So we are going to talk about a very interesting topic, interesting topic in a way, because I think the advances are becoming so that we will have an opportunity to intervene. That's when we start getting excited in medicine. Otherwise, we just ignore everything, right? Like if we can't do anything, sometimes it's better not to see. We are gonna talk about the new definition. This is an older slide. It still says NAFLD, but it is not NAFLD as you know anymore. But I wanted to share these numbers because this gives you an idea globally what a large problem we are dealing with. And here in the MENA area, here we do have even higher risks than in some other areas in the world. It's a global problem. And why it's also important is that this indeed in populations decreases the life of the individuals, the expected life. As you can see, it increases cardiovascular disease. It increases non-liver cancer risk. It increases cirrhosis, of course, complication from cirrhosis, liver cancer, liver transplant. This is almost head to head in the United States currently and surpassing hepatitis C. So what is the nomenclature? Before we start diving into what we can do for everybody and ourselves, what do we really call today is MASLD, the metabolic dysfunction associated steatotic liver disease. MASLD, I believe, is much better nomenclature than NAFLD, which we did call in the past. And it really describes excess fat in the liver, nothing else at this point, with at least one cardiometabolic risk factor. If you're an endocrinologist in here, you would understand I actually compare it to SIADH. You know, when you have to rule out other causes to make the diagnosis of SIADH, this is the same for MASLD. You need to make sure it's not alcohol-induced, hepatitis C-induced, medication-induced. At the end, you're dealing with MASLD. And alcohol intake in countries that are consuming alcohol is around 140 grams of alcohol consumption in women and 210 grams of alcohol consumption in men per week is considered higher amount of alcohol. What does that mean is around 14 gram is a serving, like a bottle of beer, a glass of wine, a shot of whatever, is around 14 grams of alcohol. So you can calculate how much that equates to. But if someone has a MASLD and you still get an alcohol consumption history, that becomes a combination, so you can still have a combination of disease. What are the cardiometabolic risk factors? So just to refresh our minds, the BMI more than 25, and that is important because no one even in the United States, BMI 28 and more is when they start getting worried about. But BMI of 25, which is overweight, is a risk factor for cardiometabolic disease. And in Asian population and some of the Central or South American descent, we do 23 is when the problem starts. Anything that is dysglycemia, fasting blood glucose of more than 100, or glucose more than 142 hours after a glucose load, hemoglobin A1c that is in pre-diabetes range, or full-blown history of diabetes, all are clustering, clusters of cardiometabolic risk factor. When you have hypertension, that is blood pressure more than 130 over 85, fasting triglycerides of 150 or above, HDL 40 or below in men, and 50 or below in women. So everything that is linked to cardiometabolic risk. So what other terms are important to know so that we can intervene with appropriate interventions and medications? MASH, the space of NASH. MASH is the metabolic dysfunction associated with steatohepatitis. And the more advanced form of MASH-LD. So one is just having a fatty infiltration. The other one is when you start seeing some inflammation. I again see this like Hashimoto's thyroiditis. You know, it just helps me to compare it with something that I'm more familiar with than liver necessarily. And Hashimoto's thyroiditis is this hepatitis, steatohepatitis is what Hashimoto's thyroiditis is in the liver. There's an inflammation and changes and some cellular death. And this, exactly like the thyroid, with repeated hepatitis, repeated insult to the liver, starts having formation of fibrosis. And fibrosis is bad news. There are four stages of fibrosis. You don't have to know them, however. Because it affects our treatment options currently, it's important to be familiar with them. There's a stage one, there's a stage two, and then there's a stage three and four. Four, and then you're dealing with more like a cirrhosis and stage fibrosis. The two and three are important stages because now we have a medication. We can intervene when the patient is around two or three stages and reverse some of the fibrosis. So it's very important. So how do we know who has what? And this is very important to remember, that every patient that walks into our clinics, because in the studies, when you review the prevalence of it, 80% of an endocrinology clinic has actually Mastel-D. 80%. Remember, and even other diseases like Cushing's disease is high risk for this disease. So anyone should be really with metabolic dysfunction, should be screened with a simple FIB4 formula. And this is, for our practice, is easy because we don't have the brain cells to calculate