Early Identification of Cardiometabolic Disease: NAFLD/MASLD & NASH/MASH

QUEST WEBINAR:

Early identification of cardiometabolic disease: NAFLD/MASLD & NASH/MASH - Transcript

Presenter: Yousef Elyaman, MD, IFMCP, Absolute Health

Moderator: Trisha Winchester, PhD, Quest Diagnostics

 

Trish AI: [00:00:00] Hi and welcome. I have the pleasure to introduce our speaker, Dr. Yousef Elyaman. He's the founder and medical director of Absolute Health, where he has implemented a successful functional medicine approach to insurance-based primary care. Dr. Elyaman's impressive academic background includes being one of the first graduates of the Institute for Functional Medicine and serving as a member of its teaching faculty team.

His knowledge combines cutting edge research with evidence backed clinical applications that can be used effectively in real world patient care scenarios. Dr. Elyaman on to you.

Yousef: Early identification of cardiometabolic disease. Taking a look at nafld, mazel, and Nash mash, here are our educational objectives. Our first educational objective is to understand the prevalence and health implications of non-alcoholic fatty liver disease. So first I want to start off with the facelift that fatty liver disease has gotten [00:01:00] so over, over the years through multiple focus groups that included not only professionals, but also patients and patient advocates.

They, they finally came up with a, a name for what we used to be called. Non-alcoholic fatty liver disease, and that is maed metabolic dysfunction associated stato liver disease. And in the beginning, I, I'll be honest, for me, I'm like, oh man, now we gotta remember another name. We have so much literature with, with nafld.

But the more I looked into it, the more I was really happy with the change and, and, and it made sense. So one of the first issues was that it's non-alcoholic. Is in the name and even though it's non-alcoholic, what patients were recognizing or saying or reporting back is that even though it's, it was non-alcoholic, they would [00:02:00] tell their family that they have this and their family would, would, would think that they have a problem with alcohol.

Just the having that word in there. The other thing is, is that non-alcoholic fatty liver disease is describing the disease by what it's not. Not by what it is. So it kind of makes sense to not name it by what it isn't, but what it is. So metabolic dysfunction associated makes sense because it is a issue with metabolic dysfunction.

That's. The pathogenesis. That's what a, what? That's one of the main driving causes of, of fatty liver disease or this form of fatty liver disease. And then, and lastly, because fatty liver, the word fatty was in there. It was a bit stigmatizing. So they, so getting rid of the word fatty, they turned it into stic.

So just, you know, switcheroo, let's just call it a Latin word so people don't realize the word fat is in it. So now we have metabolic dysfunction associated [00:03:00] STO liver disease. And it is pronounced maed, like it, like there was a Z in it. Maed. So nafl became, MAED Nash became mash, and now there's a new category called.

Mash AC and what that is. Metabolic dysfunction associated stay outta hepatitis with alcohol consumption. And this is for people that have metabolic liver disease. Part of it is metabolic dysfunction associated liver disease. And the other part is because they drink alcohol and both of them are contributing to the pathogenesis.

So these are the three categories or main categories. So this metabolic dysfunction associated STA Stata liver disease or masal, really is more of a broad term and it's used to cover. A spectrum of conditions that are characterist characterized by hepatic steatosis or fat accumulation in the liver.

There [00:04:00] can be no secondary cause present, or at least that we know of that is causing that because when the liver gets inflamed, it can turn to fat. So even whether it's maed or a different condition, the liver can start turning to fat. Uh, stato is implies that there's this over accumulation of fat in the liver.

Now what that number is, and what we're looking for is if the liver has more than 5% fat in the hepatocytes, the liver is not an organ that is supposed to store fat. The liver is supposed to process and package fat and release fat. Make fat, but it's not supposed to be storing fat. So when the body gets overloaded and the liver starts storing fat, that's a problem.

It it, it affects the liver's function and it affects cardio metabolic disease. Uh, the metabolic dysfunction associated sta stat hepatitis are mash is really what, what that is, is you [00:05:00] have that mazel, but you also have inflammation happening. So it's, it's a, so there's markers of inflammation and kind of a higher inflammatory rate, and that's where you get mesh.

It's the more severe form of mazel. Prevalence. This is alarming. 38% prevalence of mazel worldwide. That means if you have a hundred people, 38 of them are going to have this. That means more than a fourth, actually, actually, actually more than a third of people have this condition, which is why it is so important.

And I applaud you for joining and listening to this because this is probably one of the most important lectures to hear in your career. I may be biased, so hi. But on a, on a serious note, it is affecting that many of our patients. The chances are you have a significant amount of patients [00:06:00] that have this, and many of them we don't even know, or you don't even know that they have it.

And that's where that's where we're gonna go over how to really pick it up and how to screen it. So what are the high risk groups? Who are people that we really want to be on the lookout for masal, well, people with obesity and features of metabolic syndrome, people with pre-diabetes or type two diabetes.

