Activity Transcript

Kenneth Cusi, MD: Hello. I'm Dr Kenneth Cusi. I'm a professor of medicine at the University of Florida in the Division of Endocrinology and Diabetes. Welcome to the program, Implementing the NASH Clinical Care Pathway. And with us, we have today Professor Fasiha Kanwal. She's a professor of medicine, chief of the Division of Gastroenterology and Hepatology at Baylor College of Medicine in Houston. Hi, Fasiha. How are you? 

Fasiha Kanwal, MD, MSHS, AGAF, FAASLD : I'm great, thank you, Ken.

Dr Cusi: Fasiha, tell us why NASH is such a hot topic and why this epidemic now is everywhere. 

Dr Kanwal: Yeah. So first of all, Kenneth, it's really wonderful to be here with you. Non-alcoholic fatty liver disease, NAFLD or NASH, I think we'll use the terms interchangeably, I think you're right, this is a new epidemic in chronic liver disease. This is much of the reason why we're seeing this still rising tide of advanced liver disease, including liver cancer. And it is increasing worldwide. This doesn't really belong to a certain part of the world. It is a global condition. 

Up to 1 in 3 individuals in the world potentially has NAFLD. So, really, just if you can imagine the magnitude of the problem here. And this is increasing, I think, in parallel with this increasing prevalence or burden of obesity and metabolic dysfunction.

And just to set the stage, NAFLD or NASH, it is a complex disease, multifactorial. There's certainly environmental factors that are important, but there's also genetic predisposition to this condition, which also varies by region. So a common problem and increasing problem and also a complex problem. So, with that, actually, Ken, could you speak a little bit to the pathogenesis or the pathophysiology of this condition? How is that related to insulin resistance, for example and obesity? 

Dr Cusi: Yeah. So, thank you, Fasiha. That is one aspect that has caught the attention of clinicians in general, from gastroenterologists, hepatologists, all the way to even endocrinologists. And as you know, I mean, there are many, many pathways from animal studies and some human studies involving the microbiome, EPISARS, powered hormone signaling, and others. But one that I like to emphasize and perhaps bias as an endocrinologist is insulin resistance. Because this pathway is as broad as it is, there are things we can do today to reverse it. So what the thinking is that very commonly NASH is related to obesity, not always, but even in people who are non-obese, the constant finding is insulin resistance. And that is a broad term that means different things for different tissues. One aspect that has caught the attention obviously of patients and doctors is that obesity tends to worsen the severity of steatohepatitis and fibrosis. And people with diabetes, type 2 diabetes, and obesity tend to have a much higher risk of cirrhosis and at the top of transplant list in this country and elsewhere.

It has also been linked to cancer, as you said. Hepatocellular carcinoma is 3-fold higher in people with diabetes and we think that NASH might be the reason. Now what really happens and why is this an important concept for clinicians? Well number one, when you gain weight, you are not only increasing your mass of adipose tissue, but it gets sick. And what does that mean? Well, it starts responding to insulin. So why is that important? Well, it's very important because the role of adipose tissue to retain excess energy in the adipose tissue, but when you're insulin resistance, insulin that holds it there fails, and now you begin pouring the breakdown of triglycerides as fatty acids that tend to be taken by the hepatocyte and other tissues. And this flow of fatty acids in the context of high insulin and high glucose promote de novo lipogenesis. And this drives triglyceride synthesis. And although we don't understand why, but steatosis will promote inflammation and there's a third biology and promotes fibrosis. So many involve mitochondrial dysfunction and others. But the observation has been that when you lose weight by any means, insulin resistance gets better and this fat attack in the liver gets better. Or when you use agents that reverse insulin resistance like say pioglitazone, this also gets better. So insulin resistance is one of the mechanisms but one that clinicians should know about because there are things we can do to reverse that. 

But there are other things that are important for clinicians and more than anything is to identify groups at high risk of developing that. So Fasiha, we work together with a group of primary care doctors, the hepatologists, experts in obesity management and endocrinologists to identify and define these 3 groups. Would you share that with the audience? 

