Welcome. Welcome to a session that is rewriting the history of diabetes complications. I'm your moderator. My name is Dr. Betul Hatipoglu. I'm a professor of medicine at Case Western Reserve and I serve as a chair for Disease State Network for Lipids and Cardiometabolic for Our Own Ace. I'm going to introduce you all our speakers at once to save the time and at the end we will all come up here and I will be glad to moderate the question and answer. Our first speaker for today's session is Dr. Scott Isaacs. He is the co-chair of Ace Fatty Liver Clinical Practice Guidelines, a member of Ace Executive Committee and Board of Directors. Dr. Isaacs attended Emory College and Emory University School of Medicine, continued his residency and fellowship there and now practices as an adjunct assistant professor of medicine at Emory. He is a fellow of the American College of Physicians, the American College of Endocrinology and a diplomat of the American Board of Obesity Medicine. He is a two-time past president of Georgia Ace and past president of the Atlanta chapter of the Atlanta Diabetes Association. He is going to cover for us understanding the epidemic of fatty liver disease. Following him, we have Dr. Romina Lomonako. She is currently assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at the University of Florida. After graduating from Argentina, she joined to do her fellowship focusing on diabetes at the University of Texas and joined to do her fellowship and continue as a young faculty to the University of Florida. Her research focuses on fatty liver disease and type 2 diabetes. She has numerous publications including original articles, reviews and book chapters. Her topic for this session will be diagnostic tools and complications of fatty liver disease. And last but not the least, our Dr. Cussey. Dr. Cussey is a professor of medicine and chief of Division of Endocrinology at the University of Florida at Gainesville and VA Medical Center at Gainesville. After graduating in Argentina, he did his training at Baylor College of Medicine and earlier career at the University of San Antonio Health Science Center. He was focused originally to insulin secretion and insulin resistance in the development of type 2 diabetes. Later his research focused to the role of non-alcoholic fatty liver disease and steo-hepatitis. Dr. Cussey has published more than 200 peer-reviewed manuscripts and contributed to several guidelines for the management of NAFLD. His research continues to be funded by NIH and his own institution to search of new treatment for NASH. He received University of Florida's prestigious exemplary teacher award and clinical research award for outstanding achievement of research discovery and productivity. He also was in 2020 the receiver of our own ACES Jack Baskin endocrine teaching award. He is going to talk to us about current and future treatments of fatty liver disease. Please sit back, relax, and welcome our speakers. Hello, everybody. I'm really, really honored and proud to unveil the ACE fatty liver guidelines that have just gone live on the ACE website today. And I really think this is going to be a new day for endocrinology. This is the first ever evidence-based clinical practice guidelines for fatty liver disease for endocrinology and for primary care. And this has been co-sponsored by the American Association for the Study of Liver Diseases. And it's really been an honor to work with this team of people that put together this guideline, including, of course, our leader, Dr. Koozie, who really made this an amazing guideline, but also just working with endocrinologists, pediatric endocrinologists, hepatologists, and pediatric hepatologists. I think we made it to be a really great day. So, I just wanted to start off with the definition of NAFLD, non-alcoholic fatty liver disease. And really, NAFLD is a hyponym. It's a catch-all term that describes all the other types of fatty liver disease. So, you'd start with simple steatosis, or NAFL, which is non-progressive. And then, you'd go on to other types of fatty liver disease. It describes all the other types of fatty liver disease. So, you'd start with simple steatosis, or NAFL, which is non-progressive. And then, you can have steatohepatitis, or NASH, which can be progressive and can progress to fibrotic NASH. And then, eventually, it could progress to cirrhosis, which is the end stage of fatty liver disease. One thing I see a lot of times, people will write NAFLD slash NASH. And that's really redundant, because NASH is covered under the spectrum of NAFLD. So, in order to diagnose NAFLD officially, you have to rule out secondary causes of hepatic steatosis or of elevated aminotransferases. So, you want to rule out excessive alcohol consumption. For men, that would be less than 21 beverages per week, and women, less than 14. You want to rule out hepatitis C, genotype 3. And then, there's a list of other rare or less common types of liver disease that can result in hepatic steatosis or elevated aminotransferases. And you also want to think about medications, corticosteroids, amiodarone, methotrexate, antiviral medications, antiretroviral medications, and others. And so, the laboratory evaluation, which is recommended, and this is all in the guidelines, is you want to start with hepatitis C. And then, you may do hepatitis B testing in selected patients. And then, there are some additional tests to consider. You may want to rule out autoimmune liver disease, hemochromatosis, alpha-1 antitrypsin deficiency. So, those are additional tests that can be done. So, just talking about histology and the histologic difference between NAFLD and NASH. On the left, we have NAFLD. And essentially, that's hepatic triglyceride accumulation with steatosis and greater than 5% of hepatocytes. But there's no inflammation or minimal inflammation. There's no ballooning. NASH, you have ballooned hepatocytes, which are those sort of whitish, round cells with the purple dot in the middle. And that's a sign of lobular inflammation and hepatocyte necrosis. And then, fibrotic NASH is going to have those same features, but also some fibrosis. And so, it's the histology that really defines these different entities. When we look at fibrotic NASH, we'll sometimes use a NAFLD activity score, which considers steatosis, inflammation, and ballooning. But fibrosis is staged F0 through F4. F0 being no fibrosis. F2 is where we start to see clinically significant fibrosis. F3 is preserosis. And F4 is cirrhosis. And once you get to that F2 is where we start to see that exponential increase in the risk for severe liver disease. So, the natural history of NAFLD. This is an extremely common condition. This is why we wanted to develop these guidelines and want to bring awareness. But it's approximately 25 to 37% of people with NAFLD actually have NASH. In the world, 25% worldwide have NAFLD. About 60 to 80 million Americans have NAFLD. Of those that have NASH, 20 to 30% can progress to fibrosis over a three-year period. And with patients who have fibrosis, about 20% of those will progress to cirrhosis over another two years. And from cirrhosis, you could have liver failure, need for a liver transplant, liver death, or development of hepatocellular carcinoma. But what's interesting is that it's a nonlinear progression to hepatocellular carcinoma. So, you don't have to have fibrosis to have increased risk. And the risk for cancer is higher in NAFLD than with other forms of liver disease. And also, the