Series Overview
Join our host, Dr. Amreen Dinani, as we discuss an often undetected liver disease affecting up to 25% of the world’s population: nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH). Each episode, Dr. Dinani is joined by hepatologists from across the United States to discuss various components of the NASH care continuum, including early identification, diagnostics, existing and emerging treatments, and the patient care journey. Whether you’re a patient, hepatologist, primary care provider, endocrinologist, or payer, we hope you can join us and learn something new!
Episode 2 - Diagnostics
Episode #2 features Dr. Dinani and Dr. Fuchs, the Chief of Hepatology and Liver Transplantation at the Central Virginia VA Health Care System, discussing non-invasive tests (NITs), which can be used to identify and assess patients at-risk for NAFLD and NASH. This podcast will cover information relating to:
Non-invasive tests available on the U.S. market
Liver biopsy as the gold standard
Advantages and disadvantages of various NITs
Considerations for PCPs and referral pathways
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Transcript
DR. DINANI: Hello and welcome back. You are listening to Episode 2 of our podcast series covering an often undetected liver disease affecting nearly a quarter of the world’s population: nonalcoholic fatty liver disease, which we’ll refer to as “NAFLD.” The more aggressive form of the disease is called nonalcoholic steatohepatitis which we’ll refer to as “NASH.” I’m your host Dr. Amreen Dinani. I’m a hepatologist at the Icahn School of Medicine at Mount Sinai Healthcare System in New York City. Today we have the pleasure of speaking with Dr. Michael Fuchs. He is the chief of hepatology at the Central Virginia VA Health Care System in Richmond, Virginia. We’re really happy to have Dr. Fuchs join us today to discuss diagnostics and non-invasive testing, or “NITs,” used to identify and assess patients at-risk for NAFLD and NASH. Welcome Dr. Fuchs.
DR. FUCHS: Hello Dr. Dinani. Thank you for having me today.
DR. DINANI: It’s a real pleasure. In our first series we discussed the burden of this disease and quickly learned that it affects a large population of the world, let alone the United States. We’re thinking approximately 25% to 30%. As we know, it’s a silent disease, typically asymptomatic. The worst aspect of it is the lack of awareness of the disease from a patient and clinician perspective, so we definitely have our work cut out for us. One of the things we would like to talk about during this podcast series is we’re talking about a silent disease that doesn’t have symptoms with no specific tests that we can use – how do we screen these patients, and how do we risk stratify these patients with NAFLD? We work in pretty different healthcare facilities, so I thought maybe we can start off by having you share a brief overview of how the VA Health Care System works, and how you think it’s different from other healthcare institutions.
DR. FUCHS: Sure. The Veterans Health Administration is America’s largest integrated health care system providing care for over 1,200 healthcare facilities, including around 170 medical centers and over 1,000 outpatient sites of care of varying complexity serving about 9 million veterans every year. The American veteran population represents a quite unique population with varying military service branches and military experiences as well as varying war time eras and have different health specific issues associated with those eras. About three-quarters of our current veterans served during war time with a majority being Gulf War veterans. “VHA,” or the Veterans Health Administration offers a large range of health care services to our veterans, and veterans that have other forms of health care coverage like a private insurance plan, Medicare or Medicaid can use VA healthcare benefits along those plans as well. We also offer certain disability compensations for service-connected medical conditions. If we look at our patient populations, substance use, mental health disorder, traumatic bodily injuries, hazardous exposures and chronic pain are very common among our veterans. Currently, nine out of 10 of our veterans are men, but as current trends in the U.S. populations continue, the veteran patient population is predicted to become more racially and ethnically diverse and not consisting of the predominantly white.