Dr Kanwal: Absolutely. And I think much of what you said, Ken actually really dictates these risk groups. It also points to the strategies that one can take in terms of managing this distribution population. So I think your overview was very, very important in that regard. So going back to the risk group, you mentioned type 2 diabetes, it is associated with more than 2-fold, higher risk of advanced fibrosis, cirrhosis complications, and liver cancer. So these are really the top risk factors. Of all the risk factors, diabetes is probably the highest, most important risk factor. You'd mentioned obesity, which I think is another important risk factor. Lipid abnormality, low HDL, high triglycerides and hypertension even. There are studies that show that 2 metabolic risk factors even in the absence of diabetes, is associated with a higher risk of progressive liver disease and liver complications. 

Dr Cusi: You published an important paper on that, Fasiha that as you added metabolic risk factors, your risk of liver trouble worsen, right? 

Dr Kanwal: Absolutely. There's a paper in hepatology from 2 years ago that showed that. It's the combination of 2 risk factors. It's an additive effect basically. But I think the point also, Ken in the paper was that the magnitude effect was the greatest or the largest with diabetes. So again, it's an important risk factor, diabetes. So with that context, there are risk groups that the AGA clinical pathway identified, and I think we're seeing that sort of resonate across other clinical care pathways that are emerging also. So one is patients with type 2 diabetes. That is an important risk group. In the absence of diabetes, individuals who have 2 or more metabolic risk factors, obesity, hypertension, lipid abnormalities, so 2 or more of these is also another high risk group. 

There is a third group that we see very commonly in clinical practice. I'm sure you see that group a lot, with steatosis on liver imaging. It could be incidental finding, it could be a result of a test that was ordered for abnormal liver enzymes. But that is a common risk group and most of those individuals have an alcoholic body liver disease. So that's a third risk group that is important for clinicians to be aware of. So these are the 3 risk groups, which I think is a move forward compared to what the pathways or guidelines were before. Because this is the first time these groups are being recognized as that high risk, which really is a starting point for any screening or risk stratification algorithm. 

Dr Cusi: I think it makes it easier for doctors to conceptualize it. So I was reading a paper that said most people that are reported as having fat in the liver from ultrasounds, nothing is ever done. Hopefully this will change that. And the other group that is also as a big metabolic risk are people with pre-diabetes. 

There are different statistics, but there are about 60 million people with pre-diabetes, we think in the United States, particularly older in populations above age 50. And rarely people think that they're the higher risk of cirrhosis or a hepatocellular carcinoma. If I tell my patient with diabetes that you have a 3 times higher risk of cirrhosis or cancer in their liver, they would be very surprised, even an endocrinologist. 

But so getting back to the guidelines, I mean what is it that we should be doing first and how to do that? Because I think that at least I know for hepatologists, this is your bread and butter, but for people who are in the trenches in primary care, endocrinologists or maybe even gastroenterologist that don't specialize in the liver, there's a broad spectrum of tests, but which would be the easiest that would be available for most practicing clinicians? 

Dr Kanwal:  Absolutely. And that goes back to this pathway as well thinking about it in a 2-step fashion. So a 2-tiered approach I think is helpful. For the very first tier, there are many noninvasive simple blood-based tests that are available. The pathway points to FIB-4, which is a test. Is a combination of a demographic factor, age, ASD, LT and platelet counts, they are easy to calculate.

So, that is the method that the clinical care pathway recommended as the first step. And there are reasons behind it. There are other similar schools that are available, but this one has the most evidence and the highest correlation with liver fibrosis, which I want to come back to it. For patients with NAFLD or NASH, there are many studies that have looked at what are the histological factors or aspects that correlate with worse patient outcomes. And consistently these studies show that it is the hepatic fibrosis or liver fibrosis that is the strongest risk factor or has the highest correlation with suboptimal patient outcomes. So really we want to find people who are at the higher risk for liver fibrosis. And that's important because FIB-4 is a noninvasive marker of liver fibrosis. 

