We are off to a great start. Two great talks by John and Sumit, so thank you. I was prepared to say we're ready to hear from you, our audience and our colleagues, but we've already got a nice list of questions, so I'm going to jump right in. I will start with the first question. I just need to move. Okay, so this is a really good question. It says, could you elaborate on the indirect form of DILI? Example given was nitroferantoin and the pathophysiology. Still not clear on what happens here. I think it's a great question. I didn't really elaborate more for the sake of time, but I think I should have said the following, and I think this will help. I like to simplify things in my mind when it comes to drug-induced liver injury, so I think of direct injury and idiosyncratic injury in liver disease as the medication impacts the liver, so the injury occurs at the liver. When you think of indirect hepatotoxins or the indirect injury, think about it has everything to do with the biologic action of the drug, so for instance, nitroferantoin and in oncology, the immune checkpoint inhibitors. Their injury is actually at the level of the immune system. The immune system then releases inflammatory mediators and cells killing lymphocytes, eosinophils that then go out and cause the injury, so that's the indirect injury. I hope that makes sense and I hope that's more clear. Again, I like to simplify things, so think of it direct-indirect, the injury is at the liver itself—I'm sorry, direct-idiosyncratic, the injury is at the liver itself, whereas indirect, it injures the immune system, which then injures the liver, so I hope that's more clear. I have one for John. Bear with me, John. I'm going to find that question for you. Actually, I think you said you wanted to answer it, and it is right here. When it comes to determining mixed pattern versus hepatocellular injury, how much of a difference should we be looking for when comparing AST, ALT elevations to ALKFAS? Yeah, that's a good question for a couple of reasons. One is that a mixed pattern doesn't mean the same thing to everyone. In essence, most liver enzyme pattern abnormality patterns are a type of mixed pattern. It's never going to be—or I shouldn't say never, but it's rarely going to be black and white, where the aminotransferases are elevated, but the ALKFAS and the GGT are not at all, or vice versa. It's usually going to be mixed, but then it becomes a game of relativities, which the liver injury tests or the cholestatic tests, which are elevated out of proportion to the other more, if that makes sense. It's a little bit of a gray area, and it's not just a calculation. It's not just a science. It's an art. But when we talk about cholestatic elevation pattern or injury elevation pattern, we're talking about which is elevated out of proportion to the other. I hope that makes sense. And a mixed pattern is where, in general, the clinician who is evaluating the laboratory parameters looks at those numbers and says, well, the cholestatic test elevations are elevated to about the same degree that the aminotransferases are. Then you reach a point where just looking at the liver tests has peaked at its value in your ability to further go down the diagnostic pathway. You can only glean so much from those liver tests, and if they don't help you differentiate, then you need to look at other testing or look again at your history and physical exam and delve deeper to help you figure that out. And if further non-invasive testing, which might involve imaging studies, other more specific blood tests, or going back and talking to the patient some more and gleaning more history and going back over their meds again and so forth, doesn't give you the answer, you may actually need tissue. And that may be the time to pull the trigger and get a liver biopsy and have the pathologist weigh in. So I think the two things to glean are the relative elevation of the cholestatic versus the injury tests and then the whole idea that it's not a calculation or a black and white number, but it's a game of relativities. And then understanding that there's only so much you can get out of these blood tests and how to expand your workup if you've tapped as much as you can in terms of information to help you clinch a diagnosis with just your liver injury and cholestatic blood tests. Thank you, John. I have two questions. I'm going to combine into one because they're very similar and it's for you, Sameet. Essentially, when do you initially start screening patients for possible portal hypertension? And what is your strategy? What do you use to test for portal hypertension? Great question. So I would start screening patients for portal hypertension when you have a concern for cirrhosis. So if they have a diagnosis of cirrhosis based off of imaging or other clinical factors, that's when I would start to consider patients for screening. If you do an endoscopy, I would typically start with an endoscopy because of ease of access, looking for varices or other changes like portal hypertensive gastropathy or gastric varices. But if these are not identified, but you're still concerned about the presence of portal hypertension, there are other methods that can be done. So our interventional radiology colleagues can measure the hepatic portal venous gradient directly. The same access that they would use to place the tips to access the hepatic vein and create that shunt of the portal vein, they actually can measure the hepatic vein pressure and then a wedge pressure to get an understanding of the portal pressure and calculate that gradient for us. There's also a newer portal pressure gradient measuring device that can be done through endoscopic ultrasound as well. We have not yet added this to our armamentarium here locally, but