Selected Podcast
Nonalcoholic Fatty Liver Disease
Kenneth Cusi, MD, FACP, FACE, joins the show to help us to understand the mechanisms leading to NAFLD and the role of obesity and type 2 diabetes mellitus (T2DM). He shares the diagnostic difficulties regarding NAFLD and he reviews current treatment modalities and future developments in the field.
Featuring:
Kenneth Cusi, MD
Kenneth Cusi, M.D., F.A.C.P., F.A.C.E. is a Professor of Medicine, on Staff, Malcom Randall VAMC and Chief, Division of Endocrinology, Diabetes and Metabolism.
Transcription:
Melanie Cole: Welcome to USF health med ed cast with USF health Shands hospital. I'm Melanie Cole, and I invite you to listen. As we discuss non-alcoholic fatty liver disease, the overlooked complication of obesity and type two diabetes. Joining me is Dr. Kenneth KUSI. He's a professor and chief in the division of endocrinology, diabetes, and metabolism in the department of medicine at the university of Florida.
He practices at USF health Shands hospital and is on staff at the Malcolm Randall VA medical center in Gainesville, Florida. Dr. KUSI. It's a pleasure to have you join us again today. Tell us a little bit about non-alcoholic fatty liver disease. What's the prevalence and what are you seeing in the trends?
Kenneth Cusi, MD (Guest): Well, thank you, Melanie. Again, it's always a pleasure be part of your program. Well, and again, we're really excited also and worried because the epidemic has been growing since the last time we spoke last year, I mean, we were able to publish a study showing that the problem is bigger than we anticipated. But what it is, is basically in the setting typically of individuals being overweight or obese or having type 2 diabetes, the liver tends to collect more triglycerides, more fat than we appreciated. And we didn't think that this was a main problem, but now we know it damages the liver. Causes scarring and fibrosis of the liver and is the number one cause of liver transplantation in the United States. So we think we need to be very proactive in identifying these patients early on and treating them.
Host: Thank you so much, Dr. Cusi. So, expand a little more for us on the importance for PCPs and endocrinologists in identifying early patients with non-alcoholic fatty liver disease.
Dr. Cusi: Well, that is really the key question. So thank you, Melanie. I mean, what happens is that in the majority of people who are overweight or obese, and particularly if they have type 2 diabetes or there's a family history of fatty liver disease, they have insulin resistance. In other words, their body doesn't respond normally to insulin. And the problem is that with excess weight, that adipose tissue behaves in an abnormal way. And it does not hold on to the stores of energy of fat that you have and to release it into your circulation. And this fat finds a home in tissues that are very poorly adapted to this fat. So, the liver collects fat. The hepatocytes, the liver cells feel that this is toxic to them. They send signals that activate this scarring, this fibrosis. Now the real problem is that we know now that if you screened for fatty liver disease, every individual with diabetes or obesity between half to 70% of people have too much fat in the liver.
And we have looked at that. The real problem is when this inflammation gets started, which we call steatohepatitis, a hepatitis induced by fats, steato in Latin is fat. And when that happens, you go down a path of fibrosis, okay. So, primary care doctors are at the forefront of this. They take care of 90% of the patients with obesity and diabetes, they have been proactive identifying complications, like eye disease, kidney disease in people with diabetes. And that's why the rates of those complications have decreased in the recent decades. But now it's time to add this to the list of things that they have to look at. And there's simple ways to do that. So, primary care doctors and also endocrinologists that deal with more complicated patient with diabetes should be doing this. And there is a big movement in that direction.
Host: Well then let's stand the mechanisms that lead to non-alcoholic fatty liver disease and the role of obesity and type 2 diabetes. Why is diabetes such a major risk factor? Explain a little bit about those mechanisms of progression.
Dr. Cusi: Well, as I said, one mechanism is that when you're overweight or obese, that excess adipose tissue is sick. Adipose tissue normally it serves as a reserve of excess energy for times in between meals. So, overnight we break down some of that fat those triglycerides into free fatty acids that feed muscles and all tissues of the body. But when you're overweight and obese and have insulin resistance or the metabolic syndrome, this release of energy happens around the clock. And then other tissues get bombarded with this. And this affects the normal metabolism of the person leading to fat accumulation.
