This transcript has been edited for clarity.
Seth J. Baum, MD, FACC, FAHA, FNLA, FASPC: Hi. My name is Seth Baum. I'm a preventive cardiologist and clinical lipidologist, the chief scientific officer for Flourish Research, and a past president of the American Society for Preventive Cardiology. I'm joined today by Dr Jay Shubrook, who is an expert in diabetes, nonalcoholic steatohepatitis (NASH), and prevention. We're going to be discussing NASH today.
He and I had a very long conversation about a year ago, I would say, where we discussed NASH, what was currently relevant at the time, and therapeutics in clinical development. We also discussed, more recently, guidelines that were going to be coming out. Dr Shubrook was very involved in that and will lead our discussion today on NASH and its current state in terms of management, identification, and our approach to NASH. We'll discuss cases and some therapeutics in development. Dr Shubrook?
Highly Anticipated Guidance: Practice Recommendations and Clinical Care Pathway
Jay H. Shubrook, DO, FAAFP, FACOFP: Thank you so much. I'm so glad to be here again. I'm happy to see you. I do think this is an exciting time to say that we've got some direction and some guidance as it relates to identifying people who are at risk for advanced disease as it relates to NASH. We have some guidance in terms of the evaluation and then some guidance, at least early on, about treatment modalities.
Even more useful is the Clinical Care Pathway that was published in Gastroenterology. The pathway is important because it gives us a roadmap to work from. We're all very busy. We all have patients who we're seeing and we're trying to make sure that we have effective ways to identify people for prevention. Just like our other cardiometabolic conditions, NASH is all about prevention. I'm going to highlight a couple of different figures here. (Figures 1, 2, 3) Seth, I'd love your feedback along the way as we go through this.
Screening for Advanced Fibrosis Related to NAFLD/NASH Download PDF
Evaluate for Other Forms of Liver Disease Download PDF
Management of NAFLD/NASH Download PDF
This is the working document and it's meant to be utilized in the busy outpatient and inpatient settings. I will say that if you go to nash.gastro.org, it is a good website with an app that has the ability to calculate all this and work through the pathway, all the references, patient educational materials, and podcasts. Let's jump right in.
On the clinical pathway, the first and most important thing is we need to have a mechanism to screen for advanced fibrosis. Now, of course, we know that nonalcoholic fatty liver disease (NAFLD) and NASH are cardiometabolic conditions. Running along the background, we're always thinking, how does this relate to excessive cardiovascular risk and how do we mitigate that? In terms of the liver, we need a way to screen because we know that we already have pathways from looking for other cardiometabolic conditions.
All team members should be aware of the way that we screen for NASH. There are really three ways that you might access or start to look at screening. First, based on these guidelines, any patient with type 2 diabetes should be screened for NASH. Any patient who has metabolic disease with two or more risk factors should be screened for NASH.
That's the advice, but we find many patients through other testing. If you happen to have a patient who has elevated transaminases, there is a pathway for which we want to make sure it's not other conditions. If it's not, put them in a NASH pathway. If you happen to have a person who's had imaging that shows steatosis of the liver, that's also the time probably to screen them for NASH.
Now, that is treated separately because we know that transaminases are not sensitive enough to really pick up many people with NASH, and there are many causes. We know that steatosis doesn't tell us about the risk for fibrosis. Although those tests are pathways to get into screening, they're not the recommended initial screening tools.
Seth, I'd like to hear your thoughts in terms of thinking about whether these are the people we should be screening. Does this sound like a large amount of people? Does this make sense?
The Metabolic Connection
Baum: First, I think it's great that we now have a pathway to consider. This should become top of mind because if we don't think about this, we're not going to identify these people. If we don't identify them, they're not going to get the right treatment. It's a common theme in medicine. We went through this with familial hypercholesterolemia several years ago, having to make that top of mind. This now needs to be top of mind as well.
