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Melanie Cole (Host):  This is UF Health MedEd Cast with UF Health Shands Hospital. I’m Melanie Cole. And today, we’re discussing treating nonalcoholic fatty liver disease in patients with type 2 diabetes. We’re going to cover how fatty liver impacts the care of every patient with obesity, type 2 diabetes and cardiovascular disease. We’re going to discuss how to identify and incorporate into patient care, the latest information on the diagnosis and treatment of nonalcoholic fatty liver disease and the latest advances in medicational developments coming in 2020. Joining me is Dr. Kenneth Cusi. He’s a Professor and Chief of the Division of Endocrinology, Diabetes and Metabolism in the Department of Medicine at the University of Florida and he practices at UF Health Shands Hospital. Dr. Cusi, it is a pleasure to have you join us today. Tell us a little bit about nonalcoholic fatty liver disease. What’s the incidence and burden of this disease?

Kenneth Cusi, MD, FACP, FACE (Guest):  This is really the next frontier in the management of many patients who are overweight or have obesity or type 2 diabetes. We’ve not identified this problem before because we didn’t have the tools we have today. And we didn’t understand that this is something that really applies to many, many patients we see in clinic. So, asking what the prevalence is, is the key question to know the magnitude of the problem. And the data is just emerging. Most recent studies suggest that about one out of four Americans may have a fatty liver. And some groups are particularly affected like in obesity; we think that it is more like one in two and in type 2 diabetes; we think it is two our of three. So, these are very common problems and just now we are beginning to see an epidemic of cirrhosis and the consequences of this.

Host:  So interesting and obviously so prevalent. Dr. Cusi, when people have nonalcoholic fatty liver disease, tell us a little bit about comorbid conditions. You mentioned obesity and diabetes. Do these come together? Is there a causal relation between the two?

Dr. Cusi:  Absolutely. That’s a great question. Because the fundamental defect is insulin resistance so, if you are overweight or obese; you don’t have only an increased fat mass, but this adipose tissue is very dysfunctional, very abnormal. One of the things that it does, it releases fat from those cells, from the fat cells to other parts of the body. Today, we’re talking about liver. The liver is very ill-prepared to absorb this amount of fat coming from the bloodstream to the liver and it begins accumulating fat and it also makes more lipids that it has to because of insulin resistance. This triggers inflammation in the liver, liver cell death and in the end, a chronic state of inflammation that triggers what we technically call fibrosis. And again, over time, this is going to lead to cirrhosis and in some cases even hepatocellular carcinoma.

So diabetes and obesity share this bottom line problem of insulin resistance. The only difference between somebody with type 2 diabetes and somebody without diabetes but that is equally overweight or obese is the person with type 2 diabetes is unable to make enough insulin to compensate for this decreased response of the body to insulin. But they are both at a great risk of NASH, inflammation and cirrhosis. So, this is a key thing.

The other observation has been cardiovascular disease. I mean has this been an issue that has been brought up to you by other providers?

Host:  Well it certainly has and for other providers, as we are understanding how the fatty liver impacts the care of every patient with obesity, type 2 diabetes and also related comorbid conditions of cardiovascular disease. So, help us to understand if you are working with someone that has type 2 diabetes and is obese and where cardiovascular disease also contributes to NASH and to NAFLD.

Dr. Cusi:  So, what we think happens is that when you accumulate fat in the liver, just think of the liver and providers need to think of the liver as a mirror of your metabolic health. Whether you are lean, overweight or obese; if you accumulate fat in the liver and there are lean patients that I have that are nonobese and that means that you are insulin resistant. A big component can be just the genes you inherited from mom and dad. But a great part is the acquired component of obesity.

So, nonobese or even lean individuals with NASH have bad genes and their body adapts poorly to a state of insulin resistance because insulin resistance doesn’t depend only on being obese. It’s a genetic defect that we don’t fully understand. But when you add obesity and lack of physical activity; you are exacerbating that background. So, in other words, why does this link obesity, diabetes and cardiovascular disease is because a number of metabolic abnormalities happen. Among them for example you tend to have this typical high triglyceride, low HDL and increased small density LDL that is very well known to cause cardiovascular disease, it also exacerbates hypertension, it exacerbates chronic kidney disease. So, there are many, many factors that have linked now the people that tend to have a high degree of cardiovascular risk, tend to have more fat in the liver and more fatty liver and what we call steatohepatitis or NASH which is when that fat is going to lead to inflammation and scarring or fibrosis of the liver.

Host:  That is so interesting and Dr. Cusi please tell us the gold standard for diagnosing it. help us to identify and help other providers incorporate into patient care the latest information on the diagnosis of nonalcoholic fatty liver disease.

Dr. Cusi:  This is the great dilemma the field has. We know it’s out there, but we don’t have a very good way to diagnose it as we have for dyslipidemia or an A1C for diabetes. It’s a more complex problem. That’s we have gone so far within 20 or 30 years of an epidemic of obesity and an epidemic of diabetes and just now we are beginning to see a lot of people with cirrhosis and needing a liver transplant. It has just been under our radar because the way we tended to think that you had a problem in the liver is when your liver enzymes are up. But many times, I would say even half of the time, you still have a fatty liver and you can have significant NASH when you have liver enzymes that are below the clinical cut off of 40.

