Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Melanie Cole.

Welcome to UAB Medcast. I'm Melanie Cole. And joining me today to highlight metabolic dysfunction-associated steatotic liver disease, or MASLD, and diabetes is Dr. Fernando Bril. He's an endocrinologist with UAB Medicine. Dr. Bril, thank you so much for joining us today. I'd like you to start by telling us a little bit about this. What is metabolic dysfunction-associated steatotic liver disease? When did non-alcoholic fatty liver disease become known as MASLD and why?

Fernando Bril, MD: Thank you for the invitation. It's a pleasure being here. So, your question brings us to the story or the history of this condition. So, if you think about it, non-alcoholic fatty liver disease is a recently identified and described condition in 1980. That name was coined for the first time. And since then, only in 44 years, we've had two name suggestions or changes. One was MAFLD or metabolic dysfunction-associated fatty liver disease. But more recently, last year in December, there was a consensus where different providers got together and they decided that it was time to change the name from non-alcoholic fatty liver disease to this new name that we hope sticks now for a long time, metabolic dysfunction-associated steatotic liver disease.

And the reason for that name change are least two important ones. The first one, we didn't want a name that was based on the absence of something, right? We didn't want to call it non-alcoholic. We thought it was stigmatizing the word alcoholic, and this is a condition in itself. It's not just the absence of alcohol. And as we learn more about this condition, we realize that this is driven by something called insulin resistance that we are going to talk a little bit later on. But basically, this is a metabolic problem, so we wanted the word metabolic to be in the name. And the second reason I also alluded to is that we wanted to reduce stigmatization for patients. We thought that the word non-alcoholic was stigmatizing, but we also felt that the word fatty was stigmatizing. So, we changed it to steatotic, that means fat in your liver.

Melanie Cole, MS: So, it's a little harder to say, but certainly does reduce the stigma. And I hear you there. That's really an excellent explanation. Can you explain the pathophysiology a little bit of MASLD and how diabetes and MASLD are related?

Fernando Bril, MD: Yeah. MASLD or this long name of metabolic dysfunction-associated steatotic liver disease. We need to think of it as a systemic condition that although affects the liver, the problem happens all around your body. And the problem starts usually when we have increased adiposity. Patients are overweight or obese. So, there are adipose tissue, because it grows exponentially and the vessels cannot keep up, so the flow of blood and oxygen gets impaired, that adipose tissue becomes sick. So, patients that are overweight and obese usually have a dysfunctional adipose tissue. And by dysfunctional, I mean, that the adipose tissue does not respond to insulin the way it should. And because insulin usually suppresses lipolysis in the adipose tissue, if we have insulin resistance, then lipolysis, the breaking down of triglycerides, is increased, and there's an increased release of free fatty acids into the circulation. These free fatty acids will end up in most of the tissues and organs, but the liver has an enormous capacity of accumulating those free fatty acids in the form of triglycerides and other lipids, so we end up with this highly enriched liver with lots of lipids and fat, and that's what we call this MASLD condition. But remember, it all started with increased adiposity, and those free fatty acids are going everywhere, so we could be talking about a fatty kidney, a fatty heart, a fatty pancreas. But because the liver can accumulate so much and we can detect it easily in the clinical study, we talk about steatotic liver disease or what we used to call fatty liver disease.

In regards to your question about the relationship between steatotic liver disease and diabetes, insulin resistance, so this lack of response to insulin, it's kind of a common thing in both conditions, so patients with specifically type 2 diabetes, their main problem is that they have insulin resistance. And at the beginning, when have overweight and obese patients, they are able to keep up with insulin production, so not all patients that are overweight or obese have type 2 diabetes. But with time, that pancreas is unable to keep up with the demand of insulin production, and those patients start developing hyperglycemia and eventually what we call type 2 diabetes. So, insulin resistance is at the core of both fatty liver or MASLD and then type 2 diabetes. And then, it's also associated with a myriad of metabolic conditions like hypertension, dyslipidemia, PCOS, heart disease, kidney disease, et cetera.

