Thanks so much, and thanks for spending a bit of your morning with me and the team here. And again, thanks for the kind invitation to speak about something that all of you will spend a great deal of time doing in your careers, which is assessing abnormal liver biochemistries. Here are my disclosures. So liver biochemistries are very commonly ordered. As you know, it's a major source of referrals. The tests that we typically see that trigger referrals from primary care doctors to yourselves include the ALT, AST, ALCFOS, and bilirubin. And just by way of review, and I don't think you need much in the way of review, but these are markers of liver injury, not liver function. And they're best referred to as liver chemistries, liver tests, not liver function tests that we all grew up with, because they really don't measure liver function. We do have liver function tests, albumin, bilirubin, prothrombin time. And they are actually used in MELD score and other disease severity indices like the Chow-Pugh score. But again, they can be affected by extrahepatic factors as well. In addition, in general, these tests are highly reproducible as well. AST and ALT are the most widely ordered, and they are both liver-specific. ALT is mainly localized in the liver, more specific than AST for hepatic origin. I'm sure some of you have seen, and we'll maybe perhaps go through this in the discussion, AST can go up when you have high CKs, if you have someone with rhabdo, or even a young person who's come from a gym, or we've seen very high AST levels with spinning classes, just for the record. Because I don't know if anyone else, where the CKs go very high. I've never done spinning, but it looks pretty dangerous based on what I have been able to glean. I mean, people get kidney failure. AST, so cardiac, skeletal, ALT is mainly in the cytosol as well, and AST is in the mitochondria. And that's the other important aspect, if you're trying to tease out if alcohol is contributing to an elevated AST. Just remember, alcohol is a mitochondrial toxin as well, and it also helps drive up the AST level, in addition to other reasons. And all of these go up when the cells die. This is apoptosis or necrosis. So what are truly normal liver tests? Well, we've adjusted this in our practice guidance, and I'm going to show you the data why. It has evolved upward over time, and I'm gonna explain that as well. But based on liver-related mortality, a normal ALT for a male is 29 to 33. For a female, it's 19 to 25. And levels above this need to be assessed. Now, this doesn't mean, by the way, that you have to pursue a full-blown evaluation of abnormal liver tests when you have an ALT for a female of 30, but you at least need to look at this and assess what is going on. There is a linear relationship between ALT and BMI, and just as in our case one, where we had a little bit of steatosis, you have to account for that. And as you'll see, that's the main driver of elevated ALTs that you're likely going to see. Normal ALT doesn't exclude significant liver disease, and the ranges obviously vary between different labs. So, why is our ALT, why did it evolve upward? Well, this comes from The Economist, and all of you know this. We've all seen this over the past 25 years, and I'm going to just take a few minutes just so you can see how much our population has changed and really why we pick up so many abnormal liver tests. So, you can go to the CDC website, and those of you taking pictures, all these slides should be available to all of you. Every single one of these should be there. So, these are the obesity maps. And so, if you have nothing better to do at night, you download all of them, which is what I did. And so, here we are, 1985. So, this is BMI greater than 30, 30 pounds overweight. And you have less than 10%, 10 to 14%. So, this is 1985. So, we're going to go now to 1987. And some don't have data. 1990, we get more robust data. 1994, we're now at 15 to 19% here. Now, we go to 1997. We go up to 20%. And you can see Indiana, Kentucky, and Mississippi are all now above 20%. In 2001, Mississippi now goes to greater than 25%. 2003, we pick up additional states. 2004, additional states. 