The are other similar markers that are available too. Some of them are proprietary. You have to get the cost to the patient and to the healthcare system. FIB-4, the advantage is it's cheap, easy to get done, easy to implement in clinical practice. So that's why a FIB-4 is recommended as sort of the first tier in this screening sort of pathway. And the recommendation, again, based upon all the evidence that we have, you can think of FIB-4 as dividing people into low risk group, the middle group, indeterminate group, and the high-risk group based upon different cutoffs. And again based upon evidence that we have, the cutoff that the pathway recommends less than 1.3 is the cutoff that is associated with very low risk of having advanced fibrosis. 

So anyone below that cutoff, the chances of that patient having significant clinically significant fibrosis is very, very low. The negative predictive value is upwards of 95, 97%. So that group in primary care practices, in endocrine practices, one can really think of that group as having low risk for advanced fibrosis and those patients can be managed in primary care practice. 

Dr Cusi: The things gets more complicated when you have a value above 1.3. So what would be those groups that now fall more into your sphere of more comprehensive workup? 

Dr Kanwal: So the cutoff that's higher, 2.67 is the cutoff that you can think of as the higher end. Patients who have before more than 2.67, the probability of having clinically significant fibrosis is high. Again, its variable, depending on where patients are being seen for example, Ken in your clinic or in my clinic, which is more liver based clinic, the positive predictive value is going to be high. 

But in patients who are seen in primary care clinic, maybe not that high. Regardless, it is high enough that in that group the recommendation is for that patient or patient is a group to be referred to hepatology for further evaluation. And we can talk about what that could look like. There is this group in the middle, which is not that small actually, would you say maybe 30%, 40% of patients would probably- 

Dr Cusi: Yeah. And people with diabetes, it's about 30%, 35% of people fall this indeterminate risk. So would you tell us why it is called an indeterminate group please? 

Dr Kanwal: Yes. So the reason it's called indeterminate is we cannot really tell them apart. It's sort of a mixed bag of people who could be low risk or could be higher risk and that is why it's indeterminate.

So the risk by average, if you look at it, the risk is higher than the normal low risk group. It falls in between. It's just that it's hard to tell them apart from completely higher person's low risk. And that's why that group needs further evaluation and further assessment, which we'll come back to in a minute. 

But Ken, I wanted to ask you about the patient with score of less than 1.3, a young patient but with risk factors, what do you think is the best way to follow up to see what happens over time? Would you think that we would- 

Dr Cusi: Yeah, that's a good point. So, that's a good point. So it's important that the audience realize that the FIB-4 has high specificity means a high number and the closer 2.67, the more likely that they have fibrosis excluding other causes of liver disease. Now below 1.3 means that it's unlike you have advanced disease means F3, which is advanced fibrosis or pre cirrhosis for non hepatologists or cirrhosis. 

But it doesn't mean that you don't have ... you're not on your way to develop it. So the only thing is that it's lower sensitivity, ability to fish out these people in lower group will give you time to hopefully catch them at the next visit. And people with less than 1.3, we add up their risk factors and eventually will repeat it at least once a year. But we're going to be very aggressive with risk factor management because studies by our group and others show that 2 out of 3 people with obesity and diabetes have steatosis. 

Steatosis is like your mirror of your metabolic health. So if you have steatosis, you are at a higher risk of cardiovascular disease. This year in June, the American Heart Association made a very nice position statement in their journal and they have a 2-fold risk of type 2 diabetes if they don't have already diabetes. 

So we have to be very aggressive with obesity management, very aggressive with diabetes management. And the good news is that some medications for obesity and for diabetes are going to help in preventing progression of NASH. But we're going to manage the hypertension very carefully, the dyslipidemia. So great question Fasiha. Again, we've been pretty good in managing cardio metabolic risk, endocrinologist and primary care. 

We've been very terrible in stratifying risk for fibrosis. So I think these guys make it easy. But the question again, back to you, when you are in this gray zone or when you're high risk, I have to say in primary care, very few people across the 2.67, but still some people with advanced fibrosis are in this gran or indeterminate risk group. What do you do next? 