Yes, we are going to screen many people if you look at those three buckets. The phenotype of a NASH patient is somebody with diabetes or metabolic risk factors, such as obesity, high triglycerides, and hypertension. How many of these people are there? Well, two thirds of America are overweight or obese right now. Many people have diabetes and that number continues to increase. The obesity and diabetes epidemics are really what are leading to our reversal of mortality trends in the United States, where we're starting to lose ground.
We will be screening a ton of people with this new paradigm, but we will be appropriately screening a ton of people so that we can mitigate some very significant downstream risks.
Shubrook: I do want to highlight that while that may seem overwhelming initially, I really do think this pathway is going to reduce referrals to gastroenterologists for liver biopsies and advanced treatment because it's really going to be able to help separate the high-risk people from those with lower risk.
Baum: I just want to add to that because you are a primary care clinician. It does put more burden on the primary care clinicians, but it puts a burden that is, for lack of a better way to express it, a good burden because you'll have the ability to identify people who are at great risk and, as you say, limit the referrals downstream to the specialists.
Shubrook: Absolutely. It's simple. For everyone with type 2 diabetes, it becomes part of my annual assessment. Now I can automize that and not have to be thinking about whether this person should be screened.
Reliable Assessment of Liver Health
The next step, I think, is really important. You don't need a lot of testing. You need a complete blood count (CBC), liver function tests, and the person's age. If you have those things and you can calculate a fibrosis 4 (FIB-4). You'll have it on MDCalc and it's certainly on the American Gastroenterological Association NASH app (available at nash.gastro.org). This is something that would allow you to do the early assessment for your patient. Based on the FIB-4 score — and again, these are labs we typically have in primary care — you could assess them to be low risk for advancing to fibrosis, intermediate risk, or high risk.
You have the FIB-4 scores listed there. It's less than 1.3, so they're probably at low risk for a liver-related complication. That doesn't mean that they're not at cardiovascular risk. That indeterminate risk is always the hardest one because it's in the middle range and you really have to consider a number of factors and you might have to do a second test.
Those with high risk, or a FIB-4 greater than 2.67, they're at very high risk for fibrosis and cirrhosis. They go directly to the hepatologist so (1) they can have the proper assessment and (2) they could get advanced treatments because there are many treatments coming.
The hope here is by doing this, it allows you to do the referrals where the hepatologist can help the most, it allows you do that second test when we're not clear if the FIB-4 score tells us enough, and it allows us to focus on just cardiovascular risk focus if the FIB-4 score is low. We know that weight reduction and improvement in cardiometabolic conditions are going to help not only their overall mortality, but also the liver-focused risk.
Have you calculated FIB-4 before, Seth?
Baum: Yes, I have. I will tell you, though, being in clinical research, I don't typically do it because I rely on other factors. We have a couple of FibroScans here. We skip the FIB-4, go directly to FibroScan, and then go into clinical studies or not.
As I'm listening to you, I'm thinking, wow, this is really great that we have a pathway like this. I'm also thinking that we always have to keep in mind that our pathways and guidelines are just guidelines, they're population based, they're structured to take care of large groups of people, and there are always going to be outliers.
We have to remember that we, as clinicians, are the ones who make the ultimate decisions with our patients about how to proceed. If we think that something is not completely right, because nothing's perfect here, we may go forward even if the pathway would indicate that you don't go forward in the pathway.
Shubrook: Of course, you never want it to replace clinical decision making if there's a high index of suspicion. You follow that, right? That's what makes medicine the art it is.
I love that you mentioned FibroScan because many people in primary care would then go to an ultrasound as the next step. We really don't recommend an ultrasound as a next step because it doesn't tell us anything about the risk for fibrosis or inflammation.
If you have a person you think is at higher risk or they need the indeterminate or the high-risk score, you should do a second test. That second test is a liver stiffness measurement. At least at the time of the writing in 2021, we had recommended a FibroScan because it is, again, a noninvasive tool that is ultrasound-based that allows you not only to look at the liver but also get an assessment of stiffness. Then you can see, again, three levels of stiffness associated with low risk, indeterminate risk, or high risk.