2007, now we're getting to greater than 30%. And these states go up. Notice a few states like Colorado always stay a little bit lower for a variety of reasons. But I'll just keep steering you through here. Now, we're going up to 35%. And now, we're at 35% by 2013. And 2014, 2016, and I just found the 2018. And you can see that 35%, which is the magenta or red color, is now fairly widespread across a broad swath of the center of the United States. Colorado still seems to do quite well, as did Hawaii and Washington, D.C. So, obviously, humans don't evolve in 30 years. So, this is obviously environmental. Okay, this is obviously an environmental contribution. But it's a big reason why ALT levels have continued to rise. And we need to find these individuals because the ALT you can use as a marker of not only liver health, but also overall health. And these were the studies here that relate ALT and AST to liver-related mortality. And you can see here, these were a variety of studies. And if you can just go to the third column, you can see that ALT and AST cutoffs for increased liver-related mortality. And they were above 18 for AST. ALT, 30 to 39 in an Asian cohort. And so, you had 45 to 90 for males, 29 to 58 for females in a different cohort. And then, 30 and 19, this was from a U.S. cohort. So, if you have an elevated ALT level, you have higher liver-related mortality. Most of these are non-alcoholic fatty liver disease. And I think all of you, if I raised your hand and said, what's the dominant consult you get now, I'm willing to bet, unless you're in a transplant setting, that most of us are evaluating, the bulk of what we're evaluating now is non-alcoholic fatty liver disease. Just like 10, 15 years ago, it was viral hepatitis. That's no longer the case. Liver biopsy is the gold standard. But just out of curiosity, if I were to ask people, we can perhaps do this during the questions, I bet most of you don't initially biopsy these individuals. We can't, we would overwhelm our radiologists. But that is still the gold standard. So, does everyone with fatty liver have to have a liver biopsy? The answer is no. And we have now developed and continue to refine a variety of fibrosis assessments for those with non-alcoholic fatty liver disease. So, in the clinics, I'm sure some of you use just the NAFLD fibrosis score. You can just go to a website and plug that in. You can also, we also use FIB4, the AST-ALT ratio, the AST platelet ratio index there. And these are simple indices that we use. You can also send off blood tests. There's a fibro test, which has a commercial test. There's a fibrometer. There's actually also, perhaps, a fibrospec. They all have reasonable negative predictive value to, in other words, they can exclude advanced fibrosis if the scores are low. In the intermediate ranges, it's a bit more problematic. And there are other tests that are coming. You also probably assess, these are the cutoffs here, and I put in the formulas here. You can, by the way, find calculators for all of these online. And for those of you in the clinic, I either encourage you to have the app on your phone or just to bookmark on the website just so that you have them readily available. We can also use radiologic tests, and I bet many of you have elastography or FibroScan. We, there, FibroScan is nice because it has an assessment of steatosis, the controlled attenuating parameter probe measurement, as well as the liver stiffness by kilopascals. You also have, you can get a FibroScan also, or elastography with an ultrasound, and this is a slightly different technique, acoustic radiation force impulse. You can also use shear wave elastography and magnetic resonance imaging, all available. All are good tests, none are great, but they are all very, very helpful in assessing whether or not we need to be moving forward with a liver biopsy. So that's AST and ALT evaluation, and then for, we're also gonna talk a bit about cholestasis. So cholestasis, this is defined as an impairment in bioflow, and so just remember, this isn't just bilirubin. Bio consists of water, bilirubin, the bile acids, and all the drugs that are secreted from the liver down into the bile duct, and a cholestatic liver profile is another consult you're going to see, and indeed, the first case we had, the ALKFOS was elevated, and typically, the ALKFOS is elevated with or without an elevation in bilirubin. You can verify the elevation of alkaline phosphatase to make sure it's coming from the liver, and this is important, particularly in the elderly, their ALKFOS goes up because of bone disease, and I'm sure some of you fractionated the bilirubin and found out, oh look, it's actually a bone issue. You can send, the easiest test is GGT if it's up. In general, that confirms the elevated ALKFOS. You can order a five prime nucleotidase as well, but that's really not done very often. It's much more expensive as well, but that helps you determine whether or not you have an ALKFOS that is of hepatic origin, and again, if someone is pregnant, their ALKFOS will be high from the placental source, and again, young kids, because their bones are growing, and then older people, because of bone turnover, the ALKFOS is elevated. Normal ALKFOS just probably is around 125. It varies very subtly from lab to lab, and again, you can order a GGT. Again, alkaline phosphatase is a hepatic enzyme, and so what you have here is, again, this comes from the hepatocyte canalicular membrane, which this is very angulated, so that's not gonna work, but on the right side of what I show you there, we have two nice little liver cells right next to each other, hepatocytes. They