Activity Transcript

Mazen Noureddin, MD, MHSc: Hello, I'm Mazen Noureddin, director of Houston Research Institute in Houston, Texas. Welcome to this program titled "Establishing Better Standards of Practice: Maximizing Patient Outcomes With Noninvasive Screening in Nonalcoholic Fat Liver Disease," or NAFLD.

Joining me today are Jörn Schattenberg, who is the director of Liver Metabolic Research Program and professor of medicine at the University Medical Center in Mainz, Germany. Thank you for joining us, Jörn.

Jörn Schattenberg, MD: Thank you, Mazen. Glad to be here.

Dr Noureddin: And, Naim Alkhouri who's the director of Fatty Liver Program and chief medical officer at Arizona Liver Health. Welcome to our discussion, Naim.

Naim Alkhouri, MD, FAASLD: Thank you, Dr Noureddin. It's good to be with friends.

Dr Noureddin: Today, we'll review the rationale of liver fibrosis screening and the role of noninvasive tests that can be used to assess the risk in clinical practice. We'll share our insights as hepatologists into the benefits of noninvasive screening for liver fibrosis with the goal of aiding your clinical practice decisions and maximizing outcomes for your patients. What is nonalcoholic fatty liver disease? It's a complex disease affected by environmental and genetic factors. And when people are predisposed to those, they develop nonalcoholic fatty liver disease. The burden of NAFLD is huge. It affects one third of the population, which we're going to talk about today. And it's currently an epidemic and the most common chronic liver disease. NAFLD is increasing worldwide, and that is in parallel with obesity and type 2 diabetes.

Why is fibrosis screening monitoring so important? I will direct my question to Dr Alkhouri.

Dr Alkhouri: Well, that's a very important question, Dr Noureddin. But before I answer your question, let me just provide some data about the global prevalence of NAFLD. We see in this map that in the United States, we estimate about 25% of the adult population may have NAFLD. The highest prevalence in this study was actually in South America at 30% and also in the Middle Eastern countries like Saudi Arabia at also around 30%. But what we can see is that NAFLD really is a global epidemic; it's not just in western countries. And this is related to many factors including the adaptation of the Western diet across the globe.

When we talk about NAFLD, we all know it's the hepatic manifestation of the metabolic syndrome. Patients with NAFLD have many risk factors including obesity, type 2 diabetes, and the metabolic syndrome. And we also know that there is a genetic component with several polymorphisms including PNPLA3.

NAFLD is a multi-systemic disorder and this is a very important point. We cannot think of NAFLD as just a liver disease. In addition to liver disease, risk of progression to cirrhosis, patients with NAFLD have increased risk of coronary artery disease, cardiovascular outcomes, diabetes, chronic kidney disease, and also potentially extrahepatic cancers. When we talk about NAFLD, this really is a spectrum of diseases. NAFLD is the big umbrella term that we use. And we estimate we have close to 80 million Americans with NAFLD. And then out of these, we have about 15 million with NASH, nonalcoholic steatohepatitis, the aggressive form. Then about 20% to 30% will have progressive fibrosis. Some of these patients, unfortunately, will progress to liver cirrhosis. We estimate that probably we have 1 to 2 million adults with NASH cirrhosis in the United States. The risk of progression in terms of 1 fibrosis stage in patients with NASH, usually, is 1 stage every 7 years. But we have about 20% of patients with NASH that progress faster than that. Once you develop cirrhosis, these patients become at risk for decompensation, what we call major adverse liver outcomes such as ascites, encephalopathy, variceal bleeding. And, unfortunately, some of them will need liver transplantation. And you and I, Dr Noureddin, published a paper showing that NAFLD is the leading indication for transplantation in woman in the United States.

With this background, let's talk now about the impact of fibrosis stage and its prognostic value. Fibrosis stage, but not the presence of NASH, has been shown to be associated with the development of severe liver disease, progression to cirrhosis. Fibrosis stage is also linked to overall mortality in patients with NASH and has been also associated with cardiovascular disease mortality. Importantly also, we know that patients with advanced fibrosis, especially with cirrhosis, they cost the healthcare system the highest amount. One study showed that actually the 10% of patients that we have in our clinics with cirrhosis, cost the healthcare system about 80% of the spending to take care of the entire NAFLD population.

This is a systematic review here showing the impact of fibrosis stage first on all-cause mortality. And you can see here that there's an infliction point once you get to F2 fibrosis. And again, this includes liver-related mortality, but also cardiovascular mortality and mortality from extrahepatic cancer and other causes. When you look specifically at liver-related mortality, you can see that that risk becomes significant at F3 fibrosis. And it goes exponentially higher once you have liver cirrhosis.