Low-risk people probably could be managed in that outpatient setting unless you have some other suspicion. For people with indeterminate risk, you're probably going to ask for some help — at least I would, being in primary care. The high-risk patients definitely need to go to a hepatologist. The goal here is to give enough information to the hepatologist or gastroenterologist to be able to have an actionable plan and not necessarily subject people to liver biopsies that may not need it.
You had mentioned that you have a FibroScan. Is this easy to do? Is it something that would be easy to implement? We don't have them available everywhere.
Baum: We have them because this is a clinical research site, but it is easy to do. All the coordinators are trained to do FibroScan and it's not a complex training. Unfortunately, it's a costly machine so that's a barrier. I think it will become more prevalent and more available as time goes on. It is already.
I really like the fact that in both your indeterminate-risk and your high-risk categories, you are suggesting referral to hepatologists, although obviously, in the high-risk category, even more so. I think that's great because if you have a kPa of 8-12 and that's in the indeterminate category, that's not a low-risk position at all.
That is a patient, given the right phenotype, who very likely does have some degree of fibrosis, it may be F1 — may not be F2 or F3 — but F1 is not a great thing. There is a frequent progression from F1 to F2 to F3 and even to cirrhosis over a lifetime. It's great that you're highlighting that. This is a really nice pamphlet.
Shubrook: We've found it to be useful. One thing that has been updated since 2021 is that one of the other tools they use to assess risk, which is the enhanced liver fibrosis (ELF) biochemical or inflammatory blood test, also has become available in the US and it could be an alternative or supplement to the FibroScan.
I think, again, depending on what tools you have available, if you're in the primary care space and you don't have either, maybe you're going to refer more often to gastroenterology or hepatology. If you have the ability to order a FibroScan or an ELF blood test, that will really help you to triage that patient just a little bit more. I do think that this will continue to evolve.
Baum: I think that's great that ELF is available. Just to reiterate that ELF and FIB-4 are both often part of these clinical studies, but I would say pretty much always a FibroScan is included. Some portion of inflammatory marker or other markers are used to gain more information and to really try to determine whether or not they can replace a FibroScan, let's say, down the road. Right now, they aren't. I'm going to just push and say when in doubt, get a FibroScan.
Baum: It does have, I think, enhanced value.
Shubrook: Again, it's noninvasive and it's affordable — when covered, of course.
The Cardiovascular Connection and Medication Considerations
Finally, I want to highlight treatment. I think the treatment is also staged into low risk, indeterminate risk, and high risk. No matter who the clinician is who's treating this patient, when you're looking at treating the patient, all patients need to have a cardiovascular assessment and need to really work on reducing cardiovascular risk.
It doesn't matter where they are on that spectrum. We're working on weight loss, blood pressure control, and reducing lipids. Again, I would highlight, unless they have really advanced disease, you're going to continue to use statins. This is not the population you're going to stop using statins because of slightly elevated transaminases. Lifestyle and cardiovascular risk reduction are universal across the board.
Now, when you go beyond that, I would say for low, intermediate, or high risk, I really want to make it even simpler than what we have on our slide here. Weight loss by any mechanism is the most important thing we can do. If it's working through a structured lifestyle program, using medications, or using metabolic surgery, these things all work but it has to be significant weight loss. It's not 50% weight loss; 10% weight loss has been shown to change the trajectory of fatty liver disease. We really need to make sure that is the focus of the priority.
Again, for low-risk people, that can be done at any health care professional's office, focusing on weight loss, doing cardiovascular risk reduction, and standard of care for diabetes, if they have it. If they have indeterminate or high risk, we're probably going to add a focused therapy that has benefits for, maybe, diabetes and has been shown to be beneficial in slowing or changing the progression of NASH.
