Ep 5: Unlocking the Fatty Liver Mistry

The NITs Are In: Diagnosing Fatty Liver Disease Without the Needle

[00:00:07] Neeraj Mistry, MD: Welcome everyone to episode five of Unlocking the Fatty Liver Mistry. I'm Dr. Neeraj Mistry. I'm the Chief Medical Officer of the Fatty Liver Foundation. And for episode five, we are dealing with NITs. Now, it's not uncommon for us in the medical world to have our entire word salad of uh, three letter acronyms, and when it comes to testing, we certainly have that. So, we have RDTs, which are rapid diagnostic tests, and VCT, which is voluntary counseling on testing. Particular to the liver space, we have something called NITs, which are non-invasive tests. And today we have Dr. Naim Alkhouri, who's a world renowned hepatologist. and he's the Chief Medical Officer and Chief of Transplant Hepatology, the director of the Steatotic Liver Program at Arizona Liver Health.

And he’s gonna help us understand and unpack this entire area of NITs. Just from my background, as a public health physician, testing has been the critical sort of junction between prevention and treatment. And when you test someone, if the test results are positive, well you know what path to take for treatment. And if the test results are negative, then you know what preventative behaviors to take in order to prevent the onset for disease. So, it's the critical nexus between prevention and treatment, and it makes sense for that in the liver space as well. So, we are gonna go much deeper into that. Dr. Alkhouri, welcome to this podcast, and we are delighted to have you here.

[00:01:41] Naim Alkhouri, MD: Thank for having me, and I look forward to this conversation.

[00:01:45] Neeraj Mistry, MD: Excellent. So, let's dive into it. So, there's this myriad of tests, and now in the hepatology space we have non-invasive tests. Tell us all about this.

[00:01:56] Naim Alkhouri, MD: So, it's very important to be familiar with these non-invasive tests because historically speaking, we diagnosed, steatotic liver disease based on liver biopsy. And this is how we made the diagnosis of MASH, which is steatohepatitis, the aggressive form of steatotic liver disease. And we determined fibrosis stage. However, liver biopsy is an invasive procedure. It also struggles with variability because the disease is heterogeneous and sometimes there is also differences in how pathologists interpret the results of the liver biopsy. And definitely patients don't want to have multiple biopsies in their lifetime to monitor for disease progression or improvement.

So, you know, for the last couple of decades there has been an urgent unmet need to develop non-invasive tests that you can do at multiple time points to detect the disease, determine its severity, and then assess response to treatment. I would say in 2025, we have arrived. We have these non-invasive tests that can help you actually risk-stratify patients. And the way I think about them, we have non-invasive tests that help us determine the presence of significant fibrosis, which typically requires pharmacologic treatment and referral to subspecialists. So, for the audience, I wanna simplify it. The way I think about non-invasive tests for fibrosis, I divide them into three buckets. The first one is scores. You can calculate based on the patient characteristics and also some basic labs like liver enzymes and platelet count. We have several of these. I would like the audience to learn one of them, which has been endorsed by all the guidelines, which is called the FIB-4 Index. Very simple score. Typically, it includes age because older patients are more likely to have significant fibrosis. It has an AST to ALT ratio because patients with significant fibrosis tend to have a higher ratio of an AST to ALT. Then the last variable in the FIB-4 index is the platelet count. Because patients, as they progress to advanced fibrosis and cirrhosis, the platelet count goes down. You put these four numbers in an online calculator, and you get a FIB-4 index. Very easy to interpret. If you're less than 1.3, you are considered lower risk. If you're more than 2.67, you're considered high-risk. And then in between, you need to do a second test. So, this is FIB-4. And we have other, you know, scores like this. For example, the NAFLD fibrosis score, NFS, we have the safe score. but again, I think FIB-4 is the simplest, easiest to calculate, and it's been validated in multiple cohorts. That's bucket number one, which is the scores.

And I think everyone can calculate these. bucket number two is more complex, serologic test, and the one I want to highlight today is called the enhanced liver fibrosis test or ELF. And this has three biomarkers of fibrosis in it. I don't think we need to know what they are, but just, you know, for the sake of being complete, it includes hyaluronic acid, pro collagen III something we call TIMP-1, tissue inhibitor of metalloproteinase-1. But long story short, ELF is a blood test, very easy to send out and then you get a number and, if the number is less than nine typically, the patient is considered to be lower risk of having significant fibrosis. There was some earlier data suggesting maybe a lower cut point of 7.7, but today we realized that this was set too low. So, this is new, but I think nine for ELF is the cut point that we should utilize to be concerned about significant fibrosis. And then if you're more than 11.3, that can indicate the presence of cirrhosis. So, this is a serologic test, but it's a specialized test and you have to send it out and then you get the ELF, back as again a number. And if it's more than nine, you should be concerned.