[3:46]
DR. FUCHS: Risk factors for NAFLD, such as obesity and Type 2 Diabetes (T2D), are highly prevalent in the U.S. population, but it’s prevalence among US veterans is even higher. With the enormous burden of NAFLD that was discussed in the first podcast, it is not that surprising that NAFLD represents a major challenge to the VHA. When we look back, the VHA has been incredibly successful in identifying, treating and curing a significant portion of veterans with Hepatitis-C. Clearly major efforts need to be undertaken to implement an effective population health management strategy for our veterans with NAFLD. This will provide, however, an opportunity to demonstrate that VHA may perform better on quality when compared to healthcare systems in the private sector.
DR. DINANI: Thank you so much for that overview. I’ve never worked in a VA healthcare system so definitely some of the things you highlighted are new to me. Thank you so much. It will be interesting to hear later on how care models for NASH and NAFLD identification and risk stratification are different between these two healthcare systems, so we’ll talk a little bit more about that. Just to talk a little bit about how we diagnose NASH – As it stands today, NASH is a histological diagnosis, which means you require a liver biopsy. We have to see certain features on the liver biopsy such as the presence of steatosis. You have to see a hepatocyte injury, including ballooning that we see on histology. Dr. Fuchs, I was wondering if you could comment on the role of liver biopsy as it stands today and how you see it evolving in the future.
DR. FUCHS: Sure. We are all aware that liver biopsy has traditionally been used to aid in the diagnosing and monitoring chronic liver disease, as well as to make treatment decisions. That was basically because we did not have any alternative diagnostic tool. With regards to NAFLD, it remains the only diagnostic tool that can identify all of the three key diagnostic features of NASH which you mentioned and include: steatosis, level of inflammation, and cytologic ballooning as well as the degree of liver fibrosis. However, the broad applicability of liver biopsies in NAFLD is limited for several reasons. First, and very obviously, there are far too many people with NAFLD and NASH to biopsy. We do not have enough providers to perform these liver biopsies, nor do we have the number of hepatologists to read them accurately. Then, the procedure itself is obviously invasive and may be associated with patient discomfort, such as pain, and potential complications, such as bleeding. Liver biopsies are furthermore less ideal for disease monitoring, and more importantly, even experienced liver pathologists are differing in their interpretations of presence or absence of NASH features in the liver fibrosis stage. It has become clear a few years ago that these limitations of liver biopsy must be overcome, particularly in NAFLD, to properly address this metabolic disease. Non-invasive tests, or NITs, will be used more routinely, replacing the majority, but not all, of liver biopsies. The shift towards NITs certainly has been accelerated by the observation that the liver fibrosis stage, rather than the other three NASH histological features, determines clinical outcomes. Development of NITs has evolved over time to focus on proper liver fibrosis assessment, and thereby minimizing the need for a liver biopsy.
[7:55]
DR. DINANI: Great, thank you so much for that explanation. One of the things that you did raise is that we know that despite trying to make the determination between having simple steatosis and NASH, what’s really important is fibrosis because if we know the stage of fibrosis and the degree of fibrosis it really impacts all-cause mortality and liver-related mortality. Hence, the reason our NITs really try to focus on characterizing accurately the degree of fibrosis. With that being said, I was wondering if you could comment on some of the current NITs that we do have available that we could use and maybe also highlight possible scenarios that you think they would be appropriate for.