come together, and they form this canalicular membrane, and this is where all the proteins are actively transported across the canalicular membrane and go into the, what we call the canals of herring, to the bile duct, and this is where the bile flows, and this is the source of the alkaline phosphatase. It does not, although you can find it subtly on staining, it does not come from the bile duct cells. They're cuboidal lining, common misconception. So just remember, it's a canalicular enzyme, and again, alkphos is found elsewhere as well, as I've told you, and you have to account for that. So when you have somebody who has elevated AST, ALT, or alkaline phosphatase, you want to assess and make sure that indeed the liver is the initial source. How do you do this? Well, if the ALT is elevated, you'd expect the AST to be elevated. If the alkaline phosphatase is abnormal, you want the GGT to be also abnormal. You need to do a history, and again, the cases that Amanda presented really show the value of getting a good history. You need to look for other medical comorbidities, use of alcohol, medicines, including over-the-counter complementary and herbal supplements, as I will show you, and then physical exam is helpful. You rarely pick up cirrhosis. Occasionally you'll pick up things like a palpable spleen. You'll pick up spider angiomotor. You'll pick up ascites, et cetera. That confirms cirrhosis, but for mildly elevated liver tests, if you find Kaiser Fleischer rings, maybe one or two of you in your career has been able to see them, it's quite difficult. Hemochromatosis, if you get very bronze, you can pick that up, but again, these are uncommon. You're more likely to confirm advanced fibrosis on your physical exam. Make sure, make sure you get, particularly now, a great supplementary or complementary alternative medicine history because they're everywhere now. And your patients come and herbal therapies have no adverse events if you listen to satellite radio when they talk very rapidly. And your patients, I'm sure, you all have the same issue when they bring out this dizzying array of supplements that you have to get on the computer to try and figure out what the heck these things are. And you ask them, what are you doing and why are you taking this? And of course, they will tell you they're natural. And that is, right, they're supplements. They can't cause any harm. You have to tell them that many things in nature are actually not safe. So we have here Hurricane Sandy, we have Mount St. Helens, and we have here a nice alligator, all of which are natural. And as I tell them, great white sharks are natural, scorpions are natural as well. So you have to be able to let them know that they do have to account for adverse events with these supplements. And there are very few safety studies for these. The LiverTalks website is actually pretty good about supplements. There used to be a country, only one in the world, that was Germany, that actually did safety studies on these. They have, you can still find them online, these German monograms where they actually assess these supplements for safety. But they don't do that anymore. And so you have to get a very, very good supplement history for these individuals. So for instance, we just had someone going to the hospital who drank coffee, Cava Cava Laced, and Cava caused a pretty nasty bump in liver tests with a symptomatic, she got a little bit symptomatic. And we've all transplanted for acute liver failure with some of these supplements as well. So educate them very well. Hepatocellular injury that is defined as disproportionate to the elevation of AST and ALT as compared to the ALTFOS is hepatocellular injury, cholestatic injury, disproportionate elevation in the alkaline phosphatase. And you sometimes have mixed patterns, and quite commonly, as a matter of fact, where they're both high. And obviously, isolated hyperbilirubinemia is defined as elevated bilirubin with normal ALTFOS and AST, and we'll go through that at the end. Stratify your approach. If the ALT and AST are minimally elevated, and this was when we were writing the practice guidance, we were very careful because we didn't want to generate a huge amount of work for individuals, but we stratify your approach. So if the AST is 60 and they are relatively healthy, you don't have to necessarily pursue everything, and I will show you the algorithms that we develop. You can actually pursue a focused evaluation and then follow them. As the ALT and AST go up, your differential broadens and the acuity of your evaluation also broadens and how quickly you want to evaluate them. Obviously, with very high ALT levels, you need to act very rapidly. And most importantly, anyone who comes in with elevated liver tests, particularly those that are quite elevated, you have to assess for acute liver failure or fulminant hepatic failure, which is defined as the rapid development