fibrosis progression can be slow or rapid. And about 20% of patients are actually fast progressors that will progress to cirrhosis in about 10 years. And interestingly, NAFLD can also spontaneously regress. So, the number one cause of death in patients with NAFLD is cardiovascular disease, and that's followed by cancer, and then liver-related disease. And this natural history can follow a variable trajectory, which is influenced by a dynamic interaction of genetics and epigenetics and environment and lifestyle and other cardiometabolic factors. So, when we talk about the pathogenic drivers for NAFLD, we start with calorie excess, excess calories of any form, especially fructose and also saturated fat, and will lead to excess free fatty acids. And really what's happening is that there's adipose overload. So, the fat supply exceeds the storage capacity of the adipocyte, and the fat starts to go elsewhere. Another driver is insulin resistance. Especially when you see patients that have that insulin resistance phenotype with increased visceral fat and decreased gluteofemoral fat. They have lipotoxicity. That's a major risk factor. We see the risk of NAFLD and type 2 diabetes is very high. Also, dysfunctional adipose tissue. So, we think about the adipocyte with a lipodystrophic state. So, there's a whole spectrum of lipodystrophy, but even a mild version of lipodystrophy can contribute to this disease. There's also genetics that are involved, and we see higher rates of NAFLD in the Hispanic population and in the Middle East, and lower rates in Africa and African Americans. There's also some genes that have been identified that I'll show you in a later slide. And then there's epigenetics, especially intrauterine growth retardation, and also intrauterine exposure to a maternal high-fat diet is considered a risk factor. And then finally, dysbiosis. And so, there's this interaction with the gut, microbiome, bile acid, milieu, and there's a shift towards more gram-negative organisms. So, all these are contributing to the development of NAFLD. And really, it's not just ectopic fat in the liver, but you can have it in the muscle, in the heart, in the vasculature, in the pancreas, and in the kidney. And this is everything I just told you for your notes. So, looking at the natural history, you know, we start with this insulin-resistant lipodystrophic adipocyte that has impaired adipose storage capacity. And that leads to adipose overload and steatosis, development of ectopic fat. But then we see some inflammation, which is what leads to the steatohepatitis. And then this leads to the release of cytokines, hepatokines from the liver, adipokines from the fat cells. And that leads to insulin resistance, peripheral insulin resistance, hepatic insulin resistance, increased glucose production. And we also see this atherogenic dyslipidemia with increase in triglyceride synthesis, increased VLDL, decreased HDL, and the increase in the small, dense LDL and ApoB particles. So, this is part of the reason why there's this increased risk for cardiovascular disease with NAFLD. And then the inflammation progressing to fibrosis, cirrhosis, hepatocellular carcinoma. And this does not follow a linear progression. And there are a lot of unknown factors as to what regulates this. So, looking at NAFLD genetics and adipose physiology, the PNPLA3 gene is the one that's receiving the most attention right now. This one is increased in the Hispanic population. And this gene affects lipid droplet remodeling. There's also the TM6SF2 gene, which affects VLDL secretion. And that is seen more in lean NAFLD. I do think lean NAFLD is kind of a misnomer because it's based just on the body index. Having a BMI less than 25 and fatty liver qualifies for lean NAFLD. But when you look at these patients, they're really, they're not lean. They have increased visceral fat and they have a metabolic profile similar to patients with obesity. And then also the GCKR gene has also been involved in lipogenesis and is part of NAFLD genetics. So, looking at the prevalence of NAFLD and NASH in the U.S., this was looking at a large middle-aged U.S. cohort. And of this, 38% had NAFLD and 14% had NASH. Of the patients with NAFLD, 37% of those with NAFLD had NASH. And in the overall population, 6% had significant fibrosis. And NASH was more common in type 2 diabetes and in obesity and in the Hispanic population. And so, you can't go to a NAFLD lecture without seeing this slide. But this is from Zobair Yonasi, who was one of the AASLD representatives on the guideline. And this is just showing the global prevalence of NAFLD in type 2 diabetes. This truly is a worldwide problem. You can see there's higher rates in Latin America and the Middle East. But the prevalence is very high throughout the world. And even though the prevalence is high, NAFLD is underdiagnosed. And it's more likely that the NAFLD diagnosis is going to be made incidentally on an imaging study than by intent. There's lack of patient awareness. Less than 5% of patients with NAFLD are aware of having liver disease compared to 38% of patients with viral hepatitis. Patients are not treated as much as they should be. There's underutilization of medications with proven efficacy in NAFLD. And the high-risk patients are not being referred to the hepatologists. So, I'd really like to show this study, but this was actually done by our other two speakers today. So, I'm really, this is one of my favorite studies. I hope they don't mind that I'm showing this. And I hope I get it right. But essentially, they looked at patients in an endocrinology clinic who are unaware of having liver disease. And found that 70% of them had steatosis and 21% had fibrosis. But of those, not very many had elevated liver enzymes. Only less than 10% overall had elevated liver enzymes. And when you look at the patients with fibrosis broken down into stages F1, 2, 3, and 4, 3% of them had cirrhosis, had F4, previously undiagnosed. And of the patients with fibrosis, still a very small percentage had elevated liver enzymes, less than 30%. And so, the take-home message for this is that if the liver enzymes are elevated, that's definitely important to pay attention to. But if they're normal, that does not rule out NAFLD. You're going to miss at least 70% of the patients if you rely only on the liver enzymes. And, you know, the prevalence of NAFLD really depends on the diagnostic tool that's used. So, earlier studies really underestimated the prevalence of NAFLD because they used plasma ALT or CT or liver ultrasound. But when you use real sensitive technology like controlled attenuation parameter, which is an ultrasound-based technology, up to 75% of patients with type 2 diabetes have NAFLD. And when you look at, again, with an ultrasound-based technology, which is more sensitive, there's a higher rate of advanced fibrosis, about 20% in type 2 diabetes. And the point to also see here is that type 2 diabetes significantly increases the risk for advanced fibrosis. And so, one more epidemiology study. This is University of Florida Colors, so we know where this one was from. But if you look at patients with a BMI of at least 35 who have type 2 diabetes, it's up to 90% have NAFLD. So, this is a huge number of people. And really, that's why when you're going to be hearing in the next talk, that really the challenge is not diagnosing fat in the liver, but it's diagnosing that risk for fibrosis. And so, this is looking at the mortality according to the