the iron stores will be very full. So the affair thing is going to be really high. Well, if you think about it, if your affair thing is really high, then your TIBC is going to be really low, right?

Because your body is like, I have a ton of iron. I don't need extra iron around that. I don't need to be sending out transfer and to keep scoring more iron. So these people's TIBC is going to be low. And then if you think about it, because again, we have so much iron, the transfer in saturation is going to be low as well, right? I mean, sorry, the transfer in saturation is going to be high. So the percent transfer in saturation is going to be high, because that transfer that is even around, even if it's little, has so much iron on it, right? So that's very high you to keep at the back of your mind on exams, right? So let's talk about the pathophysiology, right? So let's let's talk about many times to understand pathophysiology on anememic exams. It's best to understand what happens in the normal case if you don't have disease. And then after that, you then ask yourself, Oh, okay, what is the thing that happens when you do have the disease, right? So let's let's think about it. So this many times you may see on exams that you say that, Oh, people that have had each three hemochromatosis, right? They have a HF E gene mutation. That's another gene mutation they can throw in, right? So this HF E gene, typically what it does is, you know, obviously if it's a gene, if you transcribe it, you'll make the HF and if you undergo the process of, you know, transcription and translation, you'll make the HF E protein, right? And then that HF E protein, it has one job description.

It's job description is to help transferring bind to the transfer and receptor on the one of the cells, remember the guadnam is part of the small intestine, right? So it helps transferring bind to the transfer and receptor on the one of the cells so that you can suck in iron that way, right? But the thing is, if transferring, so transferring can be in one of two states, you can have transferring bound to iron or transferring that is not bound to iron. The thing is whenever transferring, so transferring that is not bound to iron can bind to the transfer and receptor on the guadnam cells. Transferring that is also bound to iron can bind to, it can also bind to the transfer and receptor on the one of cells. So let me see this again, just so people get it. Transferring can exist in one of two states. You can have transferring straight up on its own with no iron on it. That has the ability to bind to transferring receptors on the one of cells. On the flip side, you also have transferring that can be bound to iron, right? That's like such, right? They're transferring that transfer and bound to iron also has the ability to bind to the transfer and receptor on the guadnam cells, right? And again, the thing that makes these interactions happen is the HF E protein, right? Is the HF E protein? Now, the thing is, the thing that we're most concerned with because many people know hemochromatosis as an iron overload disorder, right? So let's take this path of this a little bit more, right?

So the thing is, whenever you have transferring that has iron on it, right? Whenever you have transferring that has iron on it, that essentially tells you about it. There is a lot of iron available, right? If transferring has iron on it, it tells the body that, okay, there's a lot of iron available, we don't need to be reabsorbing a lot of trans, we don't need to be reabsorbing a lot of iron. Right? Because remember, iron is reabsorbed in the guadnam. So the thing is, whenever you have transferring bound to iron, if that HF E protein helps it bind to the transfer and receptor on the guadnam cells, guess what happens? It actually causes an increase in hepsidian synthesis, right? It causes an increase in hepsidian synthesis. So the thing is, once hepsidian synthesis goes up, that's going to kill the reabsorption of iron in the guadnam. I'll say that again, once hepsidian synthesis goes up, that's going to kill iron reabsorption in the guadnam, right? So if you kill iron reabsorption in the guadnam, right, then you're not going to be reabsorbing that excess iron, right? So let's see how this relates to the pathophase of heedishrymokromatosis. The thing is, in heedishrymokromatosis, the HF E protein does not work, right? The HF E protein does not work. So because the HF E protein does not work, iron that is bound to transferring is not able to bind to that transfer and receptor in the underwater cells, right?

So since that does not happen, you have a tonically decreased synthesis of hepsidian. I'll say that again, you have a tonically decreased synthesis of hepsidian. If you have that tonically decreased synthesis of hepsidian, then you're going to have unrestricted iron reabsorption, right? Onrestricted iron reabsorption, right? And that iron can deposit in the skin that can cause that bronze skin hyperpigmentation. That iron can deposit in the heart. And remember, iron can generate free radicals. It generates these hydroxy. That's a pretty very high eoternal. It generates these hydroxy free radicals, right? So that can cause the fentin reaction, right? So if that iron deposits in the heart, you can have free radical damage of the heart and that's going to cause restrictive cardiomyopathy, right? And then remember that again, this iron, right, combined to beta cells of the pancreas, you trigger a fentin reaction, then you're going to go ahead and destroy the presence pancreas and person will get diabetes malatose. That's where this bronze diabetes, uh, uh, uh, moniker comes from with hereditary hemochromatosis, right? So hopefully again, hereditary hemochromatosis makes a lot of sense. If you really think about it, if you understand the pathophase, then all the findings seem like a joke to you, right? Because they're like, oh wait, this actually makes a ton of sense, right? Again, that's the way to go with many of these USMLE exams.