DR. FUCHS: There are numerous NITs available right now. Some of them are currently not available in the U.S., so, I will primarily focus on the ones that are available in the U.S. Those tests can be broadly categorized into blood and imaging-based tests or biomarkers, and the two most commonly used blood tests are the fibrosis-4 index, or we call it “FIB-4,” the NAFLD fibrosis score, or “NFS.” They both can be relatively easily be calculated either by utilizing an app or calculator, and only really require routine lab results such as ALT, AST, platelet count, albumin, and some standard patient information including age, BMI and presence or absence of diabetes. In addition, there are patented blood-based biomarkers such as FibroSure®, NIS-4, or ELF. Some of them just becoming available in the U.S. where analysis and reporting is done by a commercial lab. On the other hand, we have ultrasound and MRI-based tests that are very helpful with regard to fibrosis assessment. FibroScan®, or vibration controlled transient elastography, is becoming more widely available in the U.S. and around the world. FibroScan®can assess liver stiffness by a mechanically induced shield wave. Liver stiffness correlates with fibrosis as long as confounding factors such as liver congestion, cholestasis, or IRO are excluded. The FibroScan®device also simultaneously assesses steatosis by measuring the so-called controlled attenuation parameter, or “CAP.” Elastography can also be measured using MRI and the degree of steatosis is measured by proton density fat faction, or “PDFF.” MRI can also be processed with a patented technology and software called LiverMultiScan®, which corrects for the liver iron content. While images here can be obtained locally, reading the software is done by the patent owner for a separate fee. With those numerous tests available, one of the immediate questions is how to properly use them in clinical practice. Now before one can answer this, it is important to understand that NITs are being used to assess for clinically-relevant so-called advanced liver fibrosis, and to improve the sensitivity and specificity to detect clinically relevant fibrosis, two cut-off values are being utilized for those tests. In general, patients that have a value below the lower cut-off are unlikely to have advanced fibrosis while those with a value above the upper cut-off likely have advanced fibrosis. The cut-off values have been determined in different patient cohorts and different ethnicities but may require re-evaluation in specific patient populations, such as our veterans. To address this, Dr. Puri from my section has prospectively collected several of these NITs in more than 200 veterans with biopsy-proven NASH. One of the findings that he presented last fall during the AASLD meeting was that a single NIT, FIB-4, appeared to be superior to any blood-based NITs, such as NAFLD Fibrosis score or APRI, and that MRI was only slightly superior compared to FibroScan®. As a broad rule one can safely state that these tests have excellent negative predictive values allowing us to confidently exclude advanced liver fibrosis, whereas false positive results limit the ability to affirm advanced fibrosis. I think that is very important. More recently it became furthermore clear that sequential use of two different NITs can further improve identification of those patients that have advanced fibrosis, and we are currently utilizing our respectively collected data to explore the best combination of NITs to be used on our veterans.
[13:22]
DR. DINANI: Great. So it sounds like from what you’re describing, one of the things that I would like to point out is that you’ve mentioned a lot of different types of non-invasive testing, both serum-based based and blood tests that we routinely get on our patients, for instance, doing well visits, but there’s also some proprietary tests which has the implication that there will be a higher cost to some of those tests and then there’s these very elaborate imaging technologies that we can use to test the degree of fibrosis. Now for you and I who understand all this testing, when we step back a little bit, the front line really is the people who see this patient population primarily, including primary care physicians and endocrinologist. The question really becomes: how do you see the evolution of these NITs being applicable, for instance, to a primary care clinician or an endocrinologist? If you think about it, you want to be able to differentiate between the people who have very minimal or no fibrosis and those who have advanced fibrosis because it’s really those advanced fibrotic patients that you really want to engage in specialty care and do all the other things that we do in hepatology care such as vaccinations and screening for liver cancer. So, if you were to try and empower our colleagues in private care, what NITs would you recommend? Would you recommend one test? Would you recommend two tests? Any thoughts on that, or how you would do that?