histologic severity in NAFLD. The NAFLD, or isolated steatosis, used to be called benign steatosis. But again, I think that term is a misnomer because it's not benign. even isolated steatosis has increased mortality. And so the term harmful steatosis has been suggested instead of benign steatosis. The point is that there's increased cardiovascular risk, but there's also increased liver-related risk in this group. And then once you get to NASH, the liver-related risk goes up significantly. But the mortality is increased for the entire spectrum of NAFLD. And as I mentioned earlier, the number one cause of death is cardiovascular events. And the risk of cardiovascular event is linked to the risk for fibrosis. So this is looking at the FIB4 score, which you're going to, again, learn more about in the next talk. But if you have a high FIB4, more than 2.67, you can see that the risk for a cardiovascular event is more than 4.5 times that if you have a low FIB4 score. And this is also sort of a landmark study looking at the risk for mortality, liver-related mortality according to fibrosis stage. And you can see that stage 2 fibrosis is really that tipping point for liver-related mortality, and it increases exponentially once you get to stage 2 fibrosis. So when we look at patients, who are we going to screen? And this is just sort of a lead-in to our next talk. We want to identify the patients who are at high risk for the development of NAFLD. And so these three groups are type 2 diabetes or pre-diabetes, obesity or greater than two cardiometabolic risk factors, or patients who have hepatic steatosis on any imaging study or elevated transaminases. And really that means AST or ALT greater than 30. In most labs, the normal range is going to be higher than 30, but transaminases over 30 is considered abnormal. So with these patients, you're going to do a NAFLD assessment, you're going to do a history and physical exam, you're going to rule out secondary causes of liver disease, and then you're going to focus on prevention of cirrhosis and doing the fibrosis for the FIB4 risk stratification is going to help with that. And then the other thing is the prevention of cardiovascular disease. That's what's most important for the patients who are at low risk for liver disease. And so we want to optimize the management, weight management, diabetes management, dyslipidemia and hypertension. And these are all categories that are covered in the algorithm, which is part of our lipid guideline. This is just one of the slides from the algorithm. I just wanted to have this here for the sake of completeness and also so I could be the first person to ever show this, but really showing, you know, identifying these high-risk groups and focusing on that dual liver and heart. We really want to pay attention to both of those. And just more about how to risk stratify the patients for advanced fibrosis and talk more about that in the next talk as well. So take-home messages. Number one, NAFLD is underdiagnosed. Most patients are asymptomatic. Most symptoms, if they do have symptoms, are fatigue and vague right upper quadrant pain. Liver enzymes are frequently normal, elevated less than 30% of the time, and most cases currently are diagnosed incidentally, not by intent. NAFLD, the term represents the entire spectrum of fatty liver disease, starting with isolated steatosis, early NASH, fibrotic NASH, NASS sclerosis, which progresses, can progress to hepatocellular carcinoma. And it does not follow a linear progression and can spontaneously regress. Globally, NAFLD is 25% to 38%. NASH is about 14%, fibrosis about 6%. And the prevalence in type 2 diabetes is approximately triple that of the general population. And remember, mortality is increased with all forms of NAFLD, even isolated steatosis. Risk of death in NAFLD, number one, ASCVD, number two, cancer, number three is liver, but especially if they have that fibrosis stage two or greater. And then we talked about pathogenic drivers, the calorie excess, fructose, sugar, saturated fat, insulin resistance, dysfunctional adipose tissue with a lipodystrophic, the spectrum of lipodystrophy within the adipocyte, the genetics, PNPLA3, epigenetics, and gut dysbiosis. You want to identify those high-risk patients, the patients that we're seeing every day, diabetes, obesity, cardiometabolic risk, and you want to evaluate them with the FIB4 and you want to rule out other forms of liver disease. And so with that, we'll move on to Dr. Lamonaco and continue with the discussion of the guidelines. Hello, everybody. Thank you for having me. I'm going to talk about complications of non-alcoholic fatty liver disease and also diagnostic tools. So first, we're going to talk about my objectives. We're going to recognize complication of non-alcoholic steatosis, evaluate non-invasive biochemical diagnostic tools, we're going to identify non-invasive imaging tests for evaluation of NASH and liver fibrosis. So this is just the structure of my talk, and we're going to start with complications. As we know, there are liver complications and complications outside of the liver. And for the liver, hepatic complications, so Dr. Isaac talked about the natural history of the disease, and once a patient progresses to non-alcoholic steatohepatitis, there's also progression to advanced fibrosis in about 4% of those patients with non-alcoholic fatty liver disease and about 20% with non-alcoholic steatohepatitis. Of those, up to 12%, they can progress to hepatocellular carcinoma. NASH is the fastest growing cause of liver transplant in patients with hepatocellular carcinoma. And also in females in the United States, it's the leading cause of transplant as well. So as far as the extrahepatic complications, NAFLD or non-alcoholic steatohepatitis is associated with multiple metabolic problems such as cardiovascular disease and arrhythmias. Also type 2 diabetes, kidney disease, extrahepatic cancer such as colon cancer. And all that includes because they have insulin resistant and hyperinsulinemia in common. There are also some anti-inflammatory processes happening and cytokines as well. This is just to show, it's a very busy slide, with a meta-analysis that showed different studies where the association of non-alcoholic fatty liver disease and cardiovascular disease is high. And why it is important for endocrinologists to assess for this problem is because diabetes and non-alcoholic fatty liver disease, it's associated with cardiovascular disease as well because they have in common hyperinsulinemia, type 2 diabetes, myocardial dysfunction and atherogenesis. They can all lead to cardiovascular disease. And why it is important to screen for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis because we all know the diabetes complications, cardiomyopathy, retinopathy, neuropathy and maybe we can add the liver as well and that's why the American Diabetes Association included in the Standards of Medical Care in 2019 as a recommendation to evaluate patients with type 2 diabetes or prediabetes and elevated ALT or with an image test suggesting fatty liver. Now moving to the evaluation of how we can diagnose this problem. First we just have the new guidelines and this is one of the algorithms that is proposed. And first of all we have to find those patients at high risk, patients with type 2 diabetes with metabolic syndrome, hypertension, cardiovascular risk factors. Also patients with steatosis and imaging tests or elevated liver aminotransferases. And