Now let's talk about well-sense disease, right? So what's the pathophysiology behind well-sense disease? Well-sense disease. So remember, and well-sense disease, remember it's an autosomal recessive disease, right? Well-sense disease is an autosomal recessive disease. And one thing I forgot to say about hemochromatosis again, it should those people will flow bottomy, but under thing you can also do on exams is to give these people iron kilometers, like deferoxamine, right? You give those people deferoxamine, right? And it's an iron chelidory, it binds up a iron, right? So well-sense disease again, remember, this is actually an autosomal recessive disease, right? And for the most part, you trigger with penicillamine, right? Because that penicillamine will help you kill that copper, right? It will help you kill that copper. So, again, let's talk about the pathophys behind well-sense disease, right? So the thing is the normal situation, again, let's talk about normal first. The normal thing that happens is that your liver makes seruloplasmine, right? Seruloplasmine is a protein that binds blood copper. It binds about 95% of the copper that you find in your blood, right? So another thing that also happens is the liver takes up the seruloplasmine and then degrades it. This seruloplasmine that has bound copper, right? The liver takes it up, degrades it. When the liver degrades it, it then takes that copper and then excites it into the bio, right?

So that's the normal and then obviously get rid of the copper that way, right? So one of the problems that are rising well-sense disease, the problems that are rising well-sense disease are too forward. It's a transporter defect, right? The first thing I think I want you to understand is that well-sense disease is a transporter defect. Well-sense disease is a transporter defect. So what is the first thing that happens in well-sense disease? Well, copper is not embedded in seruloplasmine, right? So copper does not hang with seruloplasmine. Well, if you think about it because copper is not embedded in seruloplasmine, the person's liver copper is going to be increased, right? And the thing is because of this transporter defect, you are not even putting that seruloplasmine into the blood. I'll say it again, you're not even putting the seruloplasmine into the blood in the first place, right? So the seruloplasmine tends to be decreased. In fact, that's one of the diagnostic tests that's employed in people that have well-sense disease, right? And then another thing that is a transporter defect is, even that copper that you have from degraded seruloplasmine is actually not excreted in bio. I'll say it again, that copper that is from degraded seruloplasmine is not excreted in bio, right? So if all these things happen, you have a build-up of copper and this copper can begin to deposit in organs. And we know that copper again can generate a lot of free radicals by the fentine reaction.

The fentine reaction is not an iron-exclusive reaction. It also happens with copper, right? So if that copper excess copper begins to damage the liver, that's how these people get serosis. And if it binds to the to the putemin, right? It can cause Parkinson's-like problems, right? Because remember, the putemin is actually a part of the basal ganglia. And also, copper, that copper can deposit in the sub-thalamic nucleus. So it can cause hemibalismus. In fact, hemibalismus is a pretty classic finding in people that have well-sense disease, right? And it can also deposit in the car in the cornea, right? That's how you get those Kaiser fly-sharings that we find in people that have well-sense disease, right? So again, hopefully well-sense disease now makes sense, right? So now, the last disorder I'll talk about before we then wrap up for today is alpha-1 antitripsin deficiency, right? So again, what's the pathophase? Again, some key things I think I want to mention is remember alpha-1 antitripsin deficiency has autosomal dominant inheritance, right? Autosomal-co-dominant inheritance for the most part, right? And many times on exams, they like you to know what the alleles are, right? So remember, the normal situation is that you have the M-M allele, right? The M-M allele, M as a mom, the mom-mom allele, right? But if you're M-Z, you're a heterosigote, right? You'll have like mild alpha-1 antitripsin disease, but if you're ZZ, right?

So like Z as in zebra, Z zebra, zebra, if you're homozygote, you're going to get the recessive disease. And also one other thing I think I want to mention is that the S allele is also bad. Having that S allele is also bad as well, right? So the Z and the S alleles are not good, right? So the thing is an alpha-1 antitripsin deficiency, what is the primary pathophase? The primary pathophysiologies that when you have the mutation, the alpha-1 antitripsin you produce cannot afford properly. I'll say that again, when you have that gene mutation, the alpha-1 antitripsin that you produce cannot afford properly. So it's a 14 problem, right? So because you have this 14 problem, the alpha-1 antitripsin is actually going to accumulate in the endoplasmic reticulum of hepatocytes, right? So that alpha-1 antitripsin that means afforded alpha-1 antitripsin is going to accumulate in the endoplasmic reticulum of hepatocytes, right? And the thing that happens is that if that alpha-1 antitripsin on acolytes, right, it triggers something called the unfolded protein response, which will begin to cause damage of hepatocytes, right? And again, if hepatocytes get damaged, right? That's going to cause cirrhosis. In fact, let me tell you this, the most common cause is very high, the most common cause of cirrhosis in kids is alpha-1 antitripsin deficiency. I'll say it again, the most common cause of cirrhosis in kids is alpha-1, not newborns, kids, right?