And then the last bucket is imaging test that can actually quantify the amount of steatosis in the liver. And they can also determine the stage of fibrosis. And these are based on the concept of measuring liver stiffness. So, the number you get is called LSM, liver Stiffness Measurement. Typically, it's measured in a unit called Kilopascal or KPA. So sometimes we refer to it as the KPA number and, this liver stiffness, correlates with the stage of fibrosis. This can be measured with ultrasound-based technologies. The machine that we have available to most of us is called FibroScan® machine. but we have also newer technologies that can measure liver stiffness, including, Velacure™, Hepatoscope®, ShearWave™ elastography. And then you can also do the same with the MR Technology. We have a test called MR elastography. As I mentioned earlier, you know, with these imaging tests. You can also quantify steatosis and the ultrasound technology, FibroScan will give you a number called controlled attenuation parameter or CAP score. And if you do this with MRI, typically we rely on a specialized MRI called MRI PDFF, proton density, fat fraction. So again, the idea is that, you know, we have simple scores that everyone has access to. We have blood tests that you can send to a lab and get a report back. And then we have all these imaging tests that are becoming more widely available. And I think the key message is that we can actually determine the severity of the disease with NITs without needing liver biopsy.

[00:07:35] Neeraj Mistry, MD: That's excellent. That was really, really comprehensive and I remember back in the day walking up to a patient with a needle that long saying we are gonna do a liver biopsy, and it freaked me out a bit, let alone the patient. So, it's a tremendous advance that we've made to have these NITs available. But it is a complex picture of the types of tests that are available, and I want to sort of break it down a bit further, at the primary care level and then at the specialist hepatologist gastroenterology level. So, at the primary care level, what's really nice about the FIB-4 is that all those blood parameters are what general practitioners or primary care practitioners generally look for patient wellness, for routine medicals, they would pull a liver function test, and they can calculate that. Do doctors need to calculate that on their own, or is this now a standard thing that are included in lab reports?

[00:08:31] Naim Alkhouri, MD: It can be done both ways. So, you know, there's many online calculators that you can have on your phone. for example, MD Calc is one of them that I utilize. So, you can do it on your phone. You can also program it in your EMR, so you can do dot FIB-4, for example. And that you should be able to calculate it if you have the labs. And actually, there are some, EMRs where they implement this, as kind of, a routine measurement in all patients, at risk for MASLD, like patients with type two diabetes. So, you can get the FIB-4 calculated, and then if it's more than 1.3, you get an alert message that you need to look into this. And then it can be also done, when you send the labs to do a complete blood count, complete metabolic comprehensive metabolic panel. The lab can calculate the FIB-4 routinely for you. And there are some labs that actually will reflux from a FIB-4 if it's elevated to doing the enhanced liver fibrosis test ELF. So, it could be one blood draw, and then you get actually two fibrosis scores. And I think this will help streamline the referral process and the risk stratification process. So again, FIB-4 can be done several ways. But if you don't have access to any of this, you can just do it on your phone. Very easy to calculate.

[00:09:43] Neeraj Mistry, MD: And I like the, the escalation when, when there's a, an alarm with the, with FIB-4, they go onto the ELF test and that result then comes back, to the primary care physician and then they can figure out their referral pathway that they need to, to go down. when it comes to the imaging. This is something that is at a specialist level and is this at a radiology center? Is this with a hepatologist? Where do these imaging tests occur?

[00:10:12] Naim Alkhouri, MD: Again, it can be done, at, both, settings. So, in our clinics, the Hepatology Clinic, we actually do the FibroScan test as part of the vital signs. I think it's very important to have these numbers when you sit down with the patient to discuss the management plan. So, we trained our medical assistants to do the FibroScan as they do the blood pressure and check the temperature. I call the FibroScan machine and similar machines. I'm not, you know, just focusing on one machine, but you know the machines that can measure liver stiffness, I call FibroScan the hepatologist telescope. Okay? This is how you assess the health of the liver and the numbers we get with FibroScan. The CAP number and liver stiffness measurements, I call them the liver vital signs. So, again, you need to have these numbers to have an educated conversation with your patients. So typically, the patients come to us with elevated liver enzymes. We check them in, we do the vital signs, and then my MA will do the FibroScan, and I have the results before I actually sit down with the patient. That's one way to do it, but this is not available in every clinic. So, the other way is to do your initial visit and then you send the patients to get liver stiffness measurement done in a radiology center. And, again, this can be done with ultrasound-based technologies and MR based technologies. I think we want to have more of these point of care machines available at more and more hepatology and gastroenterology and endocrinology clinics, because I think it's a quick way to assess liver health and either provide reassurance or take action quickly when we see evidence of significant fibrosis.