then stratify depending on risk factors and risk for fibrosis. And we have low risk after evaluating with the FIB4 that I'm going to explain in a few minutes how we can calculate that. And that low risk is if the FIB4 is less than 1.3. If the FIB4 is greater than 2.67 the patient is in a high risk. And then there are this in between that it's the intermediate risk and for that it's recommended to do a second modality to further evaluate for fibrosis. And in that case the vibration control transient elastography, it's recommended to measure liver stiffness. And with that also can be evaluated through ELF, which is another blood test that I'm going to explain in a few minutes. And then depending on the results, if the patient is in the low risk, it's important to continue monitoring for evaluation in two to three years after. If the patient is under the high risk, it's important to refer to hepatology for further evaluation. And in that case it could be to do more imaging tests or to do a liver biopsy. In those patients that they're in the indeterminate risk, it's also recommended to refer to a hepatologist or they can be monitored over time depending on how advanced the results that we have. What do we have available as biomarkers or non-invasive diagnostic tests? So first we have the liver aminotransferases that we all use in clinic. And as you know, they tend to be normal in most of these patients. And this is the same study that we published last year where we evaluated 561 patients. We screened them from just primary care clinics or endocrine clinics with no knowing that they had any problems in the liver. We found that 21% of them had fibrosis, that means F2 or more. And from those patients, only 10% or less had elevated liver enzymes. So now I'm going to move, as you can see in this cartoon, there are many areas in the liver that can be evaluated for biomarkers. I'm going to focus on the fibrosis area because it's what is associated with higher mortality. So what is the FIB4? The FIB4 is a score that includes age, AST, ALT, and platelets. If the FIB4, which is just a calculation, you can Google it and have this calculator very easy with just the four parameters. If the FIB4 is less than 1.3, that rules out fibrosis. The FIB4 is higher than 2.67, that predicts fibrosis. And in between, it's a gray zone, it's an intermediate. Then the NSF or Naflde fibrosis score, this is another score that includes the same parameters as the FIB4, but also includes BMI, serum glucose, and albumin. In our clinics, we see a lot of patients with type 2 diabetes, we see a lot of patients who are obese, so it may overestimate the prevalence of liver fibrosis. Another biomarker that we can use is a plasma propeptide of type 3 procollagen, or ProC3. As you can see in the first, on the left corner, that image shows that those patients with fibrosis 2, or moderate fibrosis, or above, had higher levels of ProC3. And the same thing on the bottom part, on the right bottom graph, it shows that patients with NASH had higher levels or elevated levels of ProC3 compared to non-alcoholic fatty liver disease. This is all patients with type 2 diabetes that also had elevated ProC3 on the top graph. You can see the stages of the fibrosis, and those with 3 or above had higher levels. This is just to show the performance of the plasma biomarkers, and these are different panels to evaluate for non-alcoholic steatohepatitis and advanced fibrosis. These are all patients with type 2 diabetes, and if you see the dotted orange color is the ALT. That is pretty similar compared to the other biomarkers to evaluate or diagnose for definite NASH. This is for non-invasive diagnosing advanced fibrosis, and the ProC3, which is the black line, also the AST, which is the red line, they were pretty similar for advanced fibrosis. What is the enhanced liver fibrosis? This is one of the newest algorithms that has been available, and it's a blood test. It measures different parts of the metabolism of the liver, and it has an algorithm that uses this component. It has high sensitivity but limited specificity to exclude fibrosis, and also it's limited to diagnose fibrosis in low prevalence settings such as primary care clinics. Once you get that, you obtain this report. It comes ELF and the score, and then you have the lower risk if it is less than 9.8, and at a higher risk if it is greater than 11.2. Then I'm going to move to the imaging. What are the non-invasive imaging tests that we have? The liver ultrasound. Liver ultrasound measures the echogenicity of the liver compared to the echogenicity of the cortex of the kidney, and on the right, you have the hepatic osteothesis shows a more bright liver compared to the kidney cortex. Then first, when there is cirrhosis, there is this irregular contour of the liver. So the ultrasound is very available. It's a low-cost test, but we cannot quantitate steatosis, and it has low diagnostic accuracy. Another test is vibration-controlled transcendental elastography, or VCTE. This measures liver stiffness, and on the left is an image of how to do the test. It's very easy to be trained and very simple to use. There's large literature supporting this method, and we can do it as a point of care. The machine is expensive, but the test is not, and it's less accurate when there is mild fibrosis or sometimes when there is obesity. Another test that we have available to measure liver fat, the magnetic resonance proton-derived fat fraction. This method has good correlation with liver histology, but it's only used in research settings. The magnetic resonance and spectroscopy is very sensitive, and this is a good method for quantification of the amount of liver fat, but it's not clinically available, and also it requires a dedicated spectroscopic software. For measurement of liver fibrosis, those were for liver fat. For liver fibrosis, we have the shear wave elastography, and this is a method that is very easy to use, but it's not as well validated as other elastography testing. And the magnetic resonance and elastography, this is the most accurate test of all the imaging modalities. But the device and the test, they're both very expensive and cannot be done in the clinics, but it is available in hospitals. So this is to show you, to compare the magnetic resonance elastography with vibration control transient elastography to detect liver fibrosis. And as you can see, the white is the VCTE and the dark column is the MR. They're pretty comparable, but the MRE is still more accurate. And this is how you see both the images on the top is the MRE and the bottom is the transient elastography. And in the middle, you see the fibrosis stages and both are reported in kilopascals, but they're not correlated. The gold standard is still the liver biopsy, but the liver biopsy has, it can confirm the diagnosis, it can stage the disease, but it has limitations because it's an invasive procedure, potential for complications, and also has the reader or sample error. So just as a summary, I want to show you a case. This is a 55-year-old Caucasian woman with medical history of type 2 diabetes, gastroparesis and chronic constipation. Her vital signs were all within normal limits, BMI of 34, so obese. She had an ASD of 45 and an ALT of 21 and platelets of 193. We did a FIB4 and it was 2.8. So that put her in the high category because FIB4 graded of 2.67 is high risk. So we have right there is the high risk and then we invited her to do a trans-intelastography