And finally, I want to show this study. This is a recent paper that was published from the NASH Clinical Research Network sponsored by the NIH where they actually had over 1700 subjects with biopsy-proven NAFLD. And we can determine the presence of NASH and the stage of fibrosis. They are followed for median of 4 years. And they looked at the development of major adverse liver outcomes including transplant, hepatocellular carcinoma, variceal bleeding, ascites, encephalopathy, and then progression to a MELD score more than 15. They showed in this study that again, at fibrosis stage 0 to 2, the risk of developing these outcomes was relatively low. But once you get to stage 3, you can see that the risk is at 2.6% per year. And then, once you get to cirrhosis, we are talking about 7.5% per year.

Dr Noureddin: Huge implications. Fibrosis is really important. I'm going to go to Dr Schattenberg. Which noninvasive tests are available today for liver fibrosis, Dr Schattenberg, as it's very important in this disease prognosis?

Dr Schattenberg: Well, thank you, Dr Noureddin. That's a critical question. I think Dr Alkhouri's nicely shown how high the disease burden in our patients is and the endpoints that can be reached so let's dive into the available noninvasive test at this point. Clearly as just been shown, the stage of fibrosis predicts long-term outcome and mortality. And that holds up for both liver-related but also extrahepatic outcomes. And for that, it's important to screen and identify those patients not only in specialist hepatology clinics, but also, where the majority of these patients are tended for or cared for today, in primary care, secondary care. If you're involved in an endocrinology type 2 diabetes program, you're going to have a lot of patients with advanced liver disease that you might not even be aware of today. For that reason, I think it's very important.

There's been good research been done over the last years to develop a noninvasive tests or NITs as we call them to identify those patients. And there's a number of NITs that have been around for some time. This is an overview slide where you can see we're using indirect tests related to liver injury, ALT, AST, for example, or thrombocytes that's linked to fibrosis disease stage. Out of those simple blood-based markers, there are surrogate scores that have been developed like the FIB-4, the NAFLD fibrosis score to predict advanced disease stages. But there are also excitingly enough new and novel direct fibrosis biomarkers that are correlated to the buildup or degradation of fibrosis and fibers and using innovative technologies. These can be directly measured in serum or plasma. In the near future, instead of ordering liver function tests or platelets, and even today, I think you're going to have more and more access to direct fibrosis markers. On the other side, moving beyond the blood-based biomarkers, there are imaging biomarkers that have a high value for the diagnosis. And I'm going to be detailing those a little bit too.

Let me remind you that the field of hepatology started to identify or define fibrosis based on the fiber burden in the liver, which, currently, the only way to measure this is by obtaining a liver biopsy and then examining that specimen under the microscope. Liver biopsy, however, carries limitations. And as such, as a field, we've worked hard to actually expend and refine biomarkers that are correlated with liver histology. All the data I'm going to be showing you is mostly centered around liver biopsy as a reference standards for the accuracy to identify the changes in the liver tissue.

Here's an overview again on those surrogate scores. The FIB-4 score is the one I'd like to highlight. It's the one that's been coming out in most guidelines and recommendations. But there are other ones that have been used. And the experience in the field has been built coming from the HCV epidemic. I think we can use that data and experience to extend it into the current situation where most of the patients were actually seen in hepatology nonalcoholic fat liver disease patients today.

Let me revisit the FIB-4 score in a little bit more depth. FIB-4 is a surrogate that combines age, ALT, AST and platelet count to come up with a number. And that number gives you a cutoff to separate patients that are at a low risk of advanced fibrosis. This is the lower cutoff we'd like to use. The number you got to remember here is 1.3. If you do the calculation using the formula as shown on this slide -- you can use online calculators or your mobile device and enter the numbers -- you're going to end up with a single number to then classify patients to either be at low risk of advanced fibrosis or on the other end of the disease spectrum fall into the category of a high risk of advanced fibrosis. And that number, that cutoff is 2.67. Now in between those 2 numbers, there's a gray zone. The gray zone is an indeterminate range. And there's additional tests that are needed to actually pinpoint the diagnosis or the fibrosis stage the patient is in. It's important to remember that these noninvasive tests, particularly the FIB-4, has been designed and developed to have a high negative predictive value, that means that is a very good at ruling out advanced disease. If your patient is below the count of 1.3, the negative predictive value is a very high. It has a fair to good positive predictive value. But clearly, these tests are not as sensitive here to rule in advanced fibrosis.