Also it promotes the liver to make more fat. And what we know is that when the liver cells are distressed, they begin working in trying to repair this, and on a chronic basis, it does lead to progressive cirrhosis. So, just for primary care doctors who may be listening, out of 10 individuals that are obese or have type 2 diabetes, now we know six or seven have too much fat in the liver and they qualify for the definition of non-alcoholic fatty liver disease. About half of them have the inflammation component, what we call steatohepatits. So about 30%, three out of 10, and advanced fibrosis, the degree of fibrosis that we know left alone will lead to cirrhosis, happens in about one or two out of 10 patients.
That's a lot of people. Think that we have 30 million individuals with type 2 diabetes in the country. So, that means, you know, 20% of that, we have five, 6 million people who are heading to cirrhosis unless our primary care doctors and endocrinologists identify them beforehand, where we can do something about it.
Host: Wow. It's quite a statistic, Dr. Cusi. So, what do you want doctors to do? How should they screen for this and what are some of the diagnostic difficulties regarding it?
Dr. Cusi: That's a - every challenge comes with an opportunity, man. Good words of wisdom there? So, I think that what we have to do is begin thinking about it, because again, you'll never going to diagnose something that it's not in your mind. So first step, remember that your individuals that are overweight or obese or have type 2 diabetes are at risk of fatty liver disease. Second thing, we typically have looked at liver enzymes, but the cutoffs for liver enzymes that we use are high, are 40 international units per liter for AST or ALT. We need to lower those down to 20 in women and 30 in men. So, above those numbers, we begin having, knowing that there's too much fat in the liver. There's also a very simple biomarker or diagnostic panel better said called FIB-4, F-I-B-4, and it is because it's made out of four.
It's a fibrosis index, and it's based on four tests, the AST, ALT a, which are the liver enzymes we most commonly measure. Age and platelets. So, you just type in any web browser, FIB-4, and it gives you a calculator and that helps you start with assessing what the risk of that individual is. If that is above a number, we call 1.3, that person can be at risk. And if it's 2.6 twice that number, it is very, very likely that person already has cirrhosis. So, the second diagnostics test to do is an imaging study. So, we can do in the clinic, what we call elastography the most commonly used by hepatologists called FibroScan, like fibrosis scan, but FibroScan.
And then if you don't have it in your clinic, you can order it. Then get the result by the next visit and between those two tests, you will probably be in a good place to detect 90% of the patients that need to be seen by a liver doctor.
Host: Wow. So, then let's talk about some of the current treatment modalities and thank you so much for telling us about screening, but what is the role of available diabetes medications? Tell us how those all go together.
Dr. Cusi: That's a great point. So, once you have a patient with elevated liver enzymes, elevated FIB-4 or imaging suggestive of high fibrosis, then you typically would bring in the liver doctor who would do a further evaluation and some of them will require a liver biopsy. Others may be ruled out of not needing it, but if the patient has NASH with fibrosis, you know, with this scarring, there are A, lifestyle, weight loss of about five to 10% reduces the inflammation and may even improve the risk of fibrosis and cirrhosis, bariatric surgery does the same thing or one diabetes medication that has been studied the most is pioglitazone known in the past as Actos. This is a very inexpensive medication. It's a generic now, should cost less than five to 10 dollars, the generic in any regular pharmacy. And about 50% to 60% of patients have a complete resolution of that inflammation. And there can be a modest improvement in fibrosis. So, that is the drug that has been recommended in the current liver guidelines and guidelines across many countries and societies. And that should be the first choice. Another choice is a drug that, we've published three papers on pioglitazone and others have done similar studies.
The other option is an injectable medication called semaglutide, which is the brand name is Ozempic. That's a weekly formulation. We participated in a study that was published in the New England Journal of Medicine on November 13th of 2020, and we showed that again between 40 to 60%, almost 60% of patients, 59% of the patients with the higher dose had a complete reversal of the inflammation.