and that was consistent. So the cap is the control attenuation parameter was 311 and greater than 274 means that the patient has or there's some suggestion of having steatosis and the LSM of 11, that is a liver stiffness measurement, was above 8, so it was 11. At that time, we decided to send her to hepatology and she had an MR-PDFF that showed 10% fat and an MRE that it was consistent with F2-F3 at 3.8 kPa. And when she had the liver biopsy done, it showed NAS, a non-alcoholic fatty liver disease activity score of 4 because that includes steatosis, lower inflammation, ballooning and she had a fibrosis stage 2. So take-home messages, it's complications, NAS is the leading cause of liver transplant in women and given the rate of increase, it will likely rise in male as well to become the leading cause. We have to be very cognizant about cardiovascular disease and type 2 diabetes and try to find those patients who are at risk to evaluate for fibrosis, liver fibrosis. And for that, we just had the new guidelines from ACE and in the guidelines, non-invasive methods include FIB4 as the first evaluation and then as imaging, VCT and also MRE if it's needed in case patient needs a referral with hepatology. Now, I'm going to invite Dr. Cussey. Thank you. Thank you. Okay. Well, great presentation. It's hard to follow up with these two comprehensive presentations. I want to thank ACE for having me and here are my disclosures. It's a very exciting time with these guidelines. When Scott first invited me, it was more than two years ago. We had our first meeting in July 2020. And after 3,000 emails and many Zooms and so forth, this is what came out. We had a great group of prestigious endocrinologists, many in the audience. We want to thank ASLD, particularly Dr. Giannucci and Dr. Vinela who were instrumental. And probably the most important person was Stephanie Adams who was staff from ACE who worked many, many hours and very, very late many evenings, right, Scott, and pushing both of us to get her back what she wanted. So, we are very, very grateful and very happy with this just foundational work. And I hope the youngsters in the audience will later come up with better and improved versions as more knowledge becomes available. So here are the guidelines. And again, as was presented, we have three high-risk groups. Notice that elevated ASTLT is 30, normal AST and ALT are in the 30s. And in the hepatology world, it has been associated with increased mortality, having higher levels than those. So, that's a level that I think we need to think about. And once we, the importance of knowing that you have NAFLD as has been discussed is to A, take this as a risk factor for worse cardiovascular disease and B, something we're not very used. I know we're good at preventing cardiovascular disease, but we're not used to diagnosing the risk of cirrhosis. So, I think that's what's new. And it's the analogy of diagnosing nephropathy as we started several decades ago when I was a fellow to screen for nephropathy people with diabetes with albuminuria. Well, we had the elegant presentation by Dr. Lamonaco and our mission really is to know if people are in the low or high-risk group or intermediate group to do something about it. So, I'm just going to talk about the two greatest risk factors. Type 2 diabetes is at the very top and then obesity. We talked about this relationship. This is like a bad marriage where each part gets the worst out of the other. Obesity is the number one cause of NASH progression for mechanisms that are unclear. NAFLD makes our diabetes more difficult to control. Ramina already mentioned that the ADA had suggested that we had to begin screening for this. And a little bit just to reinforce, this is a latest, an updated version of Dr. Ioannousi's scheme where we tried to put together the prevalence of diabetes with that of NAFLD and you see where it's more red, where there's more type 2 diabetes. Not by chance, there's more fibrosis and more NASH. Overall, across the world, 12 to 20% of people with type 2 diabetes have F2, which means moderate fibrosis or worse. This means that if in the last five or six patients of yours, you didn't diagnose anybody with moderate to advanced fibrosis, maybe you missed one. And that happens to all of us. So the point is to begin thinking about this. So number one, what causes fibrosis? We're not very sure. In humans, we have very limited information. But we do know that once you have inflammation, that this triggers pro-fibrogenic pathways. So the question that I get many times, well, we don't have any FDA approved drugs, so what can we do? Well, we can do quite a bit because if we can prevent steatosis, we prevent steatopatitis. And at the core of this is insulin resistant and dysfunctional adipose tissue. So put in other words, we can summarize it as, and we're going to tell you in the next three slides. So we know all the bad things that obesity does and overnutrition and insulin resistance, type two diabetes, cardiovascular disease. So no matter how you reduce the adipose tissue mass, things get better at each level. But as in the canals we've forgotten to is that the second approach is to change the biology of adipose tissue. This means convert that fat into the fat of a lean, healthy subject. And the tool that we have to do that is pioglitazone. And I'll show you in future drugs in the last two or three slides that there are new drugs under development that are going to be doing just that. So with that background, we talked about visceral fat, Scott talked about the importance of visceral fat. For example, people who are lean with NASH, guess what? Have high visceral fat, low adiponectin. So we looked into this, looking at our people who had been treated with pioglitazone. So although pioglitazone is considered a problem because it causes an increase in weight, what it really does is shrink the fat that's in cardiometabolically harmful places like visceral fat and the liver and also muscle and puts it into the subcutaneous compartment. This is like taking the fat out of the engine of your car, putting it in the trunk. I would rather just get rid of it. But if we can, this is an approach that is helpful. And when we look with a fairly sophisticated method of which we're not going to have time, the three factors that we had that were linked to improvement in histology, both inflammation, necrosis and in fibrosis were increases in adiponectin, reduction in visceral fat and improvement in insulin sensitivity. And pictures are better than words. This is one of the patients that we did pair biopsies and we looked at the visceral fat. You can see that after treatment with improvement in glycemic control and cardiometabolic profile, visceral fat shrinks, unfortunately at the expense of an increase in subcutaneous fat. So specifically for the management of our patients, we put together the following. So number one, well, these are general lifestyle changes that are very important. The diet would be Mediterranean diet. And again, now we have to be careful in considering the stage in which the patient is. And as you can see there, I mean, when you have advanced liver disease, you want to be more careful with your medications. The most important thing to remember is that we don't have any FDA approved medications, but we have diabetes medications that can help in that. So when it comes to choose your diabetes medications, if the patient has NASH, choose a medication that will treat both. And