Let me introduce a second direct fibrosis marker that has been available in the US and it's the so-called enhanced liver fibrosis test, ELF. It's an algorithm that incorporates 3 serum biomarkers, hyaluronic acid, PIIINP, and TIMP-1, which is a tissue inhibitor of metalloproteinases. And by measuring these 3 proteins in serum, you can calculate a score, which you don't have to do that yourself. If you send it to a lab ordering ELF score, you're going to end up with an ELF score that's been given. And that ELF score has been very robustly linked to fibrosis stages using different cutoffs. So you can see here a score of 7.7 or less, rules out advanced fibrosis, rules out fibrosis in patients. The second number I'd like you to remember is the score of 9.8 because that's a crucial score. It predicts advanced fibrosis. Patients with an ELF score of 9.8 and higher are high risk of advanced fibrosis. And now, the last score that's actually been memorized that has to be remembered here is the score of 11.3. And coming out of prospective study, that score was shown to predict outcomes and liver decompensation in our patients. When using the ELF score, you have those 3 cutoffs that allow you to risk stratify your patient and manage them accordingly.

Now this is the data that has actually linked ELF to outcomes, and it comes out of a phase 2 clinical trial using simtuzumab in patients with NASH in advanced fibrosis. And you can see that over the study timeline over 42 weeks, the number of events, namely the progression to cirrhosis in the group of patients with an ELF score above 9.[76] was significantly higher compared to the group below. And that's how I and you can use ELF in your clinic today.

Let me revisit the FIB-4 because I think I've discussed its value as a diagnostic marker, but also FIB-4 comparable to the data that I've showed you has prognostic abilities. This is a very recent presentation given at the European Association for the Study of the Liver meeting this year [2022]. And you can see that there is a significant increase in outcomes, both liver-related but also extrahepatic outcomes including cardiovascular events in the group of patients that are above the cutoff of 2.67, meaning that as seen with ELF, the FIB-4 is prognostic of outcomes in our patients with NASH. And I'm saying that to show and highlight you the potential power, the value these numbers can have. You can both use them for staging, but they also have a prognostic importance for our patients.

Let me finish up this section on noninvasive tests by summarizing or by including and discussing briefly noninvasive imaging biomarkers, which are very important in managing our patients today. On this slide, you're going to be seeing technologies around transient elastography. We use ultrasound technology to detect liver stiffness. And that's very closely correlated to fibrosis stage. And as you've seen with the blood-based biomarkers, we define cutoffs to identify patients at low risk of advanced fibrosis. The cutoff for the transient elastography would be 8 kilopascal. And we have defined a cutoff of 12 kilopascal and higher to rule in patients with advanced disease. Comparable to the blood-based biomarkers, the ability of these tests to rule out advanced disease is much higher compared to the ability to rule in.

Let me finish off by saying that in the future, I would hope that we're able to incorporate this type of clinical information - blood, and maybe imaging biomarkers -- in an artificial intelligence algorithm that could be run in the backend of your electronic healthcare records. We've done a study that was recently published where we examined data from the Optum Electronic Healthcare records in an ability to identify patients with NASH and potentially advanced fibrosis by using these type of AI tools. And as technology advancement is introduced into your clinical practice. I think this is something to think about. You can use any lab test you have in your lab clinical information to be run at the back end of your system and when you see your patient actually be flagged or highlighted towards the potential existence of advanced fibrosis in these cases. I think this is moving forward, one way we can use AI technology to refine the management of our patients.

And with that, I'll hand it over back to you, Mazen.

Dr Noureddin: You showed us a list of options that we don't have to use liver biopsy and the current practice, and right now, there are many of them. And, I want to ask Dr Alkhouri if he can walk us through society guidelines and tell us what the clinical pathways the society guidance recommend in terms of which one we start first and which one we can use. Naim, if you can walk us through this.

Dr Alkhouri: First, I want to thank Dr Schattenberg for this excellent overview of all the noninvasive tests that we have available to us today in the clinic.

We have several, society guidelines discussing the noninvasive testing for patients with NAFLD to try to determine disease severity and fibrosis stage. And you see here, we listed European, British, Asian guidelines, and of course, AASLD. But today, I just want to focus on a recent guidance document that was published by the American Association for Clinical Endocrinology, or AACE. I find this guidance very practical to actually risk-stratify patients into a lower risk category that does not need to be seen by a specialist, a hepatologist, or a gastroenterologist, and then a high-risk population that needs to be seen by a specialist. So, how do we implement this? First, we start with the subjects at high-risk of having NAFLD. What I like here is that they actually include all patients with prediabetes and diabetes. Dr Noureddin, you did the cost effectiveness analysis showing that if you screen patients with type 2 diabetes at a certain age that this is actually cost effective, and it'll save us money as a healthcare system in the United States so I think this is a very welcomed step that we need to screen all diabetics now, not only for the presence of NAFLD, but for the severity of NAFLD and to see who has advanced disease. They also include subjects with 2 risk factors of the metabolic syndrome so in addition to diabetes, dyslipidemia, obesity, hypertension. And then, of course, patients with elevated ALT, so suspected NAFLD or those with incidental finding of fatty liver on imaging including ultrasound or CT scan. These are the at-risk populations.