And, and if you get any type of an imaging study that comes back showing that the liver is stato, that there's fat in the liver, remember, fat is not, the liver's not supposed to carry fat. It's not a carrier of fat. So if you see any of those, then that's, that's a very high risk group. As a matter of fact, once they have that imaging study that showed that they have that fat in the liver and then it persists for every six months, they have fatty liver disease.

Now there is a progression. You start with a healthy liver and you can go all the way to mash [00:07:00] and then fibrosis and then eventually, eventually you can get cirrhosis. So it, you start off with that healthy liver and the healthy liver, look how nice and healthy that those sinusoids are, are looking in those hepatocytes and everything's working fine.

And then all of a sudden you can start getting that fat, take a look at that fat that's starting to accumulate and, and what can then happen is you can start getting this higher inflammatory process that's happening and this higher inflammatory process, you start to see fat, but also inflammation happening.

This is where you're gonna get lipotoxicity. This is when you're gonna get those liver enzymes elevated. Um, this, this is, this is, um, um, this, this then will progress into late mash with fibrosis. And fibrosis is when the liver starts to get hard. And when it gets hard, it starts to get dysfunctional. And now, now it doesn't work as well.

And the [00:08:00] fibrosis part is the really challenging one to reverse if we can even reverse it. So when it's in the other, when it's more in the mash and it's more in the, or the early mash and the ma old stages, we, we have a really, there's a good chance that we can reverse it. But once it's the fibrosis is happening, we just want to save the rest of the liver that we have.

And if we can have reversal, then great. We'll take it. So I. If you look at that Mazel, you're looking at 38 or approximately 38% of the population has it. That's just the fat in the liver. And then 20 to 25% will progress to meash. Of those people with mesh, 10 to 20% will end up with advanced fibrosis or hardening of the liver.

Now, interesting. Some people will not have elevated liver enzymes ever. They will not have, they will not have mesh. They will just have fatty liver and they will progress to fibrosis as well. [00:09:00] So you don't have to have mash to end up getting advanced fibrosis. Now take a look at this. Take a take a person, and this is why every diabetic, every pre-diabetic, you really want to be on the lookout for, right?

So. Diabetics take a look at people with diabetics. 56% of 'em are gonna have, it's nafl because like, like I said, the name is changing, but it's really maed. 50%, 6% are gonna have maed. 37% of them are going to have mash. And then 17% of those patients, almost 20%. So, so, so, so we're looking at like one in six, one in five of those diabetics have fibrosis.

They have a hardening of the liver.

Impacts of mazel. Historically, we were very limited in treatment options, but there are new treatment options available that, that can improve impact care. Um, we, we, we have the GLP that are being studied. Um, there's, there's different studies [00:10:00] that are in research centers. we actually had our first FDA approved.

Drug to treat the fibrosis Stage two and three fibrosis for fatty liver disease. It's called ResMed, and what it is is it's a thyroid beta agonist.

It turns out that thyroid receptors, there's two types of thyroid receptors in the body. There's alpha and beta. Beta are in some organs, and alpha are in other organs. It turns out that alpha is in the heart and for thyroid receptors and beta is in the liver.

So this is a beta thyroid agonist. So it does not affect the heart. It doesn't increase heart rate, but it als, but it stimulates the liver. In order to, in, in order to increase its metabolism. And what, what, what it makes us think of in personalized medicine is alright, that means that if we can optimize thyroid levels, then that may be part of our [00:11:00] full work, full treatment plan when we have these patients in front of us.

This talk is not about therapeutics, it's about diagnostics, but, but just sharing some of our. My clinical insight and my, my clinical experience. Alright, so now the prevalence of fatty liver disease is increasing and there's a, a notable increase in the advanced stages of, of the condition and mash is one of the top causes of hepatocellular carcinoma.

Now, this is pretty interesting and important because it used to be that hepatitis, viral hepatitis was a leading cause of, of cancer. Now if you have somebody that has this fatty liver maed, and then, and, and in particular mash you, they have a higher risk of, of ending up with, with hepatocellular carcinoma or cancer of the liver.

A reason to get an ultrasound in in these patients and to follow ultrasounds. Our second educational objective is to [00:12:00] review the latest theories on the pathogenesis of fatty liver disease. So what is causing it in the first place? If we really want personalized medicine, we want to know what the causes are.

We don't wanna just say, this is a, this is the diagnosis, here is the drug. Here's the diagnostic criteria, let's make the diagnosis. This is the drug. No, let's take a deeper dive and let's take a look at what it is that, that, um, it may be driving this in the first place. So one of the things that could cause it is, is dietary glucose and, uh, elevation of dietary glucose and insulin resistance.

So too much an excess of dietary glucose or sugar. And you're gonna find a glucose, of course, from your carbohydrates, from rice, from pasta, from bread, from grains, and of course sugary and, and, and, and sweets. Now that when that glucose starts to get elevated. And, uh, your, you first start to get, your insulin levels start to [00:13:00] elevate, and then you start to get insulin resistance, and then your glucose itself will start to elevate and they get pre-diabetes.