the two that have worked so far are pioglitazone and GLP-1 receptor agonist. I'll show you a little bit more of the evidence. What about the other diabetes medications? Well, keep using them to improve glycemic control. Be careful when you have cirrhosis because you're prone to hypoglycemia, sulfonylureas that are also half metabolized in the liver will make you prone to hypoglycemia. So let's dive a little bit deeper into what the guidelines say. So number one, that's a reminder for myself, there are no FDA approved drugs. So we're going to use them under the label of treating diabetes, but they have benefits in NASH. So pioglitazone and GLP-1 receptor agonist would be recommended if you have a biopsy to have proven NASH, which is in the minority of the cases, but also if you're suspecting that they have NASH based on the imaging and biomarker test that Dr. Lamonaca just reviewed. Again, also we want to improve cardiometabolic health. You're well-versed in that. I don't need to add anything else. We talked about keeping the other medications for glycemic control, insulin for instance lowers a little bit liver fat, but we don't know if it improves histology yet. And if you don't have diabetes, vitamin E has proven to be effective. There's a little bit of an uncertainty about whether it increases cardiovascular disease or prostate cancer. And there are a lot of other things you read in the internet for NASH, but none has really proven to be true. So these were the many studies that we did. Dr. Belfort is now, was a fellow, is now an associate professor at Yale. Pivens was a study that done large, primarily in non, in people without diabetes, highly effective for pyoglitisome. This is a three-year study that we also did with Dr. Lamonaca and another study combining with vitamin E, the results have been fairly consistent in improving steatopatitis and some effect on fibrosis. You've seen this slide again before by Scott. And the thing is the following, I mean, pyoglitisome reverses a lot of these effects, but the point that I wanted to make where there's a lot of misperception is that it causes heart failure. It doesn't cause heart failure. What happens if you give it to somebody with heart failure and you happen to have edema or water retention, that's going to trigger obviously a heart failure or decompensation. But what we've forgotten is that it reduces cardiovascular disease. So in proactive, if you take the MACE endpoint, it was positive. The primary endpoint also included peripheral vascular disease, which is highly controversial. And since then there've been other studies showing that it reduces the progression of atherogenesis. And in the IRIS study in about 3,800 patients treated for up to five years who had a serovascular axon or TIA, it reduced cardiovascular events. So it is a drug that helps for that and does not increase heart failure if you don't give it to people with heart failure. So all the trials that followed after proactive, none had seen compared to placebo an increase in heart failure. Now how can we prevent, as endocrinologists, we don't like people gaining weight. So what can we do to make treatment more effective? And the easiest thing is to use lower doses. So the weight gain is dose dependent. Here I'm going to share some literature that is being probably forgotten and comparing lower and intermediate doses of pioglitazone. And what you see is that the ability to reduce A1C is quite good, about 1%. It improves triglycerides, increases HDL. But the point I wanted to do to show you is that the weight gain is moderate and these studies are not doing active lifestyle intervention. And in the studies that they gain more, like the study by Dr. Rosenthal was on insulin. The combination of insulin will promote weight gain. I wanted to share a study came out just six months ago from Italy to see what is the effect on the liver. And what they did after a year is to compare intermediate, low, intermediate and high doses of pioglitazone. And you see that there's a reduction in liver enzymes across the board, same as for GGT, of liver fat, sorry, of liver fat and even of the NASH index. So we are doing a study with Dr. Lamonaco with biopsies, seeing if the lower dose can work and it may work because you're really targeting adipose tissue, which is very sensitive to the TCDs. The other approach is to combine pioglitazone with an SGLT2 inhibitor. So on the top there are the uncontrolled trials and the bottom five controlled trials. We did one with canagliflozin, but it's really a class effect that there is a reduction in a body weight that you're familiar with, two to 3% compared to placebo, placebo subtracted. Liver enzymes go down if they are elevated, if not, they don't change much. But liver fat goes down about 20% compared to placebo. So what if you combine this with pioglitazone? This is being done in our field in a study called MPA-REG-EXTEND, in which you have an additive effect on the A1c. And after a year and a half, instead of getting that 1% weight gain with pioglitazone alone, you have a reduction in body weight. So practical aspects to take home, start 15 milligrams, I mean, you're never going to get any serious side effect or weight gain with that and or combined with an SGLT2 inhibitor or GLP-1, I'll show you that, I avoid it if the patient is already obese or already have edema or they're high doses of insulin, which also already promotes weight gain and edema. Again, if you suspect heart failure, evaluate the patient. And there is bone loss in the long term, so you would like to examine this before treatment. And then just follow up with good clinical criteria. Typically after three or four months, I use up to 30 milligrams and now rarely use the higher dose because the efficacy of 30 and 45 is pretty comparable. We're going to switch in the last five minutes to GLP-1 receptor agonist and weight loss and two slides about, three slides about future drugs. So I like to put this because Dr. Patel-Chavez, a fellow who's just finishing in our program, and Dr. Cagliarella is a young faculty at the University of Florida, did this beautiful review. A very biased opinion, of course. Well, you see that lidaglutide has been the drug most tested with the effects that you're familiar with, but in the liver, it always reduces liver fat. But I wanted to bring to your attention this study that was published last year. We were one of the sides with Dr. Newsome, and basically, this is the message of the study. They used daily doses, the dose of .4 daily, is more or less like the obesity dose of 2.4 weekly. You see that almost 60% of the patient had a reduction in steatopatitis compared to 17% placebo. There was also a significant, but not statistically, a significant trend, but it didn't reverse fibrosis, but there was less progression. And again, if you combine semaglutide with pyoglitazine, this has been done in Sustane-2, you get an additive effect on A1c, you are able to lose weight, and most people can reach targets of their A1c without hypoglycemia and with weight loss. So this is really, really important. So this brings us to weight management. And again, this is all in the guidelines. Again, I'm gonna go quickly over this because of limited time, but again, we're talking about the importance of lifestyle changes, Mediterranean-based diet, the role of exercise. Very important, I wanna rule out, highlight the effect of alcohol. It's okay to have a drink in moderation, but when you begin