Like a kid that has, you know, like grown, is alpha-1 antitripsin deficiency, right? Now, remember that many times things that go to the endoplasmic reticulum, they ultimately end up being exocytosed into the bloodstream, right? Or at least into the intracellular environment. When a person has alpha-1 antitripsin deficiency, again, because of that, afforded protein response, and because that protein does in food well in the endoplasmic reticulum, right? That's ER-goji pathway, it doesn't work well, alpha-1 antitripsin. So it never gets exocytosed to get to the lungs, right? So essentially, the neutrophilic last days will have a filled day in the lungs, and it's going to go ahead and destroy the person's lungs. That's how these people get panacenars, very high-yield, panacenar and fuzema, right? This is how these people get panacenar and fuzema, right? So that's the pathophys behind alpha-1 antitripsin deficiency. And many times you just try to tell these people to stop smoking. If they don't smoke, right? Their life expectancy is roughly similar to a person that does not have alpha-1 antitripsin deficiency that has never smoked either, right? But again, unfortunately, the liver disease can cause problems, right? So sometimes these people will need a will-need-a liver transplant. So I think that's all I'm going to say, and I'm going to go ahead and pause here. As I do at the end of every podcast, I do offer courses again for step one, step two, see, can step three.

They're very comprehensive review courses. And I also work with people on the era's applications or do that stone in Tally of Lime. So if you have like, wrecked flags, problems with your personal statements and things like that, I recommend additional letters, I work with people on all those things, I work with people with mini-radi flags on the applications that are currently residents. In fact, I've been getting a lot of emails recently from people that I worked with this past cycle that studying residency like next week or something like that. Now, one thing I wanted to say, so many of you that listen to this podcast, you know I'm a Christian, right? So the thing is I usually put life lessons at the end of these podcasts, right? But many people have gotten tons and tons and tons of emails from people saying that, wow, they're fine. These life lessons really helped me a lot. So one thing I've decided to do is actually study another website, Divine Intervention Life Lessons, right? So if you go to Divine Intervention Life Lessons.com, you will see that I did in fact start this new website. And basically, the goal of this new website is to just have very short podcasts where I talk about, for the most part, again, I use like the Bible to illustrate just key life lessons that can help many people in medicine. And also not just people in medicine, just people involved in many different careers, right? So the website actually went live pretty recently.

In fact, I just uploaded the first podcast I believe that was yesterday or no, it was two days ago. It was a podcast on focus, right? So again, most of these podcasts should be like five minutes long. You can listen to it as like a devotional on your way to work or something like that. Again, just to use like Bible Bees teaching to show you how that applies to the world we currently live in today. So if that's something you're interested in, again, feel free to hit up the podcast, Divine Intervention Life Lessons. If you go to the website, Divine Intervention Life Lessons.com, you'll actually find it. I'm actually going to be trying maybe something today to get it to Apple Podcast. So you see that's like a different podcast on Apple Podcast as well that you can learn a lot from. So thank you for listening to this. I will see you in the next episode. God bless you and have a wonderful day. Thank you.

Positive anti-mitochondrial antibodies (AMA) and damage to the intralobular bile ducts.

Hemochromatosis.

Hepato-lenticular degeneration or Kayser-Fleischer rings (copper deposits).

Alpha-1 Antitrypsin Deficiency ($\alpha_1$-ATD).

PBC affects intralobular ducts (and occurs more often in women); PSC affects intra- and extrahepatic ducts (and is associated with men/IBD).

High ferritin, low TIBC, and high transferrin saturation.

CD4+ T cells attacking mitochondrial membranes within the intralobular bile ducts.

C2 H2 Y or H63 D gene mutations, leading to iron overload.

A transporter defect causing copper accumulation and inability to excrete excess copper into bile.

Neurological symptoms (e.g., tremor, dysarthria) and Kayser-Fleischer rings/hepatolenticular degeneration.

Alpha-1 Antitrypsin Deficiency ($\alpha_1$-ATD).

Iron deposits trigger a fat necrosis reaction (Warthin's/fat necrosis), destroying pancreatic beta cells and causing insulin-dependent diabetes.

PBC affects intralobular ducts; PSC affects intra- and extrahepatic ducts.

CD4+ T cells attacking mitochondrial membranes within the intralobular bile ducts.

C2 H2 Y or H63 D gene mutations, leading to iron overload.

A transporter defect causing copper accumulation and inability to excrete excess copper into bile.

Neurological symptoms (e.g., tremor, dysarthria) and Kayser-Fleischer rings/hepatolenticular degeneration.

Alpha-1 Antitrypsin Deficiency ($\alpha_1$-ATD).

Iron deposits trigger a fat necrosis reaction (Warthin's/fat necrosis), destroying pancreatic beta cells and causing insulin-dependent diabetes.

PBC affects intralobular ducts; PSC affects intra- and extrahepatic ducts.