When that happens, when that elevation happens, then there is a enzyme called aldose reductase will, which will convert the glucose to fructose. And if you look at diabetics, diabetics have higher amounts of fructose in their cells and in their blood. Well, that what the, the issue, we'll talk about that later, but one of the issues with that is that higher fructose or fructose, what that does is that can push an increase.

The, the accumulation of uric acid and uric acid can play a role in fatty liver disease anyway. So also having the higher amount of sugar, um, when you have too much sugar and it comes in contact with a protein, I. Or, or, or, or with a fat, you can end up with these advanced glycation n products. And an indirect way of looking at advanced glycation n products is looking at a A1C [00:14:00] hemoglobin that we look at in diabetes and prior prediabetes.

However, however, that process, that caramelization process happens in other tissue, including the liver. And it can lead to advanced, or it could lead to mazel or a worsening of fatty liver disease. Now, the other thing too is that they're also finding that when you consume a lot of advanced glycation end products, like, like foods that are, have sugar or fat.

And, uh, and, and, and, and protein, and that sugar is in it and they're cooked at very high temperatures. Then you create those ages as well. And those ages are pro-inflammatory and can lead to inflammation, oxidative damage, and, and liver disease, progression of liver disease. Now. Increase insulin resistance.

So when you have insulin resistance first, what happens is higher amounts of sugar, then you get higher amounts [00:15:00] of insulin. The body, when you start overloading those insulin receptors, then the insulin receptors on fat cells, they're not going to work as well. When? When they don't work as well. When then, then what happens is, is that there is a, the enzyme in your fat cells called fat sensitive.

Lipase. And what that does is that it is responsible for breaking down fat into free fatty acids. When you have insulin, insulin normally is going to suppress that, but when you have insulin resistance, then then, then that lipase gets activated and it starts creating free fatty acids. And those free fatty acids go into the bloodstream and from the bloodstream they go into the liver, and then the liver repackages them.

And what does it do? The liver will start. Turning it into triglycerides and it'll start turning it into VLDL. But what type of [00:16:00] VLDL? It's going to turn it into triglyceride rich VLDL, triglyceride rich, VLDL is responsible for when it's broken down, becoming tiny small density LDL. So your LDL or bad cholesterol can be the big fluffies or the really tiny ones.

Well, when you have insulin resistance and then you have that, these free fatty acids that are being released in the fat and going to the liver and then going back to the fat and then going back to the liver and that process, what's happening is you're creating the really tiny BA LDL and that really tiny LDL is more atherogenic.

It's 1.7 times hot, more likely to. Go through and penetrate the endothelium causing atherosclerosis, and there's a higher chance of it getting glycated and oxidized, causing the pathogenesis of atherosclerosis. Now, when that's happening, you can get an increase intake of hepatic iron. So now the, the, the liver starts getting accumulated with iron.

Which worsens the pro [00:17:00] process, increased triglycerides, synthesis, like we mentioned. And, um, I, I, I'll tell you though, so it just because triglycerides are okay does not mean your patient is okay because there is an enzyme in the liver called hepatic lipase and it's responsible for breaking down triglycerides.

And some people have higher amounts of hepatic lipase and those higher amounts will cause their triglycerides to look normal or optimal when they're really not optimal. And how can you tell? When you look at their small density, LDL on advanced lipid panel, you'll be able to see that that's elevated.

And actually that's small density. LDL on the advanced lipid panel. It, the higher that number is, the higher your risk. And if you have somebody. That you're putting on some sort of a plan for fatty liver or for masal. When you see that small density LDL start to decrease, you know that the, the, their load, the amount of fat in their liver is improving.

Now the it also this increase glucose and insulin [00:18:00] resistance can contribute to adipokine abnormalities. We'll talk about in a bit low adiponectin, elevated leptin, and elevated resistant. You get lipid peroxidation, free rad oxygen, radical species as well. And then you can get a depletion of glutathione and vitamin E.

Then we're gonna talk about that in a second, but. Glutathione is the ba body's main antioxidant. And if that's getting depleted, that means that there's a prooxidant state and the body is overwhelmed and, and it can't keep up with the oxidative stress that's happening in the liver. Vitamin E there's actually research that shows that Vitamin E may help with liver disease, with, with, with mazel, and with even with fibrosis and, and I mean, it's, it's early studies and it's not, it's not set in the guidelines yet, but.

Part of it may be because it's that vitamin E is getting depleted, but know this, there are different forms of vitamin E over the counter. Um, vitamin [00:19:00] E, normally people will get in the form of D alpha tocopherol and D alpha, co alpha tocopherol is the synthetic form of vitamin E, but it turns out there's eight forms of vitamin E, alpha, beta, delta, gamma, tocopherol, alpha, beta, delta, gamma, tocotrienol.