having advanced disease, you probably need to avoid doing that. There was a wonderful presentation by Dr. Garvey about anti, about weight loss medications. So I know that that's something in, that you are very familiar with. But in NAS, what we do have proof from what I showed you with semaglutide, there's also a small study with lidaglutide, is that GLP-1 receptor agonists are a very, very attractive and efficacious approach. About pediatric surgery, there was also nice presentations. There is a nice presentation at the meeting, but the only point to remember is the following. You can treat people with bed serum with compensated cirrhosis if it's done at a tertiary center with experience, but it's not encouraged or discouraged, it should not be done in people with decompensated cirrhosis because the outcomes are not good and there's very limited experience. So that's the key measure, but I think we underutilize pediatric surgery overall. So remember GLP-1 receptor agonists. A word about, the guidelines have a word, have a little summary like this on hypertension. The thing to remember is be cautious in patient with cirrhosis. I don't think we have to say much more about that. The issues of volume are quite problematic in that population. And I put this slide, again, that just follows overall the ACE lipid lowering guidelines, but the point to be made is don't stop the statins in your patients with NASH. Now, if you have advanced decompensated cirrhosis, you probably, that's a good point to avoid them, and child puberty, C, you don't wanna use them, it's probably okay, but it's, again, controversial. But it's safe, it's in the early stages of cirrhosis. And again, you wanna be aggressive in the LDL lowering given their high cardiovascular risk, and you're familiar with the drugs that are there. So I'm just gonna move on to talk in the last two minutes about future targets. There are a number of drugs in the NASH field that are being developed. Some are trying to do what pioglitazone does without its side effects. There are a number of dual and even triple, TLP1 with other combinations. There are AMP kinase activator, the thyroid hormone receptor agonist, that this class has one of their compounds is in phase three, and many others, we can talk about it later. Just wanna bring to your attention that pan-PPAR, that's PPAR gamma alpha like pioglitazone, but also delta, that has some anti-inflammatory effects, has been the only compound among many tested that has reduced adipositis and reverse fibrosis, telling you about the importance of reversing insulin resistance and changing the biology of adipose tissue as a therapy that's successful for NASH. One word about tercepatide that is undergoing review for FDA approval in type two diabetes. Just focus on the right. Almost 50% reduction in liver fat. It is undergoing a large NASH trial and very promising in the field of NASH. This was just published two weeks ago with Dr. Gastaldelli. It's been, we published a number of studies over the years. And there's a GLP1 glucagon receptor agonist, called adutide, that has shown also improvements in liver enzymes with a weight loss greater than lead aglutide 1.8, but it's lower than tercepatide or high doses of semaglutide, but also undergoing a NASH trial. So to finish, this is a little summary. Lifestyle, the weight loss by any means works. GLP1 receptor agonist as weight loss agents and as agents that can treat diabetes and NASH. And pioglitazone, as we discussed. Unfortunately, our goal is to reverse cirrhosis, but it's in your hands to diagnose it early on. And we don't have any trial in patient with cirrhosis. So that's kind of a pending assignment. So with that, I'm gonna let you here, remember three things. High risk groups are the people you're seeing in your clinic. You are at the top of the battle to reverse NASH because guess what? The concentration of people with NASH in your clinics is twice as that in primary care or family medicine clinics. And then we just need to think a little bit of prevention of cirrhosis in the same way that we do for diabetic nephropathy or retinopathy. So with that, thank you very much for your attention and we'll be here. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. The question I have mainly is regarding the algorithm. I got a little confused because the algorithm says diabetes, obesity, and then elevated liver enzymes. But then when you talk about the ACE guidelines separately, it says diabetes and elevated liver enzymes. So is it like do I screen with FIP4 on all diabetic patients? Or is it diabetic patients with liver enzyme elevation? Because I got a little confused there. Go ahead. In both patients, both groups. But I think the thing to remember is that the liver enzymes can be normal and they can still have disease. So really, what we're recommending in the guidelines is all patients with type 2 diabetes should be screened with the FIP4. So all diabetic patients, obesity, pre-diabetes, everybody will need to be, that's actually something very radical change I would be doing in my practice then. So this is the thing. So you can have a lean person without risk factors to elevated liver enzymes. So that is something you need to look into. Or they can be in the three groups. But because people with diabetes, we just presented last week at a meeting in Barcelona the results of a screening in about almost 600 people. And in the endocrine clinics, 20% of your patients have moderate to advanced fibrosis. We're just missing it. It's higher than the rate of diabetic nephropathy. So we can do something to reverse that with a test that costs nothing. FIP4, we have FIP4 incorporated into our Epic electronic medical record. And we just click and it calculates. Or you can create a dot word for it and you can have it. And it's free. And it's not very sensitive. You'll still have people that might be low and you have some fibrosis. But it will catch everybody with a high number as needing more work. So it has high specificity, moderate sensitivity. Sure, so if I'm going to calculate the FIP4 score, how often do I need to do it? That's your last question. You will go back to the line if you have more. But we'll answer that because we don't know. So we say at least once a year. I mean, because the progression of fibrosis, people with type 2 diabetes had the fastest rate of progression. But it wouldn't happen sooner than two years to advance from one stage to the next. Okay, thank you. Thank you. Yes, sir. Thank you. So I have, can you comment about the, if you use vitamin E in treatment of the, of NASH or an FDL? Or the other thing is the coffee, how much coffee you recommend? Because there was a paper today in about this press who can increase your cholesterol. Is that right? Okay, me? Okay, so vitamin E, Piven's very good study showed benefit. So in people without diabetes, 800 units a day. In people without, with type 2 diabetes, we added it to pioglitazone, but it didn't add much. The debate with vitamin E is that it's been associated with increased cardiovascular disease and some metanosis and increase in prostate cancer. So again, it depends. If you have somebody with advanced liver disease, you will need to weigh what's more important at that stage. It's still controversial, but it is used. Coffee, again, there's a lot of papers about coffee. I think it's nice, but I don't think it will prevent you from getting cirrhosis if you have advanced disease. So it is the art of