Melanie Cole, MS: Dr. Bril, are we screening patients with MASLD for diabetes? Are we screening diabetes patients for this type of liver disease going back and forth? Does this screening happen naturally? Is it something that you would tell other providers it's a good idea to do? And then, does the presence of one or the other influence your treatment strategies?

Fernando Bril, MD: All very important questions. So, I already alluded to the fact that insulin resistance happens at the core of both. And then, once you have one, you are at increased risk of having the other one. So, if you do have a stetotic liver disease, then you're at risk of developing type 2 diabetes. Also, if you have stetotic liver disease and you have type 2 diabetes, usually your hyperglycemia is harder to control. And then, if you have type 2 diabetes, you are at really high risk of having fatD in your liver. So, yeah, it's kind of a bi-directional relationship when one gets the worst of the other one. And definitely, having both increases your risk of a cardiovascular disease and other complications.

So, yes, we should be screening for diabetes in patients that have a fatty liver. But now, what guidelines tell us in patients that have diabetes, and this goes even beyond type 2 diabetes, when do we need to screen for this liver disease, and how do we need to screen for this liver disease. And the important thing is that because in obesity and type 2 diabetes, the prevalence of this metabolic dysfunction-associated steatotic liver disease is so common. So, MASLD is so common in obesity and type 2 diabetes, around 60-70% of patients have it. We don't necessarily need to screen for it, but as this liver disease progresses, patients can develop liver fibrosis and eventually cirrhosis or hepatocellular carcinoma. So, what guidelines recommend is that we need to screen for the presence of liver fibrosis, because that's what will determine how fast your liver disease will progress. It also predicts pretty well your overall mortality.

So, guidelines recommend us that, if you have prediabetes or diabetes, to screen for liver fibrosis and we do that by means of a FIB-4 index, which sounds complicated, but it's actually a calculation that it's based on ALT, AST, age, and platelets, and we oftentimes order these. We just don't take the 20 seconds that takes going into any online calculator or there are apps for it where you can just put those numbers for ALT, AST, platelets, and age, and you get the result of a FIB-4. And if that's over 1.3, that should raise suspicion that there may be some liver fibrosis, and there is a whole algorithm to follow after that, which involves a second non-invasive test before you decide what to do with a patient. And if it's below 1.3, that FIB-4, then you can feel relieved that that patient is at low risk of liver fibrosis, and you can just repeat that FIB-4 every year. And as long as it remains below 1.3, the chances of liver fibrosis are pretty low.

Melanie Cole, MS: Dr. Bril, tell us some of the current treatment guidelines for managing MASLD and diabetes and how the treatments for one or the other and the pharmacologic treatments for type 2 diabetes that we know that we're learning more and more about as we go how they impact one or the other.

Fernando Bril, MD: The field of treatment for MASLD has changed dramatically in the last few years, so we used to tell everyone, "Well, we don't have any FDA drug approved specifically for this condition," and that's no longer true. The first drug became available in March of this year. But regardless of that FDA-approved medication, we also have many medications that we use in the field of type 2 diabetes that we can use for patients with MASLD, especially if they have some liver fibrosis, so several medications that we have to have in mind.

So, a little bit of how to think about these patients and how we are going to treat them, I would say if patient is obese, or if they have type 2 diabetes, they probably already have an indication for a GLP-1 agonist. The ones that have the highest degree of evidence in MASLD are probably semaglutide and tirzepatide. The results of the tirzepatide study on improvement in histology were just released last month showing improvement in both metabolic dysfunction-associated steatohepatitis, or MASH, which is the subgroup of patients that have inflammation in the liver already. That study also showed that tirzepatide improved liver fibrosis.

So, we have evidence that GLP-1 agonists with or without the GIP agonism, either semaglutide or tirzepatide, both help patients that have a steatotic liver disease. pioglitazone is an old medication that has become generic years ago, that also has very strong evidence that helps with resolution of MASH, this form of the disease with inflammation and necrosis. And some meta-analysis also suggesting improvement in liver fibrosis with pioglitazone.