All eight of them are naturally found as vitamin E. And one of the theories is, is if you just give one the D alpha tocopherol, which is the one that is more readily available in supplements, although there's others that are the mix, is, is, is available. But if you just give the one, you're blocking the other seven from getting in and you're making a more vitamin.

E Vitamin E deficient, which is why in the literature there's data that shows replacement of vitamin E might be good for a cardiovascular system, some showing that it might be bad and you might have increased all types of morbidity and mortality. And it may just be the form of Vitamin E used. But in general, the, the study that was showing maybe some improvement with fatty liver was looking at a mix of eight forms of vitamin E, alpha, [00:20:00] beta, delta, gamma, tocopherol, alpha, beta, delta, gamma, toca, triol.

All right. There's the, there's a correlation between intact insulin and Mazel. So, so the positive predictive value for Mazel is about 79%. When, when, when your intact insulin level is greater than 10.5, and mind you, 10.5, most labs will go up to 20 as a normal, right? So if you're at 10.5, the lab will look green.

So just be careful of that if that level is higher. It, it greater than 10.5. You want to think, does this person have the maed? And then 85, the PO positive predictive value is 85 when the insulin resistance score is greater than 31. So now that already tells you, part of our panel that we can look at is we can look at an insulin.

Um, I like looking at a C-peptide and I also am gonna wanna look at this insulin resistance score. Because remember, [00:21:00] insulin resistance causes what it causes the hormone sensitive lipase to be to, in the, in the fat cells. It causes, it, causes it to, to, to be able to go rampant. So the resistance does not turn that off.

And then that hormone sensitive lipase is gonna start breaking down those, those fat cells and releasing those fatty acids. And the fatty acids are gonna get packaged and sent to the liver and the liver's gonna send it back to the fat and back. And you get caught up in this vicious cycle, right?

 All right. Pathogenesis of MAs continuing. So. Fructose and uric acid. Very interesting research. So traditionally we always thought of uric acid as a more of a, more of a predictor of gout, and it turns out that uric acid actually is more than just gout. It actually is a survival mechanism that is put in place in, in, in, in mammals so that when uric acid levels [00:22:00] would go up, they would, they, it would increase the storage of fat and it could in, it could also increase the storage of fat in the liver and it can decrease nitric oxide and, and, and, and, and significantly, significantly increase the risk of cardiovascular disease.

So, but, but how's it happened? We always were told that, you know what? That if you have high uric acid, then uric acid is a disorder of purine metabolism. And, and, and, and, and since it's being that then decrease like liver and foods high, high in these purines. But what, what we're finding out now is that, is that when you consume lots of fructose, then the liver, uh, especially, especially in ways that it's not found in nature like juices or beverages, and you get high hits of, of, of, of fructose or fructose, what ends up happening is when the liver processes it.

It actually will needs a TP. And remember what a [00:23:00] TP is? Adenosine, tri phosphate and adenosine is adenine and adenine is a a a is a purine. And, and what happens is, is that as you're using, your body is, is metabolizing and dealing with the fructose, uric acid levels are going up. And when uric acid level is going up, it's telling the liver to make more fat.

It's telling the liver to not break down fat. And it can a among with other cardiometabolic things that elevation in uric acid may cause, may cause a fatty liver disease. So, uh, elevation in fatty and and uric acid can increase triglycerides, it can increase oxidative stress, increases fat storage and decreases fatty acid oxidation.

So fat is gonna stay in the liver more now. What about hepatic iron? So if you have an elevation in hepatic iron, that does increase your risk of a more worse progression. But, but the, what's interesting is that if you look at, when you're looking at the [00:24:00] classic genetic disorder of, of iron overload, and that is hemochromatosis, you could be heterozygous, which usually they say you don't have the phenotype, meaning that you don't express a problem, you just are a carrier.

But there's actually some research that shows that if you have one of the genes and your heterozygous, you may be at increased risk of mash. So, so I would, I would want to take a look at the, the iron levels. That doesn't tell us what's happening in the liver, but I can tell you if it's high in the blood, the chances are it's gonna be high in the liver.

But what happens is, is that when that process is happening, then you have this hepo, this parenchymal hepatic iron that accumulates and it generates free oxygen, radical species. What does your body need to do for that? It needs antioxidants. And remember, you, you get depleted in [00:25:00] antioxidants in particular vitamin E, you get depleted also in of glutathione.

So that's part of the damage that's happening. So the parenchymal, hepatic iron. Correlates with the severity of fibrosis. So the more iron that's in your liver, the higher and the more severe the fibrosis or the hardening of the liver. But remember, just because it's normal in blood doesn't mean that's not what's happening in the liver.

And, and, and in that case, as long as it's not like a hemochromatosis thing that is fueling some of that iron in the liver, the decreasing that inflammatory process should be our goal so that it's not taking up that iron. All right. A depakine abnormalities. We had already said that insulin resistance can lead to adkin abnormalities.