DR. FUCHS:Well that’s a challenging question. I may not be able to give you a single straightforward answer that fits under all kinds of scenarios. I think we certainly need to utilize more of those NITs; however, which test we use clearly depends on their availability and the experience a provider has utilizing them. For example, some of those non-patented tests like FIB-4 are easily available, and they can be incorporated in a medical record system. They can be ordered and even commercial labs, like LabCorp, are putting those numbers out. In our facility, for example, whenever a hepatic panel and CVC is ordered, we automatically get the FIB-4 calculated. So, the FIB-4 seems to be a very attractive first-line NIT to utilize, at least to separate and identify those that less likely have any clinically likely fibrosis. Now when you compare those tests with imaging-based tests, then obviously cost comes into play. A FibroScan®is certainly less expensive and better and more widely available then any kind of MRI-based test. Now in the VA Healthcare System we are probably more fortunate because we, unlike the private sector, don’t need any kind of prior-authorization to run those tests. So, that allows us to allow many more MRIs in our patients and compare with FibroScan®and FIB-4. So, if you ask me right now, I would think that it’s reasonable to state that if one starts with the FIB-4, those patients that have unlikely advanced fibrosis can remain with the primary care, and primary care can try to optimize those comorbidities. While those patients who do not fall into that category certainly require a second test as a single NIT, be it FIB-4 or any other one, it is not adequate enough to further filter those patients that should be referred to hepatology. What we have instituted is basically that our second line test is a FibroScan®, not only because FibroScan®is pretty much widely available throughout the VA Healthcare System, but it can easily be incorporated into day-to-day clinical practice. It has also become such a popular tool at our facility that we offer FibroScans®almost every day. I call it actually the electrocardiogram of the hepatologist. We basically have our patients undergo a FibroScan®to determine those that we further want to work up. Now, the challenging part comes when you have a FIB-4 that is just slightly above the cut-off or in the middle of the cut-off, and your FibroScan®does not place the patient at an increased risk for advanced fibrosis. Those in discordant scenarios, I think comes clinical judgements into play. Sometimes for further clarification, we obtain an MRI elastography, or even perform a liver biopsy, but I think the sequence of FibroScan®to FIB-4 is a reasonable one. There is another test I mentioned which belongs in the category of patented tests, which is the ELF test. That test is going to become available in the U.S. soon, but the most experience has been obtained in the United Kingdom, where that test is utilized together with FIB-4 to determine which patient should be referred to a hepatology or specialty care. So, in the United Kingdom it is the FIB-4 and the ELF test that determine which patient is being referred to hepatology.
[19:26]
DR. DINANI: Great. So, you highlighted some very key points. One of the things that I heard is that if you’re going to choose an initial test, something that is simple, easy… it has to be cost-effective if we’re going to be screening or evaluating a large population. FIB-4 seems like maybe an appropriate test because those are basic, routine blood tests that we get in well visits. For instance, the problem like you mentioned is that there is this indeterminate range which can be as high as 30% of the patient population. That’s when having an additional test such as a FibroScan®or an ELF test could be helpful to decrease that indeterminant fibrosis population. But, you’re right – even within our healthcare system we do have a sequential approach, where you apply one test, and then to increase the sensitivity of the test you can apply a second test, such as a FibroScan®. It sounds like just like the VA Healthcare System, FibroScans®are very useful for point-of-care testing. You are able to get information on the degree of fibrosis within three to five minutes, and the nice thing about that also is that you are able to communicate that information to a patient and explain to them what that actually means. That’s very, very useful. What we also do is when you have a discordance between that NIT, that’s when we make a judgment call to try and decide if we want to do a MRI elastography, but those are the people that would probably benefit best from getting a liver biopsy just to get a histological confirmation of the degree of fibrosis. Based on what you have described, there are definitely some advantages and disadvantages to the NITs like cost and applicability to the general population. One of the things that we didn’t highlight that I want to mention is that the age can play a factor in the accuracy or the sensitivity of some of the NITs because age is one of the parameters that you put into the FIB-4. That’s something that is being looked at, and maybe there is some thought that the cut-off should be different based on the age of the patient or the population you’re looking at. So, there is more to come in that area. At your institution, it sounds like you do a FIB-4 first, and then you proceed with the FibroScan®as needed and decide if you need to do an MRI elastography or a liver biopsy. Is that correct?