them every day, every moment of the day. We just have it inside the medical record. It pulls it, it calculates for us by pulling the information for the patient. But you can find it in the internet. And just add, you will need liver enzymes, you will need platelet count, the age of the patient counts, and you just calculate what we call FIB4 score. It just scores the patient, and we will review this soon, and gives us an idea about the risk of the patient. What is the risk for this patient to advance to fibrosis? Is this fibrosis, or am I just dealing with a fatty liver, Mastel-D? So that is the important part to know. The other population, not only people who walks into your clinic with a FIB4, but you need to also think about perhaps doing more advanced screening for individuals who might have had scanning of some kind for a different reason. I have so many patients, has a right upper quadrant pain, they go to emergency room, or whoever sees them, they get an ultrasound of right upper quadrant. And suddenly the report comes, there's a fatty liver. I'm like, oh my God, there is a fatty liver. So what do you do? You cannot ignore it. In old days, I used to, oh there's a fatty liver, lose weight, but that's not the case anymore because we do have tools we can offer. So when you have someone with changes that are seen in a CT scan, and an MRI, and an ultrasound, you should further evaluate to see what is happening to them. So let's look at what we are going to see. The FIB4 score is really to understand what the risk of the patient is. And if you have a score 1.3, this you have to remember, maybe 13, a bad luck, there you go, 1.3 is 13, a bad luck, remember like that. If it is more than 1.3, you're dealing with a patient that might need to go through a second phase of screening. Now there is one important thing to remember. Unfortunately, as we get older, and because the formula has age in it, if people are older than 60, the number we use is a little bit different than 1.3. We use two as a cutoff. This is like creatinine clearance in a way. You know how as we get older, because the formula includes age, it decreases as we get older, the same thing. So you need to really use a different cutoff in patients who are older. So what do we do? Let's look at it, I wanted to just make sure you just focus here in this area. So now you screen someone, let's say I come to see you, you say, hey, Dr. Hatipolu, you have a horrible family history of this and that, and you have prediabetes, which is true, and now you say, let me check your FIB4 score. And now you say, all right, your FIB4 score is less than 1.3, we are in great luck, I will let you go, but I will keep screening you every one to two years. So you need to repeat it every one to two years, because anything can change as a patient of yours in my disease progression. And then if I was, let's say, 65 years old, and I was even 1.8 or 1.9, you could have said, okay, you are still okay, go ahead and come back later. But if you are dealing with a FIB score of more than 2.67, and this is tricky too, I don't know how to give you a tip, 13 was a tip, but I don't have a tip for 2.67, you should double it, oh, that's a great idea, then you send them directly to hepatology. Goodbye, my friend, it's beyond my focus, unless you love Mastel-D and you wanna deal with it, you can, otherwise we just send them to hepatology. What do they do, actually? They don't do rocket science stuff, unless they do the biopsy, they might go ahead and order something called ELF. ELF is Enhanced Liver Fibrosis Marker. It is a blood test, we don't have it very much all over the U.S. yet, it's quite expensive, we don't use it in everybody, but it is a simple blood test that you can actually see what is the ELF of the patient and decide what you should do next. The other more simpler version that some of my colleagues indeed has in their practices, like the hemoglobin A1C machine, they do FibroScan. The FibroScan is a non-invasive scan that can tell us how stiff is the liver, so it gives you an idea how fibrotic is the liver. So here you can see, for example, you are doing the FibroScan, or you decide to do ELF blood test, anybody who has a FibroScan reading of more than 12 or ELF score more than 9.8, they are extremely high risk, they might need to be assessed by the hepatology and indeed might need a biopsy to stage. If you have a very suspiciously high numbers, you might not need the biopsy and you can go ahead and treat the patient with advanced treatment options we have. So for fibrosis management, again, we have few other tests, but I'm not gonna spend time to, you know, at the end of the day, you will curse me to death, so I'm not gonna do that to you. ELF, remember, FibroScan, remember. Now, FibroScan is a trademark, which means, I don't know if you remember, in old days we would tell to the nurses, what's the acu-check of the patient? I don't know if you used to do that. Acu-check is the name of the device, and we would just make it look like it means the blood sugar. It's almost like, I don't know, you know, using something, instead of