You have leptin that can be released from fat, and what that does is it increases inflammation and it can, may, may contribute to the development of fibrosis. You [00:26:00] have resistant, also made in the fat, which also can, in, can, can increase, can, can be pro-inflammatory and, and cause that process to be worse.

And when fat cells are unhealthy, our adiponectin levels go down and adiponectin, actually, you want them high. Because adiponectin is, is is what its role is, it's going to help clear lipids, and it's going to help with insulin resistance, and it's gonna help enhance beta oxidation of fatty acids. And it's going to suppress TNF alpha.

And what happens in this, in, in, in, in this whole thing, is that you will, with, with, um, um, with, uh, with unhealthy fat cells, your adiponectin levels will go down, worsening the problem. Dysbiosis. So much research now coming out about gut bacteria and the role that they play. As a matter of fact, there's research that indicates that our, our gut bacteria can be as metabolically [00:27:00] active as the cytochrome P four 50 system, so small intestinal bacterial overgrowth.

Is has been associated with fatty liver. If you look at things like, uh, inflammatory, I'm sorry, not inflammatory, but um, irritable bowel syndrome. A large subset of patients with irritable bowel syndrome, we have found, actually have small intestinal bacterial overgrowth. And that's where the small intestine that's not supposed to have that much bacteria get overgrown with bacteria.

And that is going to lead to an increase in permeability of the, of the intestinal wall. And that increase in peer mobility, in, in peer mobility can cause things to leak into the bloodstream that really don't need to be there. And they can make their way to the liver. Liver and also endotoxemia. So now from the lipopolysaccharides of the bacteria.

They can leak into the bloodstream, they can increase TNF alpha and they can worsen the pathogenesis. So when they, you have people with irritable bowel symptoms, you want [00:28:00] to think, Hey, does this, uh, does this person have fatty liver as well? And remember, you want to differentiate irritable bowel from inflammatory bowel.

Um, definitely if they have these symptoms, you wanna make sure they have had a colonoscopy and a little pearl. There's a test that you can do a stool for calprotectin. And if that's high, if the calprotectin is high, um, greater than a hundred, you gotta worry about inflammatory bowel versus irritable bowel.

But if it's low, then you think it's more irritable bowel. Just a little side pearl. All right. I wanted to mention this as well. There's something called a condition called. Um, TFL as well. And it's not the same as Mazel. This is when you have those patients and those patients don't have the traditional list.

The risk factors for fatty liver, maybe they're thin, um, but there's in industrial chemicals that they've been exposed to and that can cause the fatty liver. I just want you, if when you see the fatty liver, I do want, want you to be aware of that. So [00:29:00] diagnosis of Maslow, the diagnosis requires all of the following.

You want to show hepatic steatosis by imaging or by a biopsy. You want to exclude significant alcohol consumption. Remember, if it's a mixed, it could be kind of a mixed maed with ac, with alcohol consumption. You wanna exclude other causes of hepatic steatosis and you want to rule out coexisting chronic liver disease.

It can't be due to something else, which will make us think it's me metabolic associated all. So a hepatic ultrasound is a good test, but it's not perfect. There's, it has an 85%. Sensitivity and a 94% specificity compared to a biopsy. So it's gonna miss, for, from a sensitivity point of view, it's gonna miss about 15% of people that actually have it.

And this sensitivity's decreased in OBA obese [00:30:00] patients. So there are other tools we can look at. And I wouldn't just rule it out based on a, a, a abnormal, or a, I'm sorry, a normal, uh, ultrasound. Let's say you got a CAT scan and it showed fatty liver disease. The ultrasound was normal. I still wouldn't call that normal, but you could do, we'll talk about it later, something called a fibro scan.

Alright. You wanna exclude secondary causes of steatosis, so you wanna make sure it's not due to excessive alcohol consumption. And there is a, there's that, that PETH level, if you're not really sure, you can get that blood level and it'll give you about three weeks of what their alcohol consumption has been like.

You're going to want to rule out hepatitis C, you're gonna wanna rule out lipodystrophy, you're gonna rule out certain medications. You're gonna make sure that it's not a pregnancy associated liver disease ray syndrome. You're gonna rule out malnutrition the A beta lipoprotein anemia and also rare [00:31:00] autoimmune causes.

We already mentioned hemochromatosis ruling that out. Autoimmune hepatitis. You're gonna wanna rule out alpha one antitrypsin. Remember sometimes they get liver disease and lung disease. That's a genetic alpha one antitrypsin deficiency. And then Wilson's disease as well. And remember, with Wilson's disease, Wilson's is a excess amount of copper.

But when you check your copper levels, sometimes your copper levels will be low and they have Wilson's disease and that's because the carrier for copper ceruloplasmin can now also be low. So if you see a low copper level, make sure you check ceruloplasmin. And if ceruloplasmin is low, then it's it. It's Wilson's disease till proven otherwise.

