A (3:45)

And when you say terminology for patients, how do you describe this to patients?

B (3:50)

Yeah, this is a real challenge. So I basically. And this is maybe not 100% accurate, but I talk about insulin resistance at the level of the liver. Insulin resistance can affect the pancreas, it can affect the muscle, it can affect the liver. And so they say, oh, this is my. Since I have a diabetes focused practice, this is how diabetes affects my liver. And, and that can make sense to them because it ties all these organs in together.

A (4:14)

Interesting. Now, focusing on MASL D and mash, how common are they? And are there certain populations that are at higher risk than other populations?

B (4:27)

So I heard a really wise family physician say this is the most common disease you never heard of. I think I'll quote Dr. Skolnick on that. And it is really important to recognize that this is very common. 30% of the world's population has Mastle D and more than 60 to 70% of people with diabetes have Mastle D. So this is already something that's quite common. If you look at the more severe form, people with diabetes are more likely to have the severe form, which is mash. And that can be as much as 16% of people with diabetes. And so this is something that we're seeing every day. And quite honestly, if we're not diagnosing Mastle D every day in our practice, we're probably missing it because diabetes and obesity are the most common risk factors.

A (5:17)

It sounds like it. And so it sounds like it's very common. 60% of people with diabetes. Do we have any sense in people with obesity without diabetes? Are there how common it is? Are there groups within that category of obesity and whom it is more common?

B (5:35)

So that's a really great question. And I think What I would want to take from that is that if you have excessive adiposity, overweight or obesity and one other metabolic risk factor, you are in the high risk group. And so you're just like, you have type 2 diabetes. The there are people who have excess adiposity that don't seem to have metabolic disease, but that's the exception, not the rule. And so I would really say that most people who have obesity, if they have dyslipidemia, if they have hypertension, if they have an increased waist circumference, or if they have dysglycemia, they're at high risk. People with prediabetes really have very similar risk to those that have diabetes.

A (6:15)

That's so helpful. So it's common. Let's now turn to how MASH progresses. Can you go over the concept of progression from MASTL D to MASH and then where fibrosis fits in?

B (6:29)

Yeah, this is really a core concept. We actually. The liver can be a forgiving organ. So on average, and this is not universal, but you could progress from stages F0 to F4 on average 7 years per stage. So this is a condition that we're seeing progress very slowly in front of us. If we are thinking about it and paying attention. F0 means that you just have excessive fat content in the liver. Maybe you're not actually seeing markers of inflammation that can progress to F1, which is where you're starting to see some changes, maybe in the transaminases, maybe you're seeing very early cellular changes. Once you start to get to F2, you're starting to get changes in stiffness in the liver. F2 and F3 is really the most actionable stages today. And then when you get to F4, you're actually starting to see cirrhosis. And what I want to make sure you take from this is that there are not symptoms that you can rely on to look at this progression. You actually just have to be aware that this is going on quietly in the background, just like diabetes, and that we have to have evidence based screenings to identify these patients and try to get them to the right stage so we have the right treatment options for them, which I'll discuss later.

A (7:44)

I love that analogy to diabetes and how it's happening quietly in the background and how we have tools to detect what's going on with the different stages of fibrosis. Let's shift now to talk about the clinical impact of mash, both with regard to its impact on the liver, where we think about as a liver disease, but it Also has impact in other places, other metabolic diseases and heart disease. Can you go over that?

B (8:13)

Sure. So I think much of the work in masldia MASH has been focused on those liver outcomes, and they're not insignificant. So we know that MASH is a leading cause of hepatocellular cancer and either the first or second cause of cirrhosis needing transplant. And so those are quite significant liver conditions. But probably what's even more relevant to the diabetes focused practice or primary care is that the day you're diagnosed with Mastle D, you have a double the risk of cardiovascular disease. And many more people are going to die from cardiovascular disease or non liver cancers than those liver focused complications. No matter what happens with our patient with Mastle D or mash, we're really focused on those non liver outcomes in addition to working with hepatology on those liver outcomes. And so I think our work continues to do cardiovascular risk reduction screening for other cancers because this is a systemic inflammatory condition that does affect more than just the liver.