[00:11:50] Neeraj Mistry, MD: So that's great. So, we have the tests, the different types of tests, and we have the different levels or environments in which these tests are conducted. The next thing I wanna ask. Ask because it's very often that we need to differentiate between screening tests and diagnostic tests and then staging tests. And I think then, the pattern is now starting to fall into place from what you've explained. But can you give us a bit more insight into screening, diagnosis and staging?

[00:12:19] Naim Alkhouri, MD: Yeah, no, very good question. So, I think when we talk about non-invasive tests, we talk about the context of views and what are you trying to accomplish with the test? And the first context of use is to determine the presence of the disease. And, this is, typically done in, High risk populations like patients with Type 2 diabetes patients with metabolic syndrome. And the key is that you need to measure liver enzymes. Make sure you have blood count, so you have the platelet count, and then you can screen based on the liver enzymes and calculating the FIB-4 index. But then the next context of use is to determine the severity of the disease. We need to know the stage of fibrosis and, um you know, these NITs are very good today, especially in combination, to help you determine if the patient has significant fibrosis or not. The next context of use is how do we utilize these noninvasive tests to assess response to treatment, whether it's a lifestyle intervention or weight loss surgery, or new medications like tirzepatide or semaglutide. And then how do we assess, if the disease is progressing? Because some patients may have early disease that doesn't need pharmacologic treatment, but then in two or three years they may progress, and we need to know. So, the third context of use is how do we monitor disease regression and progression?

And finally, we also utilize these noninvasive tests to determine prognosis at baseline and over time, because now we realize that liver stiffness, for example, when there is increase above a certain threshold that can predict the development of what we call major adverse liver outcomes, or MALO events. So, again, NITs can serve in different capacities and that's why we rely on them because you can repeat them over time. You can look at the delta change, and this is not typically available through liver biopsy because of its invasive nature and low acceptability by patients.

[00:14:17] Neeraj Mistry, MD: So, so that's really helpful for, for us in understanding the, the sequence of events, or how they should unfold. I wanna come back to the liver biopsy because it was considered the gold standard, and now that we have the NITs, is there a role for the liver biopsy?

[00:14:35] Naim Alkhouri, MD: I would say only in cases when there is suspicion for another diagnosis. Typically, autoimmune hepatitis, so patients with elevated liver enzymes, sometimes they have type two diabetes, other comorbidities associated with MASLD. We always rule out the presence of viral hepatitis, and that's easily done with blood tests. But sometimes autoimmune hepatitis, you have to do a liver biopsy to make sure that they don't have it. And sometimes when the noninvasive tests are discordant, you have one showing you. high likelihood of having significant disease, but then another one showing you low likelihood and you cannot figure it out. So, typically in my clinic what I do, I calculate the FIB-4 index and then I do the FibroScan on every patient. And if they're concordant showing me either lower risk for advanced disease or high risk, then I take the values as you know, this is the true, disease stage,  and then if there's discordance, typically I resort to an MRI, MR elastography, or sometimes other serologic tests. But if I cannot Figure out the disease stage, then we do liver biopsy. By implementing, you know, this sequential and concordant testing with NITs, we can actually, stage the disease in about 95% of patients. So only in 5% you have to do liver biopsy to have conclusive results.

[00:16:00] Neeraj Mistry, MD: And that's important for our primary healthcare community or primary care provider community because while they may not be managing the patient at that point, they certainly need to know what's happening. Once they make the referral to people like yourselves, hepatologist, and gastroenterologists. So, that's really helpful for our community.

One more question I wanna ask. When it comes to sort of being the detective at the primary care level, when we are chasing something, we certainly know and I think our, our audience really understands now, the, the risk factors of comorbidities that should give them an index of suspicion for steatotic liver disease. So, I think we are quite comfortable with that.

But there are a group of patients who don't necessarily have those comorbidities, they're not obese, they don’t have type two diabetes, hypertension, high cholesterol, metabolic syndrome, et cetera. What should be the suspicion and then what should the test that they conduct for those patients?