So the primary care identifies somebody with a number of greater than 1.3 and maybe the audience should just remember 1.3, below or above, anybody above requires that you rule out secondary causes and begin working with your gastroenterologist or hepatologist if you are not in those subspecialties. So say a gastroenterologist finds somebody with a FIB-4 of one above 1.3, what would the AGA guidelines recommend doing next? 

Dr Kanwal: I like the way you put it, make it dichotomous. So anyone above that cutoff, the next tier would be a second level test. And the pathway recommends a liver elastography for liver stiffness measurement. Fiber scan is the test that we commonly use. But there are other methods for stiffness measurement as well. 

But that's sort of the next tier. Based upon where people are practicing, one can also think of magnetic resonance, elastography also, MRE. But really more commonly it is ultrasound based elastography. And that helps really further risk stratify patients who are at a high risk based point FIB-4, again depending on the cutoff. And the pathway uses cutoff of eight and then 12. 

So anyone who is below eight has a low risk of having advanced fibrosis or clinical significant fibrosis. Anyone above 12 really needs to be evaluated in hepatology clinic if the patient is already not in hepatology clinic. And any patients who are in between, also I would think, Ken that they belong in the same group as those with a higher risk because you just, again, indeterminate or intermediate cannot tell them apart. 

So the pathway really converges for people who have indeterminate risk or higher risk for further evaluation. Most of that will be in hepatology clinic. And as a hepatologist what we will do, we look for consistency in these markers in all these non-invasive markers. If they're consistent, consistent with also clinical history, we do manage these patients as having advanced fibrosis. 

There are instances where we do recommend liver biopsy while there's getting fewer and fewer instances, especially for just routine clinical practice. MRE, depending on where you are, utilize that as well. But really I think for the audience, the next tier in this pathway is to use imaging based stratification tool, which would be transient elastography in most instances. Would you agree with that, Ken? 

Dr Cusi: Yeah, absolutely. And the question, and again the AGA guidance was based on expertise from leaders in the liver field and with agreement with primary care and endocrinologists, American diabetes, everybody involved in this and thinking of imaging with elastography as a second set is based on a large number of studies in which the results were compared. 

And these cutoffs were compared against liver biopsy. So a large and for many, many parts of the world found that this was the cheapest and most effective way to do it. And again, then in the hands of the hepatologist, they'll do the non preparatory or commercial blood testing or MRI or biopsy when indicated. 

So now the question is, you asked me getting back now into more detail and into management, let me expand a little bit on what to do with a patient I saw this morning. Because he has a low FIB-4, but his father had a history of cardiovascular disease, he has prediabetes with a glucose of 107, he had a BMI of 31. 

So when we got together for the AGA guidance, we set different layers. Number one, lifestyle intervention. Again, anybody who had again a FIB-4 below 1.3 or are a elastography test below eight, and a biopsy if it was done because the non-invasive test suggested a high risk, but in the end he didn't, lifestyle intervention is really important. 

And again, we don't do a great job at many levels. I have to tell you guys, just telling somebody to eat better or do a Mediterranean diet doesn't work. You really need to try to ... I send this person to a dietician this morning, they need to get into a structured health lifestyle and weight loss program if obese. 

And eventually we'll talk that if you have moderate or advanced disease, I mean you really need to get more aggressive with the lifestyle and eventually consider bariatric surgery. I mean, what is your approach to bariatric surgery in this setting for people in the high-risk groups? 

Dr Kanwal: Bariatric surgery and weight loss procedures, I think we are going to be seeing more and more of that. Again, studies do stress resolution and improvement in weight and with that there is improvement in NASH and liver related outcomes. 

One study just recently was published, again, it's a retrospective study, but a strong association, probably the strongest that I've seen in terms of improvement in liver related endpoints with weight loss surgery. So I think we'll see more and more of that. I am recommending for patients who are good candidates just get evaluated for weight loss procedures. 