A (9:16)

Critically important, it waves a red flag for the importance of really treating all of the metabolic abnormalities for which my understanding there's a bidirectional relationship. Those metabolic abnormalities make the liver disease worse and fibrosis fat in the liver make those metabolic diseases more severe. So we've discussed that MASH is common, that it's progressive, that it has a significant effect on health. Are there recommendations about whether we should be looking for it? Obviously, Jay, there's. There are. This is a leading question. But what are those recommendations? Who should we be screening?

B (10:00)

Yeah, so first of all, I think screening needs to occur by everyone that sees the patient. This is a silent disease, and so we have to be opportunistic and directed in our screening. The screening can be relatively easy, and I want to highlight that all of the screening programs are focused on trying to find those people who are at highest risk for. For liver disease. So when we do a screening, the first screening is called the FIB4. The FIB4 is a simple calculation done with common blood tests that you would get in primary care or any practice. And it looks at the potential of fibrosis. And just to keep it very straightforward, this is something that we should be doing in any practice that sees patients with diabetes or adults that have risk factors such as obesity, dyslipidemia and metabolic disease. And with that simple calculation, you can determine whether someone is at higher risk or lower risk.

A (10:57)

Jay, I'm going to cut you off here because I want to make sure our audience knows how Simple. This is. And you said included in the fib four are things that we commonly already have in our lab tests. Some of us have used validated scoring systems that are very complicated. We what is included in this simple scoring system?

B (11:20)

Yeah, thank you for that clarification. So the Fib 4 is made up of the AST, the ALT, platelets and the patient age. And so those are things that you should probably already have in your practice.

A (11:33)

Yeah. And in many of our EHRs, I know that in ours and EPIC, you can put in.fib4 and it actually pulls in the numbers and automatically calculates it for you. If you don't have an EHR that has has that already embedded in it, you just pull out your smartphone, go to MD Calc or a lot of other choices and it's just easy to get that number.

B (11:59)

Absolutely. And if you do that, it actually gives you a place to go in terms of is this person high risk or not? I want to make sure that we just highlight that if you see someone with metabolic disease and the FIB4 is less than 1.3, it doesn't mean that you wash your hands of the concern. It just means that person's at lower risk for liver related complications. You would still want to do all the things you would do for the metabolic disease.

A (12:23)

That's important. And then what number is used as a cutoff for making the decision? Do we need to get further testing?

B (12:31)

Yeah, and there's actually what's really nice is just about all of the guidelines are starting to congeal together and have single uniform recommendations. And so as of today, the FIB4 of 1.3 is the recommended cutoff for most adults. You're going to see some recommendations that using a 2.0 for people above the age of 65, remember, the age is in that equation, so it may overestimate the risk in older adults. So 1.3 those less than 65 and 2.0 for those 65 and greater would be the cutoff for which you need to do a second test or consideration.

A (13:10)

So that, that's so helpful. So less than 1.3, they go back into a take care of metabolic disease and re screen in one or two years to keep aware if there are changes. And then above that 1.3 or above 2, what do you do as that second level test?

B (13:28)

Yeah, so this is where it gets a little bit more complicated in primary care or in diabetes care. But the current recommendation is to do some form of vibration elastography. The fibroscan is the most Commonly used in the United States. This is a combination ultrasound and elastography test looking at stiffness of the liver. It's non invasive, it can be done very quickly. And so if you have access to. That's the next best step for a patient with an elevated FIB4. Now, that's not available for everyone. So one of the things you're seeing that come out, which has been used in Europe, it is used a little bit more in the US now, is the use of a secondary biomarker or the ELF enhanced liver fibrosis test. None of these are perfect, but again, this is a simple blood test that you could order if you can get this covered. It would also give you an additional indication if the person's at higher risk for a liver related complication.

A (14:26)

And let's take those one at a time. In transient elastography, what is the cutoff that we're looking for? Because I know it uses units even that we're not familiar with.