of acute liver injury with severe impairment of synthetic function with a prolonged prothombin time and encephalopathy without obvious previous liver disease. And regardless of the ALT level, if you find this and they don't have a history of liver disease, they need to be evaluated immediately and likely shipped off to your friendly neighborhood transplant center for an evaluation. So remember that. If you pick up Asterixis in somebody with no history of liver disease, you need to be thinking that they have acute liver failure. So here's the algorithmic flow that we have here. And again, you've got all of these on your PowerPoint slides but history and exam. And for minimally elevated, discontinue alcohol. That's easier said than done. And if you think that alcohol is actually contributing, how hard they push back when you tell them to stop alcohol is actually very helpful in gauging the contribution. Many of them will try, and I'm sure you've all seen this, they try to bargain with you. You also need to assess for fatty liver as well as viral hepatitis B and C. And then your liver tests can be ordered along with your serologic evaluation. Just because of the prevalence of hemochromatosis, an iron panel is useful as well as an ultrasound to see if you can pick up steatosis. If normal, then if the ALT is minimally elevated, you can either observe lifestyle modifications, stop the alcohol, try and lose a little bit of weight, get a better diet, and repeat these tests. And if more persistently elevated, you can pursue your more extended evaluation that we were all trained to order. And this includes immune markers, inherited markers, and then even some less common things like thyroid. You can look for celiac sprue. There are a variety of these. And then if you still can't come up with an etiology, you can choose to follow them. You occasionally biopsy these individuals and you find patients you biopsy with these mild elevations after a while. And most of the time you don't find any actionable, meaningful disease. But it's reassuring that everything is normal. With our non-invasive tests, this is becoming less of an issue for us. So alcohol use, remember the unique injury patterns. The AST is higher than the ALT, typically less than 300. The GGT is increased. They have a macrocytosis. The MCV is large. And particularly if someone has thought they might have fatty liver, when you see these parameters, they push you more toward an alcohol etiology rather than non-alcoholic fatty liver disease as well. Hepatitis C is increasing again. We had a remarkable period where the number of acute cases fell, but this is a tragic consequence of the opiate epidemic. And I turn your attention to the graph on the right, which shows 2015. So many of you in the room are like me. We had the birth cohort between 1945 and 1965. That's shown in the top left at 2005. But look what happened. This comes from New York, but this is being replicated everywhere. It's bimodal. That is, the number of individuals with hepatitis C now that they're detecting now between the ages of 19 and 39 are actually approaching the same as the birth cohort regimen. And so this has led to the U.S. Preventative Task Force to recommend a one-time screening for everyone ages 18 to 70. And the CDC has also issued a similar draft recommendation as well. Universal screening, not risk-based screening. Hepatitis B depends on your area. It's still predominantly in the U.S. We see this in immigrant populations from endemic areas. But I have the serologies here. And again, if you're looking for chronic hepatitis B, it's a surface antigen, is what you're going to order. And then obviously, if it's positive, you're gonna come back with the DNA level. You wanna make sure they're all vaccinated for hepatitis B as well. And remember, the surface antibody measures immunity. The core antibody, IgG, means that you have been exposed to hepatitis B. As your liver tests increase some, then we have the same approach here. But you wanna follow these individuals as well. And if the ALT, say, is higher, like close to three or four times the upper limit of normal and persistently elevated, the evaluation moves forward more rapidly with all of the tests that we discussed. And here you're going to look for things like alpha-1 antitrypsin, which is a fairly uncommon disease, but the heterozygote rate is one to 90. And this is where you have this abnormal alpha-1 antitrypsin Z allele. It folds abnormally in the liver. It accumulates. And again, you have to have the Z allele to get liver disease. So even so, the penetrance isn't particularly high. The ZZ, if you're ZZ homozygous, you can see here it's 20% risk of liver disease. But if you're heterozygous and you have fatty liver or you have other concomitant liver disease, you're actually going to have a bit more aggressive course as well. So it's useful to find ALT and ASTs that are five, 