For example, we know that, in type 2 diabetes, pioglitazone has evidence to show that it reduces the progression. I might use targeted therapy—pioglitazone or a glucagon-like protein 1 (GLP-1) receptor agonist, two of which now have pretty good data showing that a slowing of the progression of NASH. I'm doing that for the extraglycemic indication of not only helping diabetes but also helping the progression of NAFLD going to NASH.
Certainly, as we see more targeted therapies for our patients with NAFLD via NASH, they're probably going to be offered in specialty centers with hepatologists. Early referral for those moderate to high-risk patients gives them access to these trials that you just mentioned, Seth, and lets them have opportunities to have new treatments that become available that may be years away from being used more broadly.
Baum: I think that's great. With regard to the trials, there are over 50 drugs in development and tons of clinical trials ongoing for NASH. I do think referral for those studies is a great idea. With regard to treating the patients in clinic, pioglitazone has good data. It's important to emphasize it's not FDA indicated for the management of NASH, but that doesn't mean we can't do it. We do that all day long. We prescribe off label. It's important to note that just like vitamin E is not indicated, it has its place here.
Pioglitazone has some potential downsides in regard to bone loss and maybe bladder cancer. You would know much better than I about the current statistics with that. You also mentioned the GLP-1 receptor agonists. Given all that we've learned recently with regard to obesity and the GLP-1 class, and because obesity is foundational with regard to NASH, to me, it would make sense.
Given the fact that you require a 10% or greater weight loss in order to get the greatest benefit, ie, the reduction of fibrosis here, and fibrosis is what predicts the really bad consequences, which include cardiovascular death, cirrhosis, and hepatocellular carcinoma, it may be best to lead with the GLP-1 class. I'd like to know your thoughts on that at this point — not at the time of the writing, but at this point.
Shubrook: Absolutely. Again, I think that, at least in the outpatient setting, weight loss is the focus of therapy. The GLP-1 is going to be the best option there for the things we have available today. You're getting cardiovascular, and potentially, renal benefit. There are other potential benefits coming through GLP-1, and you've got the benefit for NASH. I think because of that kind of accumulation of all these benefits and really a good safety record, we would go to them, often, first.
The one caveat would be if the person has very high triglycerides. It's possible that we might use pioglitazone first to lower the triglycerides so that we show just a little bit lower risk for at least a concern about pancreatitis for those people who have a high risk already and get put on a GLP-1 — not that GLP-1s cause pancreatitis. That would be the one caveat in the very high triglyceride because you get about a 40% reduction in triglycerides with pioglitazone.
Baum: That's interesting. That's a very interesting point.
Case-Based Learning: 58-Year-Old Woman With PCOS
Shubrook: I have a couple of cases I thought maybe we could talk about. I'd love to hear your thoughts.
The first case is a 58-year-old female. She has polycystic ovary syndrome (PCOS) and she is complaining of unintentional weight gain. She's tried a number of lifestyle efforts and really hasn't seen benefit. She is, as I mentioned, 58, but she had two successful pregnancies. The largest one was about 8 lb. She's not taking any medication. She doesn't have any allergies. She asks the question I hear all the time, which is, "Well, could this be my thyroid? Is that why I'm gaining weight?"
Of course it could be her thyroid, but it could also be many other things. She does have truncal obesity in her exam. She has no evidence of thyroid disease. Just to move things forward, we did screen her thyroid and thyroid was normal.
When we look at the other lab parameters, she has what we would call diabetic dyslipidemia. She has a total cholesterol of 236 mg/dL. She has a low high-density lipoprotein cholesterol (HDL) of 32 mg/dL and her triglycerides are 264 mg/dL. Sure enough, it looks like prediabetes and slight elevation in her transaminases with an aspartate aminotransferase (AST) of 42 U/L and an alanine aminotransferase (ALT) of 48 U/L. Her A1c is 5.8%. Although she was worried about weight gain, now we're worried about another set of things.