And what you would do is you would do a 24 hour urine copper and make sure they don't have excess copper. All right. So laboratory tests, you can do A CMP, um, you can do a GGT. Now let me just give you a little [00:32:00] pearl about GGT. Usually we look at GGT as just a marker of, of, uh, or like a, another liver enzyme.

But the, what, what it's really looking at is the depletion or the use of glutathione. As your glutathione is being used, your GGT is going up. So when I see A GGT elevated in that top third of normal to even higher, then that's gonna make me think the patient is undergoing oxidative stress. I. Is it happening in the liver?

Is it happening in the blood vessel? Is it happening in the brain or is it happening all over and it's probably happening all over? So you get Hepatitis S serology, you're gonna look for viral hepatitis, you're gonna check an iron panel. Ferritin, you're gonna consider checking your, I would get a, it's called an autoimmune hepatitis panel, which is gonna check your anti mitochondrial antibodies or antinuclear antibodies, antis smooth muscle, an antibodies, and it's gonna check your immunoglobulins.

But also you can check in alpha one L antitrypsin level to make sure they don't have alpha one antitrypsin deficiency. So how do we assess the risk of [00:33:00] fibrosis and progression? Because somebody could have masal but they don't have fibrosis happening. Um, how, how can we take a look at that? Do we have to do a biopsy every time?

No. You, we have clues. So an elevation in GGT could be a clue that they have fibrosis. We also have the FIB four. That is a clue that to, and, and we'll talk about that in a second. And then we have the ELF score that also can clue us to them having fibrosis. This is interesting. This is showing us that an increase in GGT levels was a risk factor for advanced fibrosis in nafld now called what?

MAs. Alright. What is a FB four? Fib four is an equation. It's basically basically looking at someone's age, their a ST, and then it's going to look at platelets and a LT. But bottom line, bottom line, what it's looking at is what are your platelet levels? Even though they may look normal in the lab, what are your platelet levels when it in relation to your [00:34:00] liver enzymes?

Now, why would platelets be important here? Well, because the liver is responsible for a hormone or making a hormone called thrombopoietin, and thrombopoietin job is to make platelets. So when you start getting fibrosis or hardening of the liver, it can't make thrombopoietin. If you can't make thrombopoietin plates are going to go lower than you would think.

So fib four is something that we'll talk about in a second. You can actually add that calculation. You could get a CMP with a Fib four, or you can use one of the online calculators. Put in the platelets, the a ST, the a LT and the age, just realize that it is age driven. So once they are greater than age 65, um, and also less than age 35, you're going to, it's not going to be as accurate, take it with a grain of salt, and it's really not as sensitive as other tests that we have, which we're we'll talk about.

All right, so fib four. What populations are, do, are, is the, are we [00:35:00] recommending to screen pre-diabetes, diabetes type two hepatic steatosis and elevation of a ST or a LT? Um, there's good research that shows that a LT levels don't just go by the lab reference ranges. In women, you want an a LT less than 25 and men less than 35.

Just remember that because there's research that's showing that. That, that higher end of normal may not be normal. It may be, there may be a process happening. So patients with obesity and or uh, or or two metabolic, um, cardiometabolic risk factors, metabolic syndrome. Anytime we get a lipid panel in our office, we just do A CMP with a fib four.

So it gives us the calculation, we know the limitations of the test. If the FIB four is high, we don't freak out. We further evaluate it, but it kind of helps us. So what do we do with that? High Fib four. Well, the high Fib four will have us checking other [00:36:00] tests like an ELF score. So, and we'll talk about that in a second.

When you look at that, fib four, you're gonna get three ranges. You're gonna get the low, which is absence of fibrosis, not fully, because it's not as sensitive as we'd like. You're gonna have an intermediate, and if it's a higher risk, you're gonna wanna rule out fibrosis. Now let me just give you a little clue here, or a little pearl here.

We said that your fib four is gonna be elevated because your platelets are gonna be low because with fibrosis you can't make enough thrombopoietin. And if you can't make thrombopoietin your as much as you'd like, then your platelet levels will go down. Well, there's another thing that can lower your platelets, and that's alcohol.

Alcohol can directly. Poison the bone marrow and it can suppress the production of platelets. And that's why if they're drinking alcohol, you can't go based on the Fib four. You gotta keep them off alcohol for some time and then you can recheck it. But like I said, there's other checks we can, tests, we can [00:37:00] do.

And with Quest Diagnostics, we like getting the comprehensive metabolic panel with a fibrosis for. So the calculation is done for you. You just gotta be ready. If it's elevated, you don't want the patient freaking out. What we find is it's an attention grabber. We say, look, your platelets are lower than, than, than, than, than, than, than the calculation think they should be.

This test isn't perfect. Let's take a look at your liver a little bit deeper. Don't, don't freak out about this. All right. Now we have the ELF score. The ELF score is a really good test at picking up the potential of having this fibrosis. Um, what'll happen is, is it's going to look at different biomarkers of cirrhosis or fibrosis, and you're gonna end up with a score.