Although the scarring didn't get much better. The progression over the 72 weeks of the study was less with that medication. Now, the only thing is that we should clarify to the audience, none of these drugs are FDA approved to treat NASH. There are no FDA approved drugs, but if you're treating somebody with diabetes, these medications are available to treat diabetes. So again, those are the two main options. In addition to of course, to lifestyle weight loss that can improve, not only the liver disease, but diabetes, blood pressure, lipids, you know,
Host: Well, thank you for telling us about lifestyle, because that would have been my next question and this potential for disease co-management, which I think is going to be such an important part. And as we look to the future, Dr. Cusi, tell us what you see as future directions and developments in this field. What are you excited about?
Dr. Cusi: Well, I'm excited about number one, primary care doctors are now realizing their key role in preventing cirrhosis, and they can do it in a very simple way. So, that has been very exciting because now we know from the success that primary care has had in decreasing diabetes complications, that the same can be done with the liver complications. So, that's exciting. I'm also excited that we have relatively inexpensive medication like pioglitazone to do this. And typically I tell them, start with the lowest dose, 15 milligrams, and then you bump it up to the intermediate dose of 30 milligrams. I'm also excited that there are a number of new drugs in the pipeline that are going to help us treat these patients.
I can say that a lot, about 30 medications that are being tested in phase two and a few in phase three that will become available in the next two to three years. So, in the meantime, we can't let our patients drift into cirrhosis. Do them a favor. Pay attention to fatty liver disease, do these simple tests to make a diagnosis. And you can really save a life. I've identified many patients, and I've seen the difference between patients at the end of the road with cirrhosis and decompensated cirrhosis needing a liver transplant and those who have been stable for more than 10 years, because we identify them in time. And thank you, Melanie, because this time may have saved somebody who will do that for a patient or a neighbor or a family member. So, this is a great opportunity.
Host: Thank you so much, much Dr. Cusi. What a wonderful thing to say. And I can hear the passion in your voice for the great work that you're doing. Thank you again for joining us today. And to refer your patient, to UF Health Shands hospital, please visit usfhealth.org/medmatters to get connected with one of our providers and to listen to more podcasts from our experts.
That concludes today's episode of USF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.
Melanie Cole: Welcome to USF health med ed cast with USF health Shands hospital. I'm Melanie Cole, and I invite you to listen. As we discuss non-alcoholic fatty liver disease, the overlooked complication of obesity and type two diabetes. Joining me is Dr. Kenneth KUSI. He's a professor and chief in the division of endocrinology, diabetes, and metabolism in the department of medicine at the university of Florida.
He practices at USF health Shands hospital and is on staff at the Malcolm Randall VA medical center in Gainesville, Florida. Dr. KUSI. It's a pleasure to have you join us again today. Tell us a little bit about non-alcoholic fatty liver disease. What's the prevalence and what are you seeing in the trends?
Kenneth Cusi, MD (Guest): Well, thank you, Melanie. Again, it's always a pleasure be part of your program. Well, and again, we're really excited also and worried because the epidemic has been growing since the last time we spoke last year, I mean, we were able to publish a study showing that the problem is bigger than we anticipated. But what it is, is basically in the setting typically of individuals being overweight or obese or having type 2 diabetes, the liver tends to collect more triglycerides, more fat than we appreciated. And we didn't think that this was a main problem, but now we know it damages the liver. Causes scarring and fibrosis of the liver and is the number one cause of liver transplantation in the United States. So we think we need to be very proactive in identifying these patients early on and treating them.
Host: Thank you so much, Dr. Cusi. So, expand a little more for us on the importance for PCPs and endocrinologists in identifying early patients with non-alcoholic fatty liver disease.