10 times the upper limit of normal. You need to be thinking about autoimmune hepatitis, particularly in females. We look for the antinuclear and smooth muscle antibodies with a high gamma globulin level. And these people ultimately come to liver biopsy. Hemochromatosis, again, actually common gene, but very low level of penetrance. This is due to an inappropriate absorption of iron in the duodenum. And we have the one gene, the C282Y, which is on chromosome six, which accounts for 85% of cases of hemochromatosis. Again, you find it with an elevated ferritin and total iron binding capacity. And ultimately, we often, though not always, have to do a liver biopsy of these individuals. On the next slide, and you have this as well, I have here the diagnostic algorithm here. And again, if the ferritin level is less than 1,000, you don't have to pursue a liver biopsy in these individuals. But if you're homozygote with a ferritin above 1,000, in general, that's something you need to go ahead and move forward with. A rare disease, Wilson's disease, where the copper is not transported out of the liver. It's on that same canalicular membrane where ALKFOS is made. And you have a defective protein and the copper cannot get out. It accumulates in the liver and then lyses out of the liver into the bloodstream where you can get neurologic symptoms. You get hemolysis and sometimes very dramatic acute liver failure. It's a very rare disease, heterozygotes, one in 90. The prevalence of homozygous is one in 30,000. And some of you may have seen a case or two, but you always have to keep this in the back of your mind, particularly with young individuals presenting with liver disease, particularly with high bilirubin. And we find this typically with a low cerelloplasmin and you can check a urine copper level. And if these are abnormal, you're going to move forward with a liver biopsy. As we get to more significant elevations, the ALT is above five times the upper limit of normal. So now we're at 150 for everybody. And above, then we typically start looking at these etiologies a bit more rapidly and rather than choosing to defer and observe with lifestyle modifications. And again, you have to be assessing for acute liver failure in these individuals and they ultimately wind up getting a liver biopsy. The etiology and approach doesn't really change much as the AST and ALT go up. And again, you can see here now when the ALTs get higher, you need to be thinking of acute issues like acetaminophen overdose or drug-induced liver injury as well. And if you see somebody with a high ALT level, you need to particularly because there's an antidote, be thinking about acetaminophen exposure. Remember that acetaminophen is in a variety of narcotics. It's in a variety of other combination medicines and if you're feeling poorly, they take these and they take more acetaminophen. And so always have a high degree of awareness for this. And obviously, massive elevations require immediate evaluation as well. When it's above 10,000, the nice thing is that the differential here is fairly short. It's typically ischemia or acetaminophen or some other drug in these individuals so you go through the whole gamut. Again, acetaminophen is the most common form of acute liver failure in the United States. And you can see here that acetaminophen dominates all other medicines and used with caution. It's perfectly safe in cirrhosis if you don't drink, by the way. And so everybody knows it used to be four grams was the total amount you could give. It's now down to three grams. And so I, just because patients don't always follow instructions, tell them two grams is always safe just so that they don't keep giving themselves an additional dose. And again, but if you drink, you can get into trouble so then there's no acetaminophen. Don't forget idiosyncratic reactions which Amanda was presenting earlier today. And this is actually due to drug metabolism. The actual incidence of this is actually quite low except there are so many medicines out there. So here this has to do with the liver generating a toxic metabolite that winds up being deleterious to the liver and leads to either elevated ALT, AST, ALKFOS, or bilirubin. And here are, according to the Drug-Induced Liver Injury Network that was published fairly recently just this summer, are the most common medicines that are implicated in drug-induced liver injury here. And you can see that antibiotics such as amoxicillin, clavulanic acid are here. There's septra, minocycline. If you're a young woman who has acne, these are all very common and you should keep these in mind. If the ALKFOS is elevated, then the GGT is normal. Then it's probably bone or some other course. If the GGT is abnormal, we get an ultrasound and check for potential hepatotoxic medicines in your immune markers. And then if things are still elevated, you may have to go to a liver biopsy in these individuals. If