And if the score is 9.8. Or less than 9.8. You have lower risk. If it's greater than 9.8, uh, up to 11.3, you're kind of in that mid. And if it's greater than or [00:38:00] equal to 11.3, you're a higher risk of having fibrosis. You're gonna want to go, you're, you're gonna want to get a, uh, go another level. Um, all right, so MASH enhanced report.

What the nice thing about Quest is that, or Cardio iq Cleveland Heart, is that they have these nice graphics. So when, when, when you have the Fib four, it's gonna show us a graphic and it's gonna show the patient this graphic and they can kind of help explain to patients what it means. And the same thing with the ELF.

There, there's a really score. And remember, ELF, think of elf, think of a little elf running around. But it's not Santa's elf. It's a little elf that's causing fibrosis in your liver and it's not good. Alright, so. Another, this is something that I'm very excited about, the ultrasound based elastography. Um, we can also call, it's also called, um, by the name brand FibroScan.

And this is a non-invasive way [00:39:00] using ultrasound technology to take a look at the liver and it's gonna be more sensitive and, and then than ultrasound, but it's also gonna give us two numbers. And this is noninvasive, which is wonderful. It's gonna give us something called a cap score, and it's gonna give us a fibrosis score.

Cap score is telling us what percent fat is in the liver, and this is why it's a game changer. When I had a patient before and that patient had fatty liver, I would tell the patient they have fatty liver. I would put 'em on some sort of a plan, a lifestyle plan, and then, and then we just maybe can get an ultrasound in a year and see if they still have or don't have fatty liver.

But it's not, it, it, it's kind of like a. Like a yes you have it or no, you don't. I can't tell if they're getting better. So yeah, you could look at a small density LDL, which may help us, but with the CAP score, you can actually tell them, Hey, listen, your cap score is about two, is two 40, which means about 11% of your liver is filled with fat.

It should be less than five. Or you listen, it's two 60, about [00:40:00] 35% of your liver is filled with fat. It should be less than 5%. Let's check in again after we do certain modifications and let's see if it improves such a, it's, it's, so, it's, it's not a perfect test, but to be able to give them a number is really helpful.

And then the nice thing is, is it gives us a fibrosis. Number two can tell us is fibrosis actually happening? So definitely there are advantages to using this over, over getting a liver biopsy. Um, I, I don't know about you. If you could do a really good screening test, rule out test with blood, would you want to get a needle in your liver?

And the answer is no. I mean, some people need it, but, but to be, get an, to do these non-invasive tests to be able to do the ELF, the fib four to be able to do the ultrasound based elastography or the, or the, or the, um, FibroScan [00:41:00] that gives us good info on whether we need to go to a liver biopsy or not.

Our third educational objective, recognize guideline recommendations, testing and clinical assessment and management of non-alcoholic fatty liver disease, or now known as masal. So take a look at the 2022 recommendations for the diagnosis and management of masal and primary care and endocrinology clinical settings.

These are the guidelines. They basically say if you have a higher risk group, look at the Fib four. If the fib four. Is going to be, uh, elevated, then you're gonna look at either a ELF or you're gonna look at elastography. And then based on that, if they're low risk grade, if they're intermediate risk or high risk, you're gonna think about referring to a liver specialist there.

With the amount of people with fatty liver, with masal, it is impossible. We do not have enough hepatologists to deal with this. So this is a nice, [00:42:00] easy way of risk stratifying and seeing who needs the hepatologist and who does not. And the nice thing is, is there's a lot of research centers now that will do these fibro scans for free.

And a lot of times they have a hepatologist on board and they're putting, enrolling patients in these studies to try to help them. So just a little tip, take a look and see if there's a research group in your area. And, and just because they get the fibro scan from them doesn't mean that they have to enroll the study, but it could be a nice screening now.

Now let's take a look at this. What do I do? I don't just go by the fib four. Many times, if they're very high risk, I will do a fibro scan. It's a non-invasive test, and I will, and, and, and, and I also like checking an ELF even if the FIB four is okay. 'cause if I have a FibroScan showing fibrosis and then, but the, but the fib four is okay.

That ELF gives me another piece. But at the end of the day, just make sure that you're not letting your patients [00:43:00] slip through the cracks that really need, uh, a more elevated level of care and need more of a team management. So comorbid morbid conditions and complications. So, so comorbidities. People that have masal have a higher chance of type two diabetes, two to five time increased risk incidents, uh, uh, in incident diabetes when masal is present.

So if they have Maslow, they have a two to five time increased risk, two times as likely to have lipid abnormalities. Two times increased prevalence of chronic kidney disease. But this is the thing, this is back to w when we, when we're looking at pathogenesis, when we we're looking at what's causing things, we don't wanna say that there's five isolated conditions that have five isolated pathogenesis.