Dr. Cusi: Well, that is really the key question. So thank you, Melanie. I mean, what happens is that in the majority of people who are overweight or obese, and particularly if they have type 2 diabetes or there's a family history of fatty liver disease, they have insulin resistance. In other words, their body doesn't respond normally to insulin. And the problem is that with excess weight, that adipose tissue behaves in an abnormal way. And it does not hold on to the stores of energy of fat that you have and to release it into your circulation. And this fat finds a home in tissues that are very poorly adapted to this fat. So, the liver collects fat. The hepatocytes, the liver cells feel that this is toxic to them. They send signals that activate this scarring, this fibrosis. Now the real problem is that we know now that if you screened for fatty liver disease, every individual with diabetes or obesity between half to 70% of people have too much fat in the liver.
And we have looked at that. The real problem is when this inflammation gets started, which we call steatohepatitis, a hepatitis induced by fats, steato in Latin is fat. And when that happens, you go down a path of fibrosis, okay. So, primary care doctors are at the forefront of this. They take care of 90% of the patients with obesity and diabetes, they have been proactive identifying complications, like eye disease, kidney disease in people with diabetes. And that's why the rates of those complications have decreased in the recent decades. But now it's time to add this to the list of things that they have to look at. And there's simple ways to do that. So, primary care doctors and also endocrinologists that deal with more complicated patient with diabetes should be doing this. And there is a big movement in that direction.
Host: Well then let's stand the mechanisms that lead to non-alcoholic fatty liver disease and the role of obesity and type 2 diabetes. Why is diabetes such a major risk factor? Explain a little bit about those mechanisms of progression.
Dr. Cusi: Well, as I said, one mechanism is that when you're overweight or obese, that excess adipose tissue is sick. Adipose tissue normally it serves as a reserve of excess energy for times in between meals. So, overnight we break down some of that fat those triglycerides into free fatty acids that feed muscles and all tissues of the body. But when you're overweight and obese and have insulin resistance or the metabolic syndrome, this release of energy happens around the clock. And then other tissues get bombarded with this. And this affects the normal metabolism of the person leading to fat accumulation.
Also it promotes the liver to make more fat. And what we know is that when the liver cells are distressed, they begin working in trying to repair this, and on a chronic basis, it does lead to progressive cirrhosis. So, just for primary care doctors who may be listening, out of 10 individuals that are obese or have type 2 diabetes, now we know six or seven have too much fat in the liver and they qualify for the definition of non-alcoholic fatty liver disease. About half of them have the inflammation component, what we call steatohepatits. So about 30%, three out of 10, and advanced fibrosis, the degree of fibrosis that we know left alone will lead to cirrhosis, happens in about one or two out of 10 patients.
That's a lot of people. Think that we have 30 million individuals with type 2 diabetes in the country. So, that means, you know, 20% of that, we have five, 6 million people who are heading to cirrhosis unless our primary care doctors and endocrinologists identify them beforehand, where we can do something about it.
Host: Wow. It's quite a statistic, Dr. Cusi. So, what do you want doctors to do? How should they screen for this and what are some of the diagnostic difficulties regarding it?
Dr. Cusi: That's a - every challenge comes with an opportunity, man. Good words of wisdom there? So, I think that what we have to do is begin thinking about it, because again, you'll never going to diagnose something that it's not in your mind. So first step, remember that your individuals that are overweight or obese or have type 2 diabetes are at risk of fatty liver disease. Second thing, we typically have looked at liver enzymes, but the cutoffs for liver enzymes that we use are high, are 40 international units per liter for AST or ALT. We need to lower those down to 20 in women and 30 in men. So, above those numbers, we begin having, knowing that there's too much fat in the liver. There's also a very simple biomarker or diagnostic panel better said called FIB-4, F-I-B-4, and it is because it's made out of four.
It's a fibrosis index, and it's based on four tests, the AST, ALT a, which are the liver enzymes we most commonly measure. Age and platelets. So, you just type in any web browser, FIB-4, and it gives you a calculator and that helps you start with assessing what the risk of that individual is. If that is above a number, we call 1.3, that person can be at risk. And if it's 2.6 twice that number, it is very, very likely that person already has cirrhosis. So, the second diagnostics test to do is an imaging study. So, we can do in the clinic, what we call elastography the most commonly used by hepatologists called FibroScan, like fibrosis scan, but FibroScan.