handbag, what's the Chanel of the patient, for example? You know, it has nothing to do with the handbag, it's just the brand name, it's what you put. So FibroScan is the same thing, indeed. It's an ultrasound elastography. I'm saying this because in some other countries, it might be a different name, and in the US we keep using FibroScan as if it's the only thing. So you can use the FibroScan, which is very simple, easy to do, and you can actually decide if they have enough advanced fibrosis. The MRE, which is MRI elastography, is much more advanced, better pictures, more reliable, more expensive, so not for endocrinologists usually to do it. We let their hepatologist deal with it, and of course a biopsy. One important part, if you are seeing someone with high risks already, and they are MSLD, just go through their medication to see if there's anything you can discontinue to help the patient not to advance further towards cirrhosis. These medications are, think about it, almost like alcohol consumption. We tell them stop alcohol, we tell them lose weight, we have to do our part to get rid of the toxic medication to liver that can make things worse. Glucocorticoids, you might or you might not be able to stop it. Tamoxifen in breast cancer survivals. Some of the HIV medications, amiodarone is included. I just wrote some that I see more often. For example, atypical antipsychotics. In the United States, they use a lot of these medications, the primary care, to give people who cannot sleep. So it might be just there because they cannot sleep and might need to be switched to something safer for the patient. Alcohol use, you can either assess it with the history, but some people are not aware how much they are drinking. I had a patient one day, she came to visit me from Tennessee, I will never forget, she brought me a towel to use in the kitchen, kitchen towel. And she says, Dr. H, I thought you would like this because we kept talking about alcohol consumption and then the towel said, I listen to my doctors. I am drinking six glasses of wine a day because I have six doctors. Everyone told them to drink only one. So I thought it was so funny. And it just might be like misconception, denial, or whatever could be. So you can, I have not ordered this, there is a special test to see if someone is exposed to alcohol more than they should, which is the phosphatidyl ethanol test. Hepatitis C should be screened. Hypothyroidism, believe it or not, can be really important to know if they have hypothyroidism and treat it well as it can actually exacerbate it. Celiac disease, which I screen all my type one diabetics with celiac screening including I actually have a very low threshold for Hashimoto patients because I see that overlap and Sometimes I repeat it every three years and medications like we discussed So if you're you wanna really further dive into more advanced fibrosis Testing biopsy is the gold standard really All right, let's go to management that's what it matters really. All right, so we are gonna review It is a very busy slide but I'm gonna go over and then we will repeat each scenario and end up with the Medication that is currently approved in the United States. And then I'm gonna see if we have time for some cases so for Masol de The steatosis not a hepatosteatitis. There's no inflammation yet. Just fat what? Perfect. You need to jump on to this patient and have them lose weight The most important thing you can do is help them to lose around five to seven percent of the BMI Now this is remembering even people who are 25. There's even lower BMI You might need to help them to lose weight which meal plan is better Whatever they can follow is the best meal plan forget it I mean usually I like Mediterranean diet because people you know, it has been a lot of cardiovascular benefit So Mediterranean diet high fiber, you know natural fruits and vegetables Olive oil nuts and lean meat, you know, those those are a good solid diet however, if you have a patient like some of my Hispanic patients, you know from Mexico they come and they eat like ten of those tortillas in the morning for breakfast So you're not gonna tell them go to Mediterranean diet It's not gonna work, but at least if you can tell them just to eat two not ten That's the plus right you just pick your battle. You just pick your battle. We see so many different people And diverse which is beautiful, but then you need to understand the culture the diversity you have to respect Their culture their diversity. We cannot just impose upon people what to eat But to give them the tools so that they get the best that they can Alcohol consumption I tell them to avoid it But you know, this is a bit more moderate than me So they say they can have a little bit drinks, but I just say no drinks and exercise Exercise is extremely important to get them to move and even fidgeting Works, you know between If they are sitting and they can just stand up every hour for a couple minutes. It works. Just move a movement To help our patients to lose the weight to have that Opportunity to get to their goal so that the fat from their