So, what do I mean with this? first it’s important to again, people understand a distinction between fatty liver without inflammation, it’s called simple steatosis and when this fat in the liver is associated with inflammation in the liver and fibrosis; that is NASH, nonalcoholic steatohepatitis. Of course, number one, is a good history. You need to tule out alcohol abuse. You need to rule out other medications. You need to rule out other medical conditions that can be associated like hemochromatosis or others. So, once you ruled that out; now we are basically in a diagnosis of exclusion. How can we know that this elevated liver enzyme which is the easiest way to diagnose it is associated with is really NASH.

So, you could do an ultrasound to document that you have fatty liver. Or there are some techniques now that use elastography to see if there is fibrosis or scarring in the liver. Getting back to your question, if you are in the primary care setting; the low hanging fruit is if you see anybody with liver enzymes, not above 40, just even when they are above 30 international units; that’s when you have to begin thinking about a fatty liver. And this is what the American Diabetes Association came up in 2019 for the first time in the history of the ADA to begin thinking of this.

So, if you have a patient that has diagnosis of steatosis because he had a CT scan, or an MRI done for any reason; or elevated alanine aminotransferase or ALT; now you have to get to the second step. The second step is to answer if the patient has fibrosis because that’s what’s going to cause cirrhosis. Is this more or less clear or literally confusing?

Host:  No, it’s absolutely clear and based on what you’re saying Dr. Cusi, and given that strong association between nonalcoholic fatty liver disease, NASH and cardiometabolic risk factors; how do you for other providers currently treat this? Tell us about some treatments and is there now as of now, a definitive pharmacologic therapy that’s been approved for treatment? Tell us a little bit and if not, what should it include?

Dr. Cusi:  There are some imaging techniques to confirm that this person may have NASH. One is transient elastography, the most common used tool by liver doctors is FibroScan. There are others that are used too or MRI but it’s a more expensive thing. It’s important, because the treatment is very, very straightforward. If you lose weight by five percent, you begin melting down the fat. If you lose eight to ten percent; you can get rid in most of the patients, the inflammation and even of the fibrosis. And that might take in some patients anti-obesity medications, it might take the need of bariatric surgery. But weightloss is cornerstone. Now there are no FDA approved drugs but there are medications particularly used for diabetes that can work now.

There’s a medication called pioglitazone Actos that has been approved now for about almost 20 years that has shown in five randomized controlled trials to reduce by two thirds the chance of NASH progressing, and it causes resolution of NASH in about half the patients. Now pioglitazone also lowers the glucose, improves the lipids and has shown in studies to reduce cardiovascular disease. So, it’s a good approach to treat both the diabetes and NASH. Although it’s not FDA approved for it.

The other approaches are medications that help lose weight. For example, the group of drugs known as GLP1 receptor agonists. There are several out there. Liraglutide is the only one that has shown in a study to be effective in NASH. There are others that are being tested but again, the benefit appears to be proportional to weightloss. And finally, in people without diabetes, vitamin E at doses of 800 units a day has shown to have some benefit. But still, these drugs are under utilized in part because we’re not diagnosing the patients, in part because doctors don’t know that you can reverse NASH and in part because people think that the side effects are too significant. But this is just a misconception. Still many people think that pioglitazone is the same as rosiglitazone, but pioglitazone reduces cardiovascular risk. There was also some talk about causing bladder cancer but now a team of 23 studies have been negative, so we believe it is pretty safe. We anyway do a urinalysis before starting.

And then the weight gain is proportional to the overall management. So, if you start with 15 milligrams of pioglitazone per day, there’s basically one percent weight gain at the most. And at the 30 milligram which is the dose most frequently that I use, the weight gain is two or three percent. Again, if you follow with a nutritionist in a multidisciplinary approach, weight gain can be mitigated.

Host:  Absolutely and thank you for clearing up some of those myths for other providers Dr. Cusi. Because yes, we hear certain things and drugs are questioned and recalled but you cleared that up so beautifully for us. As we conclude, what’s on the horizon for Nonalcoholic Fatty Liver Disease? Give us a blue print for future research. What do you see happening in the next bunch of years?

Dr. Cusi:  Well we are doing a lot of research here at the UF Health Shands Hospital. We have an NIH sponsored unit. There are about 50 new medications in different stages of testing. We choose those that are we think the most significant. So, if providers want to reach out to me it would be nice if you can share my contact information, I’ll be happy to explain. There are different kinds of drugs. Some are like newer versions of diabetes medications. For example, a newer version of a GLP1 is called semaglutide which is used for diabetes. Now they have a NASH trial that is going to be able to be published next year.

There are drugs that are going to promote weight loss by different mechanisms. There are drugs that are trying to do what pioglitazone does without potentially weight gain for edema. That may happen in about five percent of patients. There are drugs of a group called FXRs that work with nuclear receptors and decrease fibrosis. It’s a broad spectrum of medications. But for the time being, what I want the providers to remember is they have to diagnose it early to prevent cirrhosis. They have to be more aggressive with lifestyle interventions, typically structured programs for weightloss work better. Consider bariatric surgery and use pioglitazone or liraglutide or vitamin E because there are things you can do today until these new drugs become available.

Host:  That is excellent information. Dr. Cusi thank you so much for joining us and sharing your incredible expertise. And that concludes today’s episode of UF Health MedEd Cast with UF Health Shands Hospital. To learn more about this and other healthcare topics at UF Health Shands Hospital please visit www.ufhealth.org/medmatters to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. For more health tips and updates on the latest medical advancements and breakthroughs follow us on your social channels. I’m Melanie Cole.