And I think with more studies, more evidence, we might be able to reiterate better. But that is something that I think we'll definitely see. But it has to be done as part of a larger management system. I think that also- 

Dr Cusi: Absolutely, it cannot be done in isolation. And the other thing, remember I want to remind the audience that the number one cause of this is cardiovascular disease. So weight loss is critical for that. But also specifically, don't stop the statins in your patients. Mild elevations ofliver enzymes are not a contraindication, so you can use it into fairly advanced disease. But for Fasiha, tell us in cirrhosis, who benefits from statins and who doesn't. 

Dr Kanwal: So I would echo what you just said. I think the statins, first of all, no one should stop statins for patients who are on statins for the right indications, the guidelines recommend them. They're saving patients with cirrhosis also. There are small studies suggesting that there might be some risk in advanced decompensated child class C cirrhosis, but for most patients with cirrhosis, statins are safe to use. 

Actually Ken, as you probably are aware, there are few very large randomized control trial that are under way right now trying to in patients with cirrhosis, with statin being the main intervention, trying to look for beneficial effects of statins inpatient with cirrhosis. 

So we'll have to wait for the results from those trials. But the point here is that they're safe to use and they should be continued if patients are on statins. Again, question back to you, what are you recommending for diabetes care? 

Dr Cusi: Well, diabetes care is as you know, important for microvascular complications, eyes, kidneys, nerves benefit from getting your sugars as normal as possible. And some of our diabetes medications also reduce cardiovascular disease, like particularly well designed studies with GLP-1 receptor agonist, almost a class effect. And what we call SGLT-2 inhibitors, particularly beneficial for heart failure, which is common in obese individual with diabetes or NASH, and also for kidney preservation, which is a common complication in advanced liver disease and cirrhosis. 

And there's a handful of case reports that have shown benefit of SGLT-2 inhibitors and cirrhosis, but again, not a recommendation that can be made at this time. But regarding NASH, we don't have any FDA approved drugs. In our guidelines, we recommended pharmacotherapy, particularly in people with intermediate or high risk and that's awaiting FDA approved drugs like several that are in phase 3. 

But today I think we need to convince everybody to be more proactive to treat obesity, GLP-1 receptor agonist being effective, particularly a very well designed study with semaglutide published in the New England in 2021 showed significant effect on steatohepatitis with a higher dose, which would be equivalent to the obesity dose, weekly obesity dose. 

Didn't have a major effect, but it was safe at least to manage their diabetes and maybe reduce their cardiovascular risk. Another drug that we use in diabetes is pioglitazone. It's a generic, it's been out there for more than 20 years. The drug has several trials that have shown a reversal of steatohepatitis with modest effects on fibrosis. 

But some indication that may slow progression. Again, we start low doses of pioglitazone, typically 15 milligrams and bump it up to 30. And with 30 milligrams you achieve most of the benefit. And in general not needed to increase to 45 as done in some of the clinical trials. But the message, Fasiha and I want to get your opinion here, is many times I hear people from all fields, including hepatologists, say, well there's no pharmacological therapy. 

But knowing that the vast majority of our people have either obesity or obesity and type 2 diabetes, what will it take for people to begin using GLP-1s or pioglitazone until we have the new drugs and even so, when they become available? Because when drugs get approved by the FDA, this is going to be a condition that's going to require several agents as we do in diabetes or hypertension. What do you think? 

Dr Kanwal: Actually I'm already seeing it in clinical practice. So my clinical practice is hepatology and we are using semaglutide now. So I think we'll see more and more of that trend towards managing this condition as really what it is, it's a syndrome. It's not just one liver condition, it really is a metabolic insulin resistance driven condition as you referred to earlier on. 

So already seeing some of that in our practice and I think more will come as we have more drugs available. But really I think the point to the care pathway and some of the work that we've been doing is to increase awareness at all levels, primary care, gastroenterologist, endocrinologist, even at the public health level, that there is a need to identify and recognize this condition as an important condition. 

And to really come up with systems and pathways that align across different societies, different entities to move them free forward. We will have drugs available that we really need to agree on, who are the patients who are at risk, how do we identify them, how do we risk stratify, and how do we link them to the right care team, which is also very important. 