liver is removed We use in in the US a lot of agents like GLP one Analogs, they are either Diabetic or not diabetic. We really go after Any of them in that pot can be used GLP one receptor agonists You could to pioglutazone if you have a patient with type 2 diabetes I would not go first with pio unless there is an issue with You know getting the GLP one agonist And of course you can try sglT2s and the dual agonist like Terzapatide has been shown in their clinical trial huge benefit to the removal of the fat from the liver GLP ones in Massoudian mash trials has been shown to decrease Significantly fat from the liver. However, they have not shown to reverse fibrosis So If someone has fibrosis We might need something else in addition to the medication and Let me think. All right, you can you know, you manage cardiovascular risk like you would always do give statin give ARB or ACE and control diabetes And bariatric surgery is important if the patient cannot get to the to the goal despite your intervention All right mash very similar, but notice more Weight loss is asked of them almost 10% of body weight Almost everything else is very similar exactly the same as Massoudi However, there is one difference here that I want you to notice if someone does not have diabetes Consider vitamin E It's not very strong But there are some benefits in the literature in addition to pioglutazone You can use it and GLP one, of course analogs. So this is just something to keep in mind When you are dealing with Fibrosis Everything is the same. Now you are asking the patient to lose even more than 10% but 10% is what I asked for Exercise diet and this and that GLP ones statin ACE and ARBs here is The difference that I'm going to talk to you briefly now is Resmetiron That's the new medication approved for us to use in patients with mass with stage 2 or 3 fibrosis Here is cirrhosis, I'm just gonna before I go to her as Resmetiron cirrhosis, of course is a disease where the hepatologist needs to be involved however, what is important here is that GLP ones and Dual agonist you may need to be careful. They are already frail. They are cirrhotic. You might not get much out of it Avoid statins Be very cautious if you're gonna use at all Pioglutazone because they are already retaining water. You third spacing is there. You don't want to make it worse and You need to be careful with ACE and ARBs. So cirrhosis Everything we talked about doing in muscle D and mash even mash with fibrosis You need to be careful with cirrhosis, which is end-stage Fibrosis. All right. Let's talk a bit about the resmetiron. What is resmetiron? So resmetiron is a medication that works in the liver, especially targeting the Thyroid hormone receptor who would have known every single specialty that our Endocrine system from cardiology to liver. I don't know what to think anymore. Everyone wants our patients fine You know, there are so many enough of them. I am I'm like take it. That's fine. That's fine So here is fascinating Fascinating that this medication is about t4 to t3 Conversion, you know when I had I don't know if you get these patients or is are they United States born and raised? I don't know. They we will see these patients who will come and say did you check my reverse t3? Do you see that? Yeah, this is international Unlike reverse t3 Did you check my free t3 and reverse t3 and blah and interfering gamma? And I don't even know where they get it. So maybe they might be right after all Look at that t4 to t3 conversion and its effect in the liver seems to be a problem in Cirrhosis and before cirrhosis in the fibrosis. There are two receptors Prominently for thyroid hormone the alpha receptor and beta receptors The alpha receptors are mainly in heart brain and bones In the beta receptor is really majority of it is in the liver some in kidney some in pituitary but majority is in the liver and Thyroid hormone through that receptor conversion to t3 and t3 acting upon that receptor affects Intra-hepatic oxidation of the lipids Formation of lipids and secretion and clearance of triglycerides as well as for in a way Controlling the inflammation what an amazing information that we did not know At least I wasn't aware until res metter on started to come out So res metter on this medication currently is indicated In conjunction with diet and exercise and other things that you might be doing in non serotic non-alcoholic Hepatitis this indication is MASH, but when it went to FDA MASH wasn't The word that was used so they had to use NASH with liver fibrosis Two or three and it is actually has been shown to decrease 30 to 40 percent Reverses the fibrosis huge benefit. I have a patient or in two right now. I don't give it I Send it to a pathology because there could be Decompensation they might need a biopsy. So it's better that they deal with it and they reversed it within six months Amazing a drug is amazing and it works in that beta receptor in the liver Helping the cholesterol as well as helping the fibrosis Most side effects is around liver related you can see some liver enzyme elevations and cholecystitis and so forth and