What's your approach to this patient?
Baum: When we see a patient like this, we say this is a high-risk patient. She's obese and she has dyslipidemia. That's very worrisome. If we were to measure it, her apolipoprotein B (apoB) would be very, very high. Her triglycerides are up and her HDL is down. Low HDL, although not causal for cardiovascular disease, does predict premature cardiovascular disease, so that's important. Her fasting glucose is high. It's not in diabetes range, but it sure is getting close. Her liver tests are elevated.
There are a number of things I'd think about. My first thought is she needs to lose weight because if she loses weight, most of this stuff is corrected. The triglycerides will be improved after weight loss. During weight loss, HDL can fall, but ultimately, it will rise again. That's not going to impact her risk for cardiovascular disease, but you should note that it will happen. Her liver tests will probably fall, and her fasting blood sugar will fall.
Even though we know we can do all of that with weight loss, we still have to intervene right now and assess her for NASH because this is the phenotype for NASH. This is a person, as I stated earlier, who has central obesity, who has triglycerides that are elevated, who has a low HDL, who has elevated liver tests, who has elevated fasting blood sugar, and is insulin resistant. This is a person who has NASH. We need to move forward with that as well. Ultimately, she will require lipid-lowering therapy. That's what I'm thinking right now.
Shubrook: I love that because that's exactly what we want listeners to think about it. Yes, you can act now on those cardiovascular risks, but in addition to that, because she's got these known risk factors for NASH, take the step to start to engage that pathway as well. If we walk through that, she's got at least two of those cardiometabolic risk factors, so she's the one we should be screening.
We did her FIB-4 score and sure enough, it was 1.41, so that puts her in that indeterminate-risk category, which to your point — I love how you say it — that's not low risk. We can look at the absence of other liver diseases. She's not a drinker. She doesn't have hemochromatosis. She doesn't have Wolfram syndrome.
We check all those other things and because she's in that indeterminate-risk category, we get a FibroScan, which was greater than 12. Sure enough, this test is now showing us that this person is not low risk and really needs to move forward to see a hepatologist.
Now, that doesn't change any of the things that we're doing. We're still going to work on weight loss. We're still going to work on cardiovascular risk reduction. We have to normalize her glucose and lipids. This is a person who's going to benefit from also early intervention with the gastroenterologist so that (1) if there's a liver biopsy that needs to be done, it can be done or (2) if there's directed therapy for the liver, it can be reinforcing to all the other things we're doing.
Do you agree with that?
Baum: Yes, I absolutely agree. I think it's also important to note her liver tests were elevated so she needs lipid-lowering therapy. Many people would say, "Oh, I don't want to do it. I'm worried about the liver." We don't have to be and that's been very well documented. This is a person who should be on lipid-lowering therapy, including statins. We can follow liver tests, and that would be a good thing to do, but we don't need to worry about adversely impacting the liver. If anything, we might clear things up a bit, so I would just mention that as well.
Shubrook: I love that. Again, in the primary care setting, absolutely you should be comfortable using the statin that makes sense for that person's cardiovascular risk because you've already ruled out those other conditions. You're focusing not only on the liver outcome but also on the thing that kills most people with fatty liver, which is cardiovascular disease. You need to do those treatments.
When I'm looking at diabetes-specific therapies for that patient, I might choose things that are less likely to be hepatotoxic initially but I'm not going to use things that are going to get in the way. For example, we mentioned GLP-1s earlier. I have no concerns about using a GLP-1 in this person, given the current lab setting. It might be things like metformin or things that sometimes can take a little bump initially when you use them. Don't let those mild transaminase elevations get in the way of your good standard-of-care treatment.
I have another case. Would you like one more?
Baum: Yes, please.