And then if you don't have it in your clinic, you can order it. Then get the result by the next visit and between those two tests, you will probably be in a good place to detect 90% of the patients that need to be seen by a liver doctor.
Host: Wow. So, then let's talk about some of the current treatment modalities and thank you so much for telling us about screening, but what is the role of available diabetes medications? Tell us how those all go together.
Dr. Cusi: That's a great point. So, once you have a patient with elevated liver enzymes, elevated FIB-4 or imaging suggestive of high fibrosis, then you typically would bring in the liver doctor who would do a further evaluation and some of them will require a liver biopsy. Others may be ruled out of not needing it, but if the patient has NASH with fibrosis, you know, with this scarring, there are A, lifestyle, weight loss of about five to 10% reduces the inflammation and may even improve the risk of fibrosis and cirrhosis, bariatric surgery does the same thing or one diabetes medication that has been studied the most is pioglitazone known in the past as Actos. This is a very inexpensive medication. It's a generic now, should cost less than five to 10 dollars, the generic in any regular pharmacy. And about 50% to 60% of patients have a complete resolution of that inflammation. And there can be a modest improvement in fibrosis. So, that is the drug that has been recommended in the current liver guidelines and guidelines across many countries and societies. And that should be the first choice. Another choice is a drug that, we've published three papers on pioglitazone and others have done similar studies.
The other option is an injectable medication called semaglutide, which is the brand name is Ozempic. That's a weekly formulation. We participated in a study that was published in the New England Journal of Medicine on November 13th of 2020, and we showed that again between 40 to 60%, almost 60% of patients, 59% of the patients with the higher dose had a complete reversal of the inflammation.
Although the scarring didn't get much better. The progression over the 72 weeks of the study was less with that medication. Now, the only thing is that we should clarify to the audience, none of these drugs are FDA approved to treat NASH. There are no FDA approved drugs, but if you're treating somebody with diabetes, these medications are available to treat diabetes. So again, those are the two main options. In addition to of course, to lifestyle weight loss that can improve, not only the liver disease, but diabetes, blood pressure, lipids, you know,
Host: Well, thank you for telling us about lifestyle, because that would have been my next question and this potential for disease co-management, which I think is going to be such an important part. And as we look to the future, Dr. Cusi, tell us what you see as future directions and developments in this field. What are you excited about?
Dr. Cusi: Well, I'm excited about number one, primary care doctors are now realizing their key role in preventing cirrhosis, and they can do it in a very simple way. So, that has been very exciting because now we know from the success that primary care has had in decreasing diabetes complications, that the same can be done with the liver complications. So, that's exciting. I'm also excited that we have relatively inexpensive medication like pioglitazone to do this. And typically I tell them, start with the lowest dose, 15 milligrams, and then you bump it up to the intermediate dose of 30 milligrams. I'm also excited that there are a number of new drugs in the pipeline that are going to help us treat these patients.
I can say that a lot, about 30 medications that are being tested in phase two and a few in phase three that will become available in the next two to three years. So, in the meantime, we can't let our patients drift into cirrhosis. Do them a favor. Pay attention to fatty liver disease, do these simple tests to make a diagnosis. And you can really save a life. I've identified many patients, and I've seen the difference between patients at the end of the road with cirrhosis and decompensated cirrhosis needing a liver transplant and those who have been stable for more than 10 years, because we identify them in time. And thank you, Melanie, because this time may have saved somebody who will do that for a patient or a neighbor or a family member. So, this is a great opportunity.
Host: Thank you so much, much Dr. Cusi. What a wonderful thing to say. And I can hear the passion in your voice for the great work that you're doing. Thank you again for joining us today. And to refer your patient, to UF Health Shands hospital, please visit usfhealth.org/medmatters to get connected with one of our providers and to listen to more podcasts from our experts.
That concludes today's episode of USF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.