I'm gonna just go ahead and do some cases. Is that okay? We have five minutes some of it is easy Some of it is not you don't have to feel bad if you don't get it normally But it just gives you an idea, but it's a practice of what we just reviewed This is a 66 year old female with a long-standing type 2 diabetes presents for routine follow-up She has been taking GLP one analog metformin and once a day insulin Her BMI is 33 blood pressure is this and on exam she has central obesity Her a once is eight point eight You notice AST and ALT are elevated as well. She underwent an abdominal CT scan at an outside hospital, she's 66 and They found that she has fatty in infiltration of her liver So risk factors on GLP one already During your visit you review the patient's current Medications which of this the medication you need to be really careful and remove metformin Dexamethasone bravo. Bravo. Yes, not the antidepressant. The woman is already depressed leave that alone Yes, even if it was causing liver fatty liver leave that alone Just the dexamethasone because then they eat more like right depression causes behavior issues. They eat more unhealthy They don't exercise at all. So it's better to keep them there. Okay, perfect Which of the following lifestyle modification would be most effective for this patient in managing? Massive D. So now you found it's a massive D I didn't give you the 5-4 score. But what should you tell her? See fabulous. You're passing the test. I can go back to us with good Feeling good about that. I taught everybody. Well, okay, let's go to this one. Let me see we have 67 year old women Presents for annual woman's health and wellness physical. She has pre-diabetes She's overweight on clortalidone for diet for hypertension And she has hyperlipidemia with rosuvastatin, which is crest or 10 milligrams Vitamin D deficient so taking you know in the US. We are all vitamin D deficient baby aspirin She mentions that her younger brother was diagnosed with fatty liver and wants to know what is her own risk And I'm giving you some stuff. So this is cheating because I didn't give you the fee before score Her fee for score is one point five one. So I'm giving you the answer One point five one. Do you remember the 13 one point three, but I gave you something else a tip She's 66 order a liver ultrasound order a fibroscan Reassure her yes, and then she goes to the next door and gets another second opinion. Of course, right? Yes. That's our story That's what's gonna happen, that's all right. Yes sure What? Why not they refer to genetics So we don't do routinely unless she was a high-risk she's one point one five one She's 66 Yeah, she's over 60 so if it was true she would have been high-risk yes Yes for her age if it was more than two she's high-risk when it's less than two she's good to go Yes. Yes. So someone is asking about genetic testing But one brother I wouldn't really an older age We don't recommend it but I mean We don't Fifty nine-year-old, let me see two more questions. Maybe we can get in. Yes Fifty-nine-year-old male history of now. I put a man here so that no one feels like I'm discriminating here Fifty-nine-year-old male with a history of pre-diabetes Sleep apnea congestive heart failure obesity Found to have this is typical my patients found to have last year on a workup mash with stage 2 Fibrosis on a biopsy. He did not qualify for GLP one or do a antagonist agonist agents like terzapatide He started rest material 100 milligram daily and overall tolerated therapy Well, no problem with liver enzymes three months out I mean she's doing very well, but now he was treated for a longer period of time He Initially lost 7% of his body weight, but then he stressed he regained everything Baseline labs and the fibroscan had a cap score of 9 Fibroscan with a score of 9 now in almost a year later His fibroscan is worse and liver enzyme is back up What is the next best option this is tricky Proceed with MRE to confirm fibroscan Stop res metter on therapy proceed with more aggressive weight loss option Continue res metter on try to get weight loss medication Continue res metter on refer to bariatric surgery So this is tough, that's why we send them to Hepatology so that we don't masturbation of you stop it because it didn't work So when it didn't respond very well, we don't continue the medication currently currently It's not approved currently to continue if the patient does not respond. It might be in the future It's not approved for a phase one I mean us we can't use it until FDA says go ahead and use it the studies that FDA approved this drug was very Fast-tracked because we had nothing available in the market So they fast-tracked it we were all not shocked that the study published if they approved it. We're like wow, that's amazing Well, the studies continues for the safety Continues for the efficacy so we will know more in a year if I come back. I will give you an update And I think my time is up. All right, so thank you so much

MASLD

fatty liver disease

cardiovascular risk

FIB-4 score

liver transplantation

Resmetirone

individualized treatment