medicine. Thank you. Hey, thanks. Great talk. I actually had a kind of practical question. So we, at a VA that's near us, we use the FIB4 very regularly, and it's an older population, and we found that we over-screened almost. Is there a way to adjust? Because it feels like age drives up the risk factor, maybe disproportionately. Is there a way to adjust for that? Well, what happened, that's a great question. So if your age is 65 and over, people say instead of 1.3, take a cutoff of 1.9 or 2. So that's the thing. The problem with FIB4, we chose it, and not only us, other societies as well, because it's free or very inexpensive, but it has low sensitivity. So if you're in the gray zone, I would always recommend you do a second test, particularly if they're in the diabetes or the high-risk groups. But you can go up to two. That's based on the literature, and it's explained in the guideline. There's a reference there. Thank you. Yes. Hi there. Hi there. So I'm from India, and just a quick comment from my clinical practice. We're doing VCT along with the liver enzymes, and what we do see, frequently we see raised enzymes, which corresponds to the VCT score. So unlike your finding where you saw that the liver enzymes are quite low, we do get to see a lot of people coming in with very raised liver enzymes. Okay, that's a good point, and it might depend on the diet. So diets that are more enriched with carbohydrates, could it be, have higher propensity of NASH? Yeah, so I was just gonna say the visceral fat, the thin fat phenotype, probably is the reason. They come within the normal BMI zone, but probably because of the thin fat category, they have more visceral fat, and that might be the reason of a higher. Yeah, so elevated ALT is more a mark of inflammation and fat, AST more a mark of fibrosis. So the typical ALT is gonna be in the 40s to 60s, and the AST in the upper limit of normal. But you need to suspect NASH when the AST or ALT above 30. Okay, so. They're frequently over 30. Oh, good. Okay, well I'm worried about you, but I'm glad that you're doing something. Thank you. Thank you. Yes, sir. Marvelous presentation to all of you, it was great. And it's nice to see that there's light being shed on this very common disease state. So I think it's pretty straightforward. If you have type two diabetes, it's a no brainer that you should be using a GLP-1 receptor agonist because of the multiple attributes noted. But what if you do if you don't have diabetes and you have fatty liver disease? Now we're kind of like in a little bit of a conundrum because now we're using agents off label at this point in time. So I don't know if the guidelines really shed light on that dilemma. They do. I'll make a comment and like, yeah, because we discussed this a lot. So the weight loss indications of GLP-1 would get you covered from an FDA indication, right? The three milligram lead agglutide and the higher dose of semiagglutide under up to 2.4 milligrams. So you can treat with those under that label. Again, you wouldn't have the label of any other anti-diabetes medication because bioglutazone is not approved except for diabetes, but you can use the weight loss doses of those GLP-1s. And then just one follow-up question because you did show some really interesting data. And again, we've all known the benefits of the thiazolidinedione class for years, PPAR-gamma. Any data with PPAR-alpha? Yeah, they don't work. PPAR-alpha work great in mice, but PPAR-alpha does not change liver fat at all. And by the way, PPAR-delta is also being tested, a compound called siladelpar didn't work. And they've combined PPAR-alpha and delta, doesn't work. So you need some, a little bit of PPAR-gamma. But the curious thing, I'm sorry, is that rosiglitidone, that's a pure PPAR-gamma, does only changes fat, does not change steatopatitis or fibrosis. So it's PPAR-gamma plus PPAR-alpha. Very unclear to me and anybody, but that's what it is. Congratulations to all of you. Thank you. And sir, you are the last who will ask a question. And there's someone else, I think. Do you wanna ask question too? Well then, just last, you. Okay. I'm Marty Grajara from New York. A comment and a question. The comment is that in my experience, people are scared of their livers. I've had numerous patients where I've been after them for years to lose weight. They have diabetes, pre-diabetes. Once I diagnosed a fatty liver, suddenly they lost weight. And I would ask them, what changed? And they said, when you told me I had a fatty liver, it really shook me up. So as an endocrinologist, I wanna just comment to the audience, people are scared of their livers and that's another reason to make the diagnosis. My question is, there are no GLP receptors in the liver. So whoever wants to comment, do you think the benefit in fatty liver disease is purely weight loss or might there be some other mechanism? Well, yeah. So I participated actively in the semaglutide trial and I've looked at their data in terms of what is the mechanism. It turns out that it's mostly weight loss, but there might be something else that we don't know. You should know that there, like many studies have been, GLP-1s change the vagal tone and have some active effects on the hepatic glucose production, independent of any change in weight or anything, acute effects. So the bottom line is largely weight loss with something else that we don't know. Yes, our last but not the least question. Hang in there. We'll be here for more questions until 9 p.m. or something. Yeah. Thank you. A question for the panel is on the use of pioglitazone in women. We were talking about the risk of progressing to liver transplant and the question is with pioglitazone, and I think in IRIS, the risk was about two times increased for the risk of fractures. So what is the approach in postmenopausal women that have their OBs, fight a liver disease? What is your approach in terms of screening? What is the benefit of preventing a little bit? We don't have outcome data in terms of progression to cirrhosis or progression to HCC, or we don't have outcome data, but we have outcome data on fractures. So how do you balance that? Well, that's the art of medicine. Good point. So when I have a postmenop, first that the bone loss is in both men and women in the IRIS study, and it's about 50%. It was an older population who had had cerebrovascular accidents than the typical, but that doesn't matter. So what I do, I do a bone density at baseline and monitor it. So we published a paper out of three-year data that basically there was no bone loss with 45 milligrams over three years, but as we give them calcium and vitamin D, or we monitor that, and they didn't gain as much bone as the placebo arm. So I would recommend that you, if it's a postmenopausal women or a higher risk person, do a bone density at baseline and monitor that. So if the person has very advanced liver disease, the decision is easy. And if it's earlier disease, well, you'll have to balance things or make your choices, but it's dose dependent. So with 15 milligrams, it's unlikely you're gonna get, all the bone studies have been done with higher doses. Again, you need to, I think that's the pending real issue to monitor with TCDs. Thanks. I wanna thank all of you and our panel for a wonderful session. Thank you. Thank you.

non-alcoholic fatty liver disease

NAFLD

complications

non-alcoholic steatohepatitis

NASH

fibrosis

cirrhosis

cardiovascular disease

diagnostic tools

screening

lifestyle changes