[21:57]
DR. FUCHS:That is correct. Now when we started about three years ago to try to develop an organizational comprehensive care strategy for our veterans with NAFLD, we first looked at what we were doing currently because I think that’s crucial if you want to develop a new program. What we found, which was not really surprising, is that there is a lot of work that needs to be done at the primary care level, particularly with regard to the awareness of the disease. If you want to build an appropriate referral model, you need to have the buy-in of your stakeholders, including primary care, so what we did first was an extensive education of primary care. We also realized in our facility that there is only so much that you can ask of a primary care provider, and that may be a little different in our healthcare system than in the private sector. In the past it has not really worked very well to demand primary care to order a litany of liver tests to rule out other chronic liver diseases in order to finally come to your diagnosis of NAFLD, so what we focused initially on was that primary cares are appropriately aware of the disease or are aware of the veterans that are at-risk for NAFLD. Having that achieved, we tried out first a model where we asked them to refer every patient with fatty liver on imaging or those that are at-risk. While that clearly increased the referral to hepatology we very soon realize that this is not a proper pathway to manage the large volume of patients that we were suddenly seeing in our hepatology clinics. Then we put into place another step where those patients were first referred to, our FibroScan®clinic, and after the veterans underwent FibroScan®testing, we did a complete chart review of the patient. We also included that we obtain more important and crucial and correct information about the alcohol consumption while we were obtaining the FibroScan®test. So, that allowed us to better risk strategy the patients and then refer ourselves those patients with likely advanced fibrosis to our liver clinics and refer those back to primary care those we were convinced did not have any relevant fibrosis. Since we collected over the last 2.5 years numerous NITs, in addition to the fibrosis, we have just recently started a new concept, and that is utilizing standard of care tests and comparing those with the NITs. Whether we can establish an algorithm or model using standard of care tests to avoid leaving a FibroScan®interpretation, for example, in the hands of primary care. It looks like this is something that actually can be achieved, and surprisingly in these different models that we are exploring right now, age or the presence of diabetes alone does not play a role. We still get a very good correlation, at least with liver biopsy, that we still consider to be a gold standard of fibrosis assessment.
DR. DINANI: Wow, it sounds like you've been doing a lot of great work in the VA System that you currently work at. One of the things that you mentioned is helping the primary care physician identify the at-risk population, so they can then be referred to the FibroScan®clinic. I’m just curious how you empowered them with that information and was the uptick pretty good?
DR. FUCHS: I can tell you that it requires frequent and repetitive enforcement, particularly because we, at least at our institution, see quite a turnover in staff working in primary care. It really requires education at the primary care level every couple of weeks initially and then also incorporating support staff working in primary care in this process. Another thing that I wanted to mention in terms of education that is often neglected and what we also have implemented in our metabolic disease clinic, is that we also need to educate our patients. If they are not educated, if they do not understand why we are doing certain things, they are not going to follow our advice. I think that is a very important component in managing this disease.
[27:11]
DR. DINANI: That’s a great point that you bring up. It looks like there are many initiatives throughout the country that are very similar to what you’re doing, and the reason I say that is at the Mount Sinai Healthcare System we have a similar approach. You highlighted empowering primary care physicians with this information requires reinforcement, reengagement, constant education and reminders. One of the things that we’ve done is screen at-risk populations, and we’ve focused on the type-2 diabetic populations in our screening for NAFLD. In the diabetes clinic, we use FibroScan®as a primary tool and use that as a referral pathway into hepatology, but at the same time giving feedback back to the primary care physicians as in, “hey, this person does not have advanced fibrosis, and you should work on managing xyz.” It does require work, but a lot of this requires making testing simple; one equation does not fit all, but the majority of the time you can apply similar tools to try to risk-stratify patient populations. It will definitely be interesting to see as more NITs get approved how we’re going to utilize and incorporate them into our regular, routine care for this patient population. I think with that we will conclude this session. I want to thank you again, Dr. Fuchs, for joining us today. We really appreciate you sharing your views on non-invasive testing as it relates to NAFLD and NASH. It looks like the VA Healthcare System, especially where you work at, is doing some great things, and I look forward to seeing some of your data.
DR. FUCHS: Yeah, anytime. I appreciate you having me on today’s episode, and I look forward to hopefully sharing future information through our NAFLD care pathways that we specifically developed for our nation's heroes.
DR. DINANI: Thank you. To our listeners, please join us next time to discuss existing and emerging treatments. This podcast series was developed by NASHNET, a global center of excellence network dedicated to NASH care delivery. Please tune in next time.