And then, we start by doing the FIB-4 index, of course, after we exclude excessive alcohol consumption. But we start with the FIB-4 and then, we utilize the exact cut points that Dr Schattenberg explained earlier. If your FIB-4 is less than 1.3, this is a lower risk subject for having advanced fibrosis. This is someone that we can keep in primary care, and they can repeat the testing in a couple of years. If someone has a FIB-4 more than 2.67, this is automatically high risk, and they need to be sent to a specialist. And then, you're going to have patients in that indeterminant zone in between 1.3 and 2.67. In our practice, this is about 30 to 40% of subjects. And these are the patients where you need to do a sequential test. You do a second noninvasive test. And that depends on what's available to you and your practice. You can start by doing liver stiffness measurement by FibroScan. And the cut point is 8 for lower risk and 12 for high risk. And then if you know you're in between 8 to 12, probably you should be seen by a specialist to determine where you're at in the disease spectrum, or you can utilize the ELF test. And the cut points are the ones that Dr Schattenberg also discussed so less than 7.7 is considered lower risk. More than 9.8 is considered high risk for advanced fibrosis. And then in between, potentially, you need to do another NIT or, in some cases, a liver biopsy. What I like about this guidance document also is that they provide practical advice how to manage these patients. And they include weight loss management. And they include also optimization of diabetes management.

Here, I'm showing a pathway to actually assess what happens if we implement these guidelines in the primary care setting. This is a paper published by Dr Rosenberg and his group in the United Kingdom where they actually started to use this algorithm in primary care physicians' offices. They started with the FIB-4 and again, applied the algorithm with the 1.3 and 2.67 cut point. And then, the sequential test was actually the ELF test. What they showed in the study that by implementing this algorithm, only about 18% of patients will need to be referred to as specialist. So the good news is that we can actually risk stratify 82% of patients in primary care as low risk for advanced fibrosis and they can be managed in primary care. But also, you need to do the assessment every 2 years or so to make sure that they are not progressing.

With this, I'll hand it back to you, Dr Noureddin.

Dr Noureddin: Those are very helpful comments and overview, guys. I really like that we have multiple options today starting with simple tests but also to pin down the fibrosis stage, we have other tests including imaging as well as specific fibrosis blood tests that we can use nowadays.

I want to ask Dr Schattenberg. We were recently at the AASLD meeting. And there were highlights about the new AASLD guidance. Dr Alkhouri showed the AACE guidance, which also is consistent with the American Gastroenterology Clinical Pathway, so they're all kind of saying the same message and same story. But I want to ask Dr Schattenberg, is the AASLD going to have the same story? You heard that talk. If you can brief us on that, that will be fantastic.

Dr Schattenberg: Yes. Great. Thank you, Mazen. That was really a nice overview, and presentation given by Dr Mary Rinella from Chicago, who led the efforts of AASLD to coordinate and come up with that new guidance. And the good news is they're aligned. They're aligned with the AACE guidelines and with the AGA guidelines so you see a broad uptake through the field of gastroenterology and hepatology, endocrinologists on that stepwise approach using FIB-4 in patients to rule out those at low risk of advanced fibrosis. And then, a stepwise sequential testing as nicely highlighted by Dr Alkhouri using the tests that are available in your setting, in your referral pathway that you are comfortable with to identify those at highest risk of advanced fibrosis. Then also was included were some management recommendations. I think it's going to be very diverse depending on where you work, how your referral pathways are set up, what you use. The good news is you do not have to be afraid of NAFLD patients overwhelming practice. But I think it is important to highlight that those with advanced fibrosis need management. Management options are available even today, including screening and the point is that these patients can be identified using the NITs and we see broad uptake and alignment across the different guidance documents. So for me, that was very reassuring.

Dr Noureddin: Prevalent disease, fibrosis matters the most. Liver biopsy can be replaced by noninvasive testing. We have many of them. Such an advancement in the field. I hope this helped our audience today. I would like to thank Dr Schattenberg and Dr Alkhouri for this great review.

I also would like to thank the audience for joining us and participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thank you very much.

This transcript has not been copyedited.