[00:17:06] Naim Alkhouri, MD: Yeah, very good question. I think, you know, to quote the. Disease, sled or MASH, you need to have at least one cardiometabolic risk factors. So, if you have none, I think, number one, suspicion should be excessive alcohol intake. And, I think, you know, doing a good job quantifying the amount of alcohol is key. But we also have a test called pet. Testing, which is phosphate, ethanol that can quantify alcohol consumption over a period of three to four weeks. So, this is a test that we are implementing routinely now in our practice. The other thing is it's important to note that we have other categories for steatotic liver disease, including what we call specific etiology, SLD. So that includes things like medications, for example, if the patient is on prednisone, tamoxifen, amiodarone, we have a long list of medications that can cause steatosis. And then we also have certain genetic diseases like Wilson Disease, for example, can present with fat and the liver. And I'll never forget, I had a patient who was 17 years old, was told she had steatotic liver disease for three years before she presented basically with ascites and decompensating liver disease. And we made the diagnosis of Wilson, and she needed liver transplant. Had that diagnosis been made. Three years before the presentation to us, and maybe if she was started on Wilson therapy, you know, we could have salvaged her liver. So very important to know that not all steatotic liver diseases, MASLD and MASH. And then hepatitis C for example, if you have genotype three that can cause steatosis and the liver. It’s important also to look at things like celiac disease in these cases. And then finally, we have a small percentage of people, we call it cryptogenic thetic liver disease, where you do the testing for common genetic disorders. You look at the medications and you just cannot pinpoint why they have thetic liver disease. I think this has to do with some genetic predispositions that we don't test for routinely. But this is a very, very small percentage of patients. But again, not all steatotic liver diseases are MASLD and MASH. So, it's very important to actually dig deeper when you have someone with no metabolic risk factors that have steatotic liver disease.

[00:19:20] Neeraj Mistry, MD: And there's two other cohorts I wanna point to as well. One is, we have, patients who are living with HIV and as a consequence of the disease and the therapy, I. They are predisposed to lipodystrophy and with the accumulation of that, and the other is a large percentage of the population that has, lean Nash. So, they're not the typical features of the comorbidities that we see. Can you talk about those two communities?

[00:19:51] Naim Alkhouri, MD: Absolutely. So, I think it's important to understand with lean MASH, we are looking at their body mass index, and this is how we define it. But these patients typically have at least one cardiometabolic risk factors. So many of them have high triglycerides, low HDL, they can have pre-diabetes or even diabetes. So, this is what we call Lean MASH. The BMI is lean, but they typically have, you know, some of the metabolic syndrome features. This is very common in Asian Americans and, Southeast Asia, and they, tend to have also the progressive form of the disease and they can end up also, with advanced fibrosis and cirrhosis. And, we have actually guidelines how to take care of these patients. Weight loss, a smaller amount of weight loss between three to 5% is still helpful. And then, managing the metabolic comorbidities is very important in this population.

Patients living with HIV also, they, as you said, tend to develop steatotic liver disease. Luckily with the newer medications there's less of the lipodystrophy, but it's still an issue. And we believe that the virus itself can lead to more progressive MASH and potentially faster rates of fibrosis, progression. And I'm glad you brought this up, because we are excluding these patients from the typical phase three MASH clinical trials, and I think this is a very high unmet need and we need to design trials specific to this population. Or I prefer to actually not exclude these patients and start, you know, including them, and, analyzing the data, as part of the total cohort, but also as a separate cohort, to see if there are any nuances and differences in the response to treatments. But I think this is important to, look into, I think in terms of lean, MASH, going back to what we do have some patients in the, semaglutide, phase three trial essence trial that had lean MASH. So more to come on this, but we are including these patients in some of the clinical trials.

[00:22:14] Neeraj Mistry, MD: That's excellent. And, you know, at the Fatty Liver Foundation, we are certainly working to mobilize various communities, which would include a webinar that we'll be co-hosting with patients living with HIV and the intersection with MASH.

Dr. Alkhouri, I can't thank you enough. This has been a very important step in unlocking the fatty liver Mistry, and, and certainly gives our primary care, provider community a good sense of the profile of patients when the index of suspicion should arise, as well as, the protocols that they can follow in order to, to get to screening, diagnosis and staging and referral. So, thank you very much and please keep up the good work, and we look forward to engaging you in future.

[00:23:02] Naim Alkhouri, MD: Thank you, my friend. I appreciate you unlocking all these mysteries for our primary care physicians and hope to join you in the near future.

This transcript has been lightly edited for clarity.