it's minimally elevated, you can observe. And if you see ductal dilatation, then you need either an ERCP or an MRCP in these individuals. And finally, if that's normal, obviously we wind up with a liver biopsy. We typically see primary biliary cholangitis, this cholestatic liver disease, predominantly in females, positive anti-mitochondrial antibody. Or in younger men, primary sclerosing cholangitis, chronic cholestatic disease that progresses to cirrhosis. There you see obliterated fibrosis with the intra- and extra-hepatic bile ducts with inflammatory bowel disease. And you have to keep these in mind. When the bilirubin is elevated, the evaluation really is similar. The only issue here is that if the bilirubin is up, you may choose to do a liver biopsy a bit sooner in these individuals. And again, let's just talk now about elevated bilirubin that's unconjugated. Here you're thinking hemolysis or Gilbert syndrome, a hematosomal recessive trait here. And you can actually look for the polymorphism. There are blood tests now available for these. And again, this is quite common, but the AST and ALT are going to be normal in these individuals. And if you fast, the bilirubin goes up. Or of course, hemolysis is also in the differential. If the conjugated bilirubin is up, well then you really do have some kind of liver disease. And you need to be looking at your medicines. You need to be looking at the AST and ALT levels. Elevated conjugated bilirubin above 0.3 is not normal. And so here you want to be looking for sepsis, TPN, cirrhosis, biliary obstruction. Again, going down the same differential. And again, you're going to likely be doing imaging and or a liver biopsy. Imaging, you might find something here like an MRCP where you have this very nice stone at the bottom here. And we've largely replaced ERCP with MRCP unless we have diagnosis. So my key takeaway slide here is that you're going to encounter elevated liver tests quite commonly, particularly non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis are most common. Normal AST and ALT levels we have here. And again, they need to be assessed. This doesn't mean, again, you have to do the complete evaluation, but you need to be looking at these individuals. And the degree of ALT elevation is going to guide your evaluation. NAFLD, there's so much here. Use your non-invasive tests to guide and target those for evaluation who you think have abnormal parameters for fibrosis. Use your non-invasive markers. The NAFLD fibrosis score, use elastography, help use those to target who we biopsy or you'll overwhelm your radiologist. And again, always consider medicine and supplements. Thanks again for inviting me to speak. Thank you. Thanks, Dr. Kuo. That was an excellent talk. We're now gonna open up the room for questions. You're welcome to approach your microphone. We have a few minutes for questions for Dr. Kuo. I have just one to start. You mentioned that exercise can cause elevation of AST in particular. Is there a best time that you would advise a patient to go get their labs drawn? Yeah, so I wait. So the half-life is somewhere, AST and ALT are somewhere one to three days. So I tell them to take it easy on the weekend and then come in Monday morning. And sometimes, particularly some of these people who are just enthusiastic, just so disciplined in their exercise, you have to tell their spouses to sedate them. Just right on the weekend, you must stop exercising. But it really is an issue. And so we've had people, for instance, life insurance, they actually can't get a good rate because their liver tests are high. You tell them just take it easy and they do okay. Thank you. Microphone on the right. Yes. I don't want to talk about trying to buy you, and it's necessary, but how can you reassure the council that? Yeah, so that's a very, so the question is, you have an idiosyncratic reaction, and they say, is this going to happen again? And again, the polymorphisms, as you said, there are, people are trying to look for polymorphisms now, and this, I think, will be a major role in the next few years of precision medicine, which will be to develop tools to allow us to predict who's going to get into trouble. We have just one that we commonly use now, which is thiopurine methyltransferase, or TPMT, which, for those of you who use azathioprine, you can use this to help predict who's going to get into trouble with the metabolic enzymes, but we don't have many tools right now in our command. You reassure them, and then you look at the class of the medicine, so in general, if you have, so let's take a common one, like statins, for instance, where sometimes liver tests go up a little bit, although they're generally incredibly safe, if they do go up, you can actually sometimes treat through it, so there's this process, the elevation in AST and ALT go up, and there's this, and this is classically described with