SGLT2 inhibitors, we still don't have evidence that they help with histology in this disease, so no improvement of mass or liver fibrosis that we know of, just because the studies have not been done, but there are several studies suggesting that fat comes down, based on magnetic resonant imaging studies, so they can be safely used in patients with diabetes that have fatty liver. And then, this new medication is not from the diabetes world. It's called resmetirom. It's a thyroid mimetic, but it's very specific for the liver and it shows resolution of MASH and also improvement in liver fibrosis. So, there is a subgroup of patients with fatty liver that have at least stage II or III of fibrosis that could benefit from that medication as well. So as you can see, several options that we need to consider when we are in front of these patients.

Melanie Cole, MS: What an exciting time with so many advancements. How important is the multidisciplinary care in managing patients with MASLD and diabetes together? And tell us a little bit about your team and the many practitioners that are involved, because we're looking at hepatologists and primary care and nutritionists and exercise specialists. And I mean, there's so many people, because there are lifestyle and management behavior things to take care of as well, yes?

Fernando Bril, MD: Yeah. So, this is a team effort for sure. So, these are patients that may come to your clinic, just because they have a fatty liver or just because they have type 2 diabetes. But once you start looking, you see that with this insulin resistance comes all the problems that I mentioned. So, we need a team approach that involves all the providers and more. So, all the ones you mentioned, but even more. So, we need to think do these patients have heart failure because of the degree of obesity they have. We need to focus on their diet. We need to weigh in whether they may need bariatric surgery when they come with really elevated BMI, so we may need to involve surgeons as well. So, yeah, this is definitely a team's approach. The hepatologists are looking at the liver. Endocrinologists, we are paying more attention to type 2 diabetes. Nephrologists are paying attention to the kidney, cardiologists to the heart and so on. But at the end of the day, these are patients that have increased adiposity, insulin resistance, and then everything is getting out of whack, but we need to hit at the core. We need to try to have better communication between the different providers so that we have medications that can work at different conditions, right? So, we have the GLP-1s that recently showed that they have nephroprotection, so they improve kidney disease. We already know that they work for heart failure with preserved ejection fraction.

For SGLT2 inhibitors, we know they have an indication in heart failure. We know they have an indication in chronic kidney disease, obviously in type 2 diabetes. So, these are medications that all providers are using. We just need to improve communication. And If we move on to lifetime intervention, this definitely needs a team approach because it's hard to change habits. It's difficult for patients to achieve their goals with weight loss, especially if we don't get a coverage for medication, so we need to have a very good team approach to try to improve lifetime intervention.

Melanie Cole, MS: What an informative episode this was, Dr. Bril. You're a great educator. As we wrap up, what advice would you give clinicians who are just starting to treat patients? patients with MASLD and diabetes together. What would you like the key takeaways to be?

Fernando Bril, MD: Yeah. I think the main point is that this is highly prevalent, that it's a progressive disease, and that although most patients with type 2 diabetes and fatty liver are likely going to die of cardiovascular disease, some percentage will have liver disease. And we see that because we get patients with cirrhosis already or needing a liver transplant. So, we need to consider the potential damage to the liver. We need to be really aggressive treating cardiovascular risks in these patients because, as I said, most of these patients die of cardiovascular disease. So, using aggressively the statins, even if liver enzymes are slightly elevated, in patients with fatty liver, we know that liver enzymes tend to come down even after starting statins or at least they don't get worse.

And then, early diagnosis and early treatment is key. So, the role of primary care physicians is to screen for liver fibrosis. As I said, with a FIB4, and then eventually, if it's 1.3 or higher, to consider a second non-invasive test, and then referral when this needs to happen, and considering medications that primary carers are very familiar with, like GLP-1s to treat obesity and type 2 diabetes, or STLT2s to treat type 2 diabetes, pioglitazone to treat type 2 diabetes that they probably also work for fatty liver.

Melanie Cole, MS: Thank you so much, Dr. Bril, for joining us today and sharing your incredible expertise for our listeners. And for more information, please visit our website at uabmedicine.org/physician. That concludes this episode of UAB Medcast. I'm Melanie Cole.