for instance, in that situation where you're concerned about the risk of portal hypertension and trying to confirm a diagnosis of portal hypertension in one setting, one could theoretically do an endoscopy, assess for varices, and if negative, proceed with a portal pressure gradient. Through endoscopic ultrasound techniques to measure that gradient and confirm or refute the concern for portal hypertension. I hope that answered that question. Yes, I think it's great. I've got three that are for me and I think I can go through them quickly and then I've got one for John, so we have plenty of time to get to everything. The first one is, can DILI occur slowly? The answer is yes. If you look at the literature, they talk about up to six months or 180 days. Certainly within that 180 days of a drug being started, if you have concern for DILI, it absolutely can occur slowly, so keep it in mind for at least up to six months. Someone did not hear clearly what was said about what we give for acetaminophen toxicity and it's N-acetylcysteine or NAC. There's very nice algorithms all over the internet. You can find it up to date. You can probably just put NAC for Tylenol toxicity and get a nice image of the nomogram and it can also be used. It is worth considering in all types of DILI. Again, it's not going to injure the patients and it may help. The last question is about ferritin. Can ferritin rise from other causes? The answer is yes. We can see a rise in ferritin in people that have infections, so for example, sepsis. We can see it in non-alcoholic fatty liver disease and other causes of secondary iron overload. I think if those three alone give you a broad differential diagnosis to think about ferritin elevation, that is not related to hereditary hemochromatosis. John, I'm looking for—here it is. Regarding liver lab abnormalities for Gilbert's syndrome, is unconjugated DILI the only lab value to really look for? It came to mind during case studies. Any other clues from the lab work for Gilbert's? Yeah. That's basically it. Gilbert's is one of those things that doesn't have importance in and of itself. You're basically wanting to ascertain that there isn't something else going on. It's kind of like when we do lower GI endoscopy for rectal bleeding. We're not going in there to look for hemorrhoidal bleeding. We're going in there to look to make sure it's not something else. If it's just hemorrhoidal bleeding, well, that's not dangerous. We're just wanting to make sure they don't have cancer or something that we could and should treat like inflammatory bowel disease. Same thing with Gilbert's. We're not checking to see if they have Gilbert's. We're checking to make sure that DILI isn't elevated for something more insidious. If you really want to check something, you could just check a liver profile. That's a relatively inexpensive test panel, as you know. Those are going to be normal in Gilbert's because it's a condition. It's not a disease, and it doesn't have really any deleterious clinical importance to the patient. I hope that answers that question. The other thing, Joe, that I wanted to point out, you brought up a good issue, which was the use of NAC. And there was a nice question that came up that I went ahead and answered in writing in the Q&A box that had to do with the utility of NAC not only in acetaminophen toxicity but also in other things. Acute liver injury. There is mounting literature in the last few years demonstrating usefulness with positive outcomes demonstrated in administering NAC not only for acute liver injury but also for acute liver failure. It just looks like that cheap and simple drug is finding more and more uses, and it's kind of nice when something old, generic, and inexpensive actually turns out to be way more useful than you ever thought. That is such a win-win from also the cost effectiveness and cost efficiency standpoint, which I know all of us are big fans of in this day and age when so much of medical care is so expensive. I think that's a great point, and I want to tell our colleagues in the audience they have great questions. We'll do our best to answer them all live, but if we can't, as always, we will answer them in the box. Sarah's with us, so Sarah, if there's a question you think we should get to, it's hard for me to scroll through everything. Let me know, or if there's something you want to answer, please let me know. Otherwise, I'm going to go to Sumit. Sumit, would you recommend EGD for variceal screening for those without indications or signs of portal hypertension and no ongoing liver injury, particularly those with normal platelet counts? If you have concerns for cirrhosis, then an initial screening EGD should be considered, but if they don't have any evidence of ongoing liver injury, let's take the example of Dilly. So if they have a discrete episode of Dilly without ongoing liver injury and no concerns for portal hypertension or cirrhosis, then no, not necessarily. I wouldn't necessarily consider an endoscopy for variceal screening in that situation. But if they do have underlying cirrhosis, then an initial one-time endoscopy for variceal screening would be considered. If there's no evidence of ongoing liver injury, then you wouldn't necessarily need to continue endoscopy surveillance. I guess the question would come up, so if you have cirrhosis that's well compensated, how frequently should you do that? The recommendations would be every three years. But again, if it's not cirrhosis, if it's less advanced fibrosis, or if it was a discrete episode of liver injury without ongoing injury, then no. All right. Yep, that sounds great. Sorry if I seem distracted. I was just going through questions and making sure we cover. Let's see. There's a good one about the copper. Yeah, actually, that's