Case-Based Learning: 40-Year-Old Woman With Type 2 Diabetes
Shubrook: This is a 40-year-old patient, also female. She has known type 2 diabetes. She has a history of type 2 diabetes, hypertension, and dyslipidemia. We call that the diabetes triad. She's on metformin 1000 mg twice a day. She's on a high-intensity statin, atorvastatin 40 mg daily, and she's on losartan/hydrochlorothiazide at 100 mg/25 mg. At least for many of our patients, those are three things that we expect them to be on, right? Foundational therapy for diabetes, a statin, and a renin angiotensin system (RAS) agent.
No allergies, no tobacco, and no other medication. She does have truncal obesity with a BMI of 32. I think that when we look at her, she's someone that we probably should be screening also for fatty liver disease and NASH.
Sure enough, we know that when we look at her labs, she has the same kind of diabetic dyslipidemia, 236 mg/dL total cholesterol, triglycerides in the mid-200 mg/dL, her AST 68 U/L, and her ALT is 48 U/L. She does have platelets that are 350 × 109/L and her A1c is 6.8%.
You might think that her glucose is fine, but her cardiovascular risk is not fine. If we want to now engage in determining her FIB-4 score, it actually might be relatively low. In this case, it was 0.96.
What do you think about that?
Baum: I have a problem with this because the FIB-4 is going to be low because she's so young. Just based on the equation for FIB-4, she's young and her platelet count is high. Those two things are going to make her FIB-4 score low.
To me, when I look at her, she has NASH. This is the classic NASH patient. Established diabetes, obesity, dyslipidemia, liver tests that are very high, and AST higher than ALT. This is classic NASH. I would not stop here. I would do a FibroScan on her. That would be my approach.
Shubrook: I love that. I do think it's important, as you mentioned earlier, that these guidances are just a pathway for you, but you don't let it get in the way of your decision making for the patient in front of you. This pathway is really to help you identify those people who are at high risk for fibrosis and cirrhosis.
I would say if you ruled out the other liver conditions, of course she has NASH. NASH has a number of stages, and if we keep going without any intervention, she is going to advance to a higher FIB-4 score.
If we really want to be sure, going to the FibroScan is going to let us know whether we can really feel comfortable staying with standard of care for her for comorbid conditions or if we need to do more right away. This patient doesn't have a FibroScan, so I can't tell you what it would be.
Certainly, when you see this and you're looking at it regularly, don't let the guidelines stop you from moving forward because, again, this is a young person with many years to protect.
Baum: Yes, agreed. Good case.
The Importance of Teamwork in Optimizing Patient Care
Shubrook: I hope the listeners take from this that there is some guidance now for what I think is a very common condition. It is probably a really exciting area because we're going to see new therapies that are going to be available, but patients won't get these therapies if we don't identify the condition. We really have to recognize that this is part of the cardiovascular milieu, but we can actually do things that can help reduce the most common cause of cirrhosis in the United States, as now, it's overtaking hepatitis C.
Absolutely, we want to make sure that we're doing the best we can for the number one cause of death, cardiovascular disease, and preventing these unnecessary advances in liver disease.
Again, we're a team, so they might see the cardiologist, the primary care clinician, or someone in the ER. We all need to have a high index of suspicion and not become numb, as we mentioned earlier, to the slightly elevated transaminases and truncal obesity — what is it, 90% of the population is overweight or obese now? We need to make sure that we're taking a population approach.
Baum: That was great, Jay. I want to thank you for leading that discussion. It was excellent. The cases were great. I think you provided a wealth of information and insight for me and for the audience. Thank you.
Shubrook: Always a pleasure. I enjoy working with you.
Baum: I enjoy it as well.
Image 1: Courtesy of Jay H. Shubrook, DO, FAAFP, FACOFP
Image 2: Courtesy of Jay H. Shubrook, DO, FAAFP, FACOFP
Image 2: Courtesy of Jay H. Shubrook, DO, FAAFP, FACOFP
© 2022 American College of Cardiology & Medscape
Cite this: The State of the Art in NAFLD/NASH Identification and Management - Medscape - Oct 03, 2022.