B (14:38)

Yeah, So I think that's important, that if you have this test done, it's going to come back with an interpretation so you don't have to be an expert in that. Currently, the most common elastography is the fiber scan. And a KPA or stiffness score greater than 8 is an indicator of higher risk. And it can go up quite a bit higher than that. But any number greater than eight, you really need to have kind of a liver evaluation that's helpful.

A (15:03)

And then for the ELF test, the.

B (15:07)

ELF test has a little bit more variability in the kind of cutoff. But what you're going to see most commonly recommended is any elf score above 9.2 probably should have a further evaluation. And again, what's great about these tests is that if you order them and someone else does them, they're going to come back with an interpretation telling you whether they are lower risk or higher risk.

A (15:28)

That's so helpful. And so as we think about our approach to case finding and screening in primary care, it's a multistep process. We get that fib 4, a good number of people fall out as needed. Continued screening and attention and metabolic issues. And then we have our transient elastography and. Or ELF if it is. Let's take that next step, step one step at a time. If those are less than the cutoffs you mentioned, what do we do?

B (16:00)

Yeah, most important thing, right. Because what we want to do, that gives us an opportunity for earlier intervention to prevent all of these things. So if they're lower risk, we look at cardiovascular risk reduction which would be continue to do those things that help with that, like statin use, physical activity, weight loss, there seems to be a magic cutoff that 5% weight loss can slow progression. 7% weight loss can really be helpful in terms of changing outcomes and 10% weight loss can reverse. But in this early group, 5% weight loss would be fabulous and could really reduce their risk. So statins, blood pressure control, glucose control, weight loss are the mainstays. And then of course avoiding alcohol, which is a co factor to for this condition.

A (16:50)

So for those people with numbers below the cutoffs, it's really us in primary care that provide the bulk of care. And across a range of things, as you discussed, what do we do for people whose numbers on transient elastography and or ELF are above the cutoff?

B (17:11)

Yeah, so that's an important question. And so it really will depend on what your skill set and comfort is. But I think it's a great time to involve gastroenterology or hepatology for at least a one time evaluation to assess what are their liver related risks. And so if they're elevated, I think you get that consultation and then you two will work together in terms of comprehensive management. We're still going to do all of those things that I mentioned earlier, lifestyle, statins, avoiding alcohol, but often we're going to start using targeted therapies as well. And many of those therapies we might initiate in primary care or in diabetes focused care, but there may be also treatments that they're going to recommend. Surveillance is one of the things I really rely on my hepatologist to be doing along the way. And just like kidney disease, the sooner we get them, the more likely they can monitor them and catch them earlier if they're progressing.

A (18:04)

That's so helpful. So it really becomes team based care at that point where we all have something to contribute and we're looking for those people, people with F2 or greater. Just to remind our listeners with this cascade of testing that we're doing. Jay, we're about out of time. Do you have any final thoughts for our listeners?

B (18:25)

Mastle D and MASH are very common in your practice. There's a lot that we could be doing in primary and diabetes focused care. And no matter what stage someone's at, we have a critical role into the evaluation and treatment of those patients to prevent both liver and non liver outcomes.

A (18:44)

Dr. Jay Shubrich, you crystallized this better than I could imagine anyone doing. Thank you so much for joining us.

B (18:52)

Thank you.

A (18:53)

And most of all, of course, thanks to our listeners. We thank you for joining us on this first of a three part series on a critical and emerging public health issue. In the first episode, we focus focused on the epidemiology of mash, how it progresses, the consequences of mash, as well as who to screen and what to do with those screening tests when they come back, ranging from fib 4 initially to then transient elastography and or the ELF test, the enhanced liver fibrosis test. In the second episode, which is going to be exciting, we will talk about treatment, but both new treatments as well as future treatments. Then in the third episode, we'll bring it all together with some cases. This special series of Diabetes Core Update is sponsored by Baringer Ingelheim. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.

B (19:59)

Sam.