I think we touched upon the multidisciplinary nature of the team that is necessary to manage suspicion population. So- 

Dr Cusi: It's a great point. I think that the FIB-4 with all its limitations, because it may miss many people with moderate fibrosis, what we call F2, but it will probably catch most with F 3 and F 4. So we're trying to at least start by identifying those with the most advanced risk. So we are trying with the FIB-4 to identify those with more advanced disease and hopefully identify many with F2. 

But I think as you said, this is more about building a case finding or screening muscle by gastroenterologists and endocrinologists and primary care to later replace it with a better test. But we have to start now. And I think it's really important that all guidance have been consistent in using FIB-4, like the one release in May by the American Association of Clinical Endocrinologists or AACE that basically has an identical pathway but recommends a preparatory test in case that you do not have access to a elastography test. 

And this brings to me the fact that some diabetologists or primary care say we don't have transient elastography in clinic. Well, you don't need it, just order it in the same way you order an x-ray or a bone density and it'll be available for the next visit. I also want to share that the American Diabetes Association and its standards of care this year incorporated the AGA 2021 guidance. 

The ADA was a strong supporter of the guidance. Dr Echo was the president of the ADA and endorsed it and it is being incorporated this year and will have a greatly expanded section coming in January. There was a very, very coordinated effort to align all the screening or case finding effort through the FIB-4 and a second imaging technique being elastography or preparatory test like ELF. So there are no discordances of how we have to do it. Now, it's really the mission of all of us to educate our mentees and our fellowship programs and younger faculty to do this and let the doctors in the field try to prevent cirrhosis by early identification. 

So my question for you, Fasiha how is a dialogue coming along with those that are non pathologists, if you're going to put them all together? 

Dr Kanwal: Yes, it's a process, Ken. And one has to start somewhere. So I think we are at the beginning, started this clinical care pathway I think was a great step forward. But as you can imagine, lots of work needs to get done. So we are I think using multiple different forums as you are, our institutional audience, meeting with the stakeholders, primary care, endocrine, setting up multidisciplinary clinics, coming up with protocols that are based on the clinical care pathway, but also having these conversations at larger national meetings. 

This alignment across all the different guidelines, it's really outstanding.

Dr Cusi: This is something practical because what I hear is many gastroenterology, hepatologists say, well, that's a diabetes medication. I don't even touch metformin, but come on guys, you've been treating hepatitis C with Interferon. I mean it can't be any harder than that. So just write the prescription and tell your assistant or your nurse to teach them how to use it. It's very, very simple. 

And injectables or pioglitazone, these are options that are easy and I think that they're going to be making a big change in the natural history if we can really get the message out. So Fasiha, any last words for our audience? What do you want them to leave with? 

Dr Kanwal: I think just remembering the simple things. I'm all for keeping things simple. The great advance here is that at least there is guidance and consistent recommendations from all the different societies, multidisciplinary groups, that certain risk groups of patients that are at high risk for liver fibrosis from NASH and NAFLD, diabetes, those with metabolic risk factors and hepatic steatosis on imaging. 

I think that's probably the most important aspect part to remember. If you see those patients in your clinical practice, make sure you move forward with the further risk stratification, which again is very simple using FIB-4, and then for patients who are at a higher risk based upon the cutoffs going to the second tier with liver elastography. 

And we reviewed all the recommendations around what we know right now about managing this patient population, but really more is going to come in the next few years about pharmacotherapy. Having said that, enough information is already here to guide us, at least to find these people, create a platform that we can build on.

Dr Cusi: It is always fun to spend some time with you, Fasiha. And Fasiha said it very well, the pathway is simple. You just need to think about NASH being a possibility in your patients, FIB-4. And my message is start treating now. I mean, not just a pat on the back and lose some weight, but there are medications that are helpful for your person with obesity or type 2 diabetes. 

And it's your responsibility to be prescribing them and preventing something that has incredible consequences for your patients. So thank you Fasiha, and I hope that you have enjoyed these few minutes with us.