the one I was just looking at. So why don't you take, go ahead and read that one, Sarah. Great minds think alike. John, maybe this is a good one for you. The comment is that this individual has had a couple of patients who have come in with mild elevations in serum copper. Can we elaborate on the workup of an elevated copper? And are there other causes that we should be thinking about other than Wilson's disease in that case? Yeah, I must admit, that's actually beyond my level of expertise in hepatology. And so I'm going to have to pass that on to another faculty member. Anybody else have some insight into the workup of a mild elevation in copper? And I'm assuming that this is asymptomatic, so I'm not sure why the serum copper level was ordered. Yeah, I would agree, John. I'm not really sure. My mind always goes to Wilson's. I think that's if we're being honest. And one of the things I like about this course, we're transparent. That's one we can answer. We'll answer in the chat. And actually, I'll do a little homework to see to make sure we get you the right answer. But I really think of Wilson's. I can't think of anything else. Sameet, any thoughts? Not, I can hear me, not directly offhand. I agree. Ceruloplasmin is typically what we would be assessing, not necessarily the serum copper level itself. So I don't know what the correlation is. I don't know what the correlation is between a serum or plasma copper level, a one-time measurement compared with the ceruloplasmin. Yeah, I mean, there's additional testing that you can do that's more specific, including a liver copper level. But I think, you know, when you're talking about a mild copper level, and copper levels are rarely checked for anything other than, as Dr. Vicari points out, looking for Wilson's, I think I need some, you know, some history, patient history context here as to why the copper level was checked. Because the only correlation between copper levels and liver disease that I'm aware of is Wilson's. And so I think we need some context there. So I can just add in, I actually have a liver transplant background. I've seen a mild elevated copper from just oral intake. And so certain foods maybe have some copper in them, traces of them. But those patients that I've seen with it are coming with the GI symptoms, like that nausea, vomiting, diarrhea, and not liver related. Like Dr. Vicari said, we can certainly look into it a little bit and see what we can find. But I'm wondering if maybe that was the case, and it wasn't necessarily pertaining to the liver itself, more of kind of that heavy metal poisoning type of thing. And there is another comment just for the faculty, neurology had ordered it and then referred the patient. I think if neurology ordered, I think they were thinking Wilson's disease and the neurologic complications of Wilson's disease. But that's the only thing I could think of. It's a great question. If anybody else in the audience has any thoughts, feel free to put them in the Q&A also. I'm going to jump in with a question. Have you seen dilly with turmeric or green tea? What are the supplements that need to be avoided? Again, this is a good question. We don't see as much liver injury to herbal and dietary supplements. Turmeric and some of the extracts from green tea have been known. I've not seen them personally to cause liver injury. Black hohosh is another one. Senna, I think. There are some very nice tables you can look up, but I have personally not seen it with turmeric or green tea, but they have been noted as well as other supplements. This is one where I think our brains can only remember so much. And we have to think of herbal and dietary supplements. So when I see a patient, if I see an herbal dietary supplement, I always look it up, especially if I'm not familiar with. And I think that's where things like UpToDate and other resources are really helpful. So as long as you're thinking about it and you see a supplement you're not sure about, look it up, then I think you'll be doing the right thing for your patient. And I'm more than happy to have anybody else jump in in case they actually have a real-life example. I actually just want to put a plug in. Janelle, I don't know if she's still on here, but Janelle pointed me to liver tox, which is available through PubMed, which is a great resource for looking up medications and their risks associated with acute liver injury. I will put that in as well. Liver tox is excellent. So thank you, Janelle. It's a great point and it's easy to use, easy to access. Yes. Yeah. It's a great resource for looking up, you know, there's like thousands of different drugs and herbal supplements on there and they give you typically the liver enzyme trend and how long to expect the injury for and gives a lot of information. Sameet, we'll go back to you. Use of portal venous duplex for gradient measures as a non-invasive test. Some thoughts? That's a great question. I haven't seen actual measurements, per se, of the portal gradients by duplex. Duplex I find to be most useful when you're looking for changes, portal venous thrombosis and effects of flow with that. With that, I guess if they do see reversal of flow or changes of flow without a thrombus, that would suggest portal hypertension, but I don't know how discrete their measurements can be on a duplex. I'd have to defer to some expert radiologists on that, but I've not seen that personally. Hi, this is Jill Olmstead, Dr. Kari. Hi, I wanted to chime in. I actually did have a patient that had elevated liver enzymes and all we could figure out was her use of turmeric. And it's the combination of the turmeric and the black pepper that can cause the potential liver injury. And there was a great article that was published in 2022 through the