isoniazid, which is called adaptation, so you know, you'll actually adapt over time, so the ALT goes up, you keep treating, we see this a lot in the oncologic literature, and the AST and ALT go down, because the liver adapts to the toxic metabolite, clears it, and it goes down, and we see this with isoniazid, so many people have liver test levels that go up, but over time, they'll go down, some don't, some get acute liver failure, so the issue is, then, particularly if it's a fairly rapid increase in the AST and ALT, you generally don't re-challenge those individuals with the same medicine, if there's a substantial idiosyncratic reaction, as opposed to just mild one, where you could treat through, but you can reassure them that you generally, say it's a trimethylamine, cephalomethoxazole, you can just switch your class of medicines, and because these polymorphisms are rare, if you do that, you'll be able to find therapies for the individuals, and you reassure them, make sure that the allergies and sensitivities are appropriately documented. So I have sort of a two-prong question, and you're from California, so I hope you can, I am too. So CBD, which I think is kind of nationally accepted, I wonder if you can speak to whether or not that impacts liver functions, and also THC, cannabis. Yes. And whether it's smoked or eaten. Yeah, or a salve, so the CBD available now is not the CBD that we watched on movies in the 70s, okay? It's way more potent now than what we used, and so people use these oils, people use salves and all of these, per se, we have seen, we're actually writing up a case report right now because somebody actually got elevated liver tests from using CBD enemas from, so, yeah. No, no, no, California, sorry. Yeah, no, so, and actually what we found was oil droplets in the sinusoids from the vehicle, so it was fascinating. So you have to ask about that. Per se, in CBD, so I haven't seen too much in the way of hepatotoxicity with CBD, but it's probably going to happen. It will probably be the vehicles more, although I wanted to stress that the potency of CBD is, this is just a lot, these are, the concentrations are just much higher than they used to be. So in general, what we do is we try and encourage, well, we don't encourage CBD, but it's out there, and we account for it. When we have elevated liver tests, we actually tell them to stop it for a while, and again, you'll find out how much they're attached to it by how hard they push back when you tell them to do that, but we tell them to do that. I have not seen, per se, any systematic reports where CBD is causing a huge number of elevated liver test issues with this, but will it eventually happen? Probably. Well, and then how about actual cannabis with smoked or eaten? Does that impact? No, edibles and smoke, not that I have seen, per se. It's associated, there was a literature prior to the DAA era where these medicines were actually deleterious in contributing to hepatic fibrosis in hepatitis C patients, and it was actually with inhaled as well as, I think they also looked in co-infected individuals who were taking a derivative, darabinol, and so they had slightly elevated fibrosis levels, but there are other studies that say that this has not been replicated, so it's out there. We all have to account for it. What I would say is if the liver tests are elevated and you can't find another great explanation, I would encourage them to take a holiday and just see what your patient satisfaction score does. Thank you. Right? One more? Dr. Quah. Yes. The liver learning sessions that involve liver testing, the liver tests, indicate that we're not supposed to be calling these liver function tests, as you stringently emphasized at the beginning of your speech. How are we supposed to address this with the long-term patients who call up and say, what are my liver function test results? Yeah, so you simply take out the word function. Hi, I'm calling you about your liver test results. Okay, and then what you do is you also educate them that particularly unless they're cirrhotic, you reassure them that their liver is functioning normally, right? So your liver tests are abnormal, but I want to stress the function is just fine, and I use automobile analogies. The car is running just fine. The car is running, you have a few door dings or it's raining, but you're actually, your car is running just fine. And because patients become very anxious that their liver, just like you said, is gonna fail. And for most of these individuals, and that's not the case, even with fairly high AST and ALT, the liver functions normally. It's only when the INR goes up, bilirubin goes up, then things are more exciting, and you have to pursue them more rapidly, okay? Great, thanks, Dr. Kuo, thanks very much. Thank you.

liver biochemistries

liver tests

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AST

bilirubin

albumin

prothrombin time