American Journal of Medicine. So it's liver injury associated with turmeric, a growing problem, 10 cases from the drug-induced liver injury network. And I routinely use the liver talks website. I actually have a bookmark. I'll even review it with my patients when we're trying to figure out what the elevated liver enzymes are from. Thank you, Jill. I think this is another example of this course, how much the faculty is really into the course, excited, excited to teach. So these live kind of off-the-cuff interactions are great. I'm going to take this one. I think it's a very nice—it's kind of a case that someone had recently, a patient with cirrhosis, cryptogenic. No other—no obvious underlying cause was found for cirrhosis. And they had been on minocycline, BID, for a very, very long time and ultimately found to have autoimmune hepatitis. Well, minocycline is actually a drug that can cause drug-induced liver injury. It can cause an acute hepatitis and it can cause a chronic form that is immune-mediated. So it's certainly possible that this person had a minocycline-induced autoimmune hypersensitivity reaction. Very interesting. And it's also possible that they truly had autoimmune hepatitis and the drug had nothing to do with it. But I'd be very, very suspicious on the minocycline. So thanks for sharing. And just another nice example that in the real world, these drug-induced liver injuries happen. And the more we think about them, the less likely we are to miss them. So thank you for the case. Let's see. I think back to some meat. I have a cirrhotic patient with elevated AFP, about 120. Recently, fortunately, I had no evidence of HCCN MRI. Am I able to trust the imaging? So I think it's a nice conversation about the value of AFP. I'm sure you have some thoughts. So we can find elevated AFPs in the setting of active inflammation, active disease. AFP of about 120, though, is higher than I would typically think of in somebody with an elevated AFP just from active viral hepatitis C or autoimmune hepatitis or something like that. If the MRI is a good quality MRI, you've had a chance to review that with your radiologist. It was contrast enhanced with the appropriate phases. Then maybe you can trust that. But you also have to think about there are these diffusely infiltrating types of HCC, which may not appear as a discrete mass. And so there may be a need to consider a liver biopsy in that situation. I would be careful with elevated AFP of that degree of elevation. That would still be suspicious. Thank you, Sumit. Let's see. I think we could probably do one more. We're doing very well this morning. It's staying on time. I think everybody needs a break. So, John, I'm looking at this one that says PSC versus, I think they mean PBC. We recently had a 38-year-old male with family history of Crohn's, otherwise healthy, but acute jaundice and normal liver enzymes and had to go for liver biopsy. So I'm wondering if maybe some comments on PSC versus PBC. Sure, Joe. You know, it's one of those unfortunate things where the abbreviations are sort of so similar and the diseases are so different. Another one of those is IBS and IBD, which get mixed up all the time and have absolutely really nothing to do with each other, aside from affecting the abdomen, more or less. So primary biliary cirrhosis, PBC, which is sometimes called primary biliary cholangitis or cholangiopathy, is an autoimmune disorder and so is primary sclerosing cholangitis. They're different because with primary biliary cirrhosis, the large or visible bile ducts are unaffected. With primary sclerosing cholangitis, in most cases, the bile ducts are affected by a sclerosing or a scarring disorder that results in strictures, which are narrowings in the bile duct. Let's talk about PSC first since that's what I'm describing to you right now. In a typical patient with PSC, the majority of whom actually have coexisting inflammatory bowel disease, IBD, so either ulcerative colitis more commonly, but also sometimes they could have Crohn's disease. The majority of PSC patients have one of those inflammatory bowel diseases, more frequently ulcerative colitis. And the typical scenario is a patient with UC who develops elevations in their liver enzymes, and you will then undertake non-invasive imaging, typically an MR, because you know these patients have a propensity to develop the disease, and it may demonstrate some strictures in the bile ducts on MR. If then, typically, if they have jaundice developing or cholestatic pruritus, which is itching due to poor bile flow, or their MR demonstrates focal stricturing or other features that may concern you for the development of bile duct cancer, cholangiocarcinoma, then one may order an ERCP to obtain cells or tissue from that stricture to determine whether or not cholangiocarcinoma may be developing. There are patients who have primary sclerosing cholangitis, but in ducts or ductules that are too small to visualize on an ERCP or an MR, and those patients have what is called small duct PSC. PBC is a different disorder that does not demonstrate radiologically identifiable changes in the bile ducts. And in PBC, the microscopic ductules can be involved in the development of cholestasis. It's also autoimmune. And in those patients, the treatment is medical rather than endoscopic. It is usually diagnosed when a patient has cholestatic pattern of liver enzyme elevation, and you will then order an autoimmune marker panel, and typically their anti-mitochondrial antibody, or AMA, will be elevated. And there isn't a particular association in this disorder with inflammatory bowel disease, although they can coexist. Thank you, John, and thank everyone.

liver diseases

drug-induced liver injury

DILI

hepatocellular injury

portal hypertension

LiverTox