Right. It's not like, oh, you have fatty liver, plus you have type two diabetes, plus you have cardio atherosclerosis, plus you have kidney disease. The same underlying imbalances that causes one causes all of them. Plus what is the liver? The [00:44:00] liver is the center of metabolism. All that metabolism is happening and processing within the liver.

If the liver is off, if it's filled with fat and filled with inflammation, it can't work. It doesn't work as well. It's gonna cause all these other things. So instead of just looking at as, oh comorbidities, we really wanna look at as a unified driving pathogenesis that is leading to different phenotypes or different diagnoses.

Alright, so just showing us the interconnect connectedness. If you take a look at complications of non-alcoholic fatty liver disease, the most common cause of death in people that have masal is going is going to be cardiovascular disease. That's the most common. So you work on their fatty liver disease and you get that better.

You are decreasing their, their risk of cardiovascular disease, but be mindful of that. Uh, they don't usually die from the liver disease. They die from this, the, the, the next complication with cardiovascular disease, but also [00:45:00] they do have a higher chance of hepatocellular carcinoma and end stage liver disease.

And that also is a complication and which is why we're gonna wanna watch it. And the fourth educational objective, I'm excited, but I'm also sad because our journey is about to kind of take a little break once we finish this, but create a personalized laboratory workup for patients with fatty liver or masal.

So let's take a look at some personalization. Mazel is one of my top priorities. When I see patients, I have not seen a diagnosis that drives people to change more than this. When I tell them I'm worried about their liver, they stop drinking, they start eating healthier, they start. As a matter of fact, sometimes I'll see an isolated elevated liver enzyme and I'll talk to them and they leave and I send them to get a fibro scan and I send 'em to get the workup.

And by the time they come back to me, they didn't even [00:46:00] have fatty liver disease, but they've lost like 10 pounds and they're much healthier. And they gave up bad habits because, because for some reason people when they hear that their liver is off. It can drive them to make changes. Now, we don't wanna scare the crap out of them, but we don't wanna make it just dismissive either.

So when I see that they have fatty liver disease, I'm gonna latch onto that because I know that when I latch onto that, and if I can get the patient's attention and we can work hard on reversing it, what happens is I'm reversing all the different cardiometabolic diseases that can lead, or, or that the underlying pathogenesis could lead to.

So, so, so, but you focus on the liver and you watch that liver get better, you're watching that patient get healthier. I obtain a liver ultrasound it, um, almost usually with all of them. And I, I'm gonna wanna check that every once in a while, especially if they're not getting better. Um, any type of elevated [00:47:00] transaminase to me is an opportunity to get a deeper workup and to make sure that it didn't just uncover, maybe they had a virus that uncovered, or a illness that just uncovered something that was brewing in the liver.

I'm gonna try to get a FibroScan if available. I would try if it's available in your area, and refer if it's indicated. Remember the guidelines refer to hepatologists if indicated, but you can work on managing that patient's cardiometabolic comorbidities. I'm gonna track and monitor the patient. I'm going to work on a 10% body fat loss because there's great data that shows a reversal of fatty liver.

But I will, I will tell you this, if all you do is get 'em to lose weight, and let's say that they lose 10%, but they still have an abundance of fat and they keep maintaining that lower weight, but they don't start making healthy lifestyle changes, their liver could start filling up with fat again. Right?

But when the process happens for them to lose fat, the same thing in this happening to digest [00:48:00] the fat in the liver. But I, I would work on, there's really good data I. On a, on, on a modified Mediterranean food plan. There's good data on exercise, me, Mediterranean food plan and exercise independent of weight loss can help with fatty liver, which is, which is nice, which is where you don't, they, they just have to change some of the things they're eating and increase their activity.

They don't even have to lose weight on the scale to see an improvement. I'm gonna get the CMP with a fib four. I'm gonna check an ELF. I'm gonna check a C, B, C, like we mentioned, an insulin resistance panel with a, with a insulin, with with a score. I'm gonna check A A1C hemoglobin, A uric acid, high sensitivity.

CRP. I'm gonna want to look at ferritin iron. Iron binding capacity. Transferrin saturation. I'm gonna look at tra triglycerides. Remember what was that enzyme? If that enzyme is high, tri growth size is gonna look fine, even though the liver's not, it was called hepatic lipase. Well, I'm gonna look at an A small density LDL because it [00:49:00] correlates with disease.

I'm gonna look at oxidized LDL because if oxidation is happening, rust is not good, especially for fatty liver. And I'm gonna look at A GGT because if that's high, what's happening is I know that there's an oxidative process happening and the body is using too much glutathione. And I'll just throw another one in there.

I'm gonna check a homocysteine because if homocysteine ISS high, it is associated with a higher risk of fatty liver and homocysteine, is it Being elevated? Tells me that they may have the MT HFR gene mutation. They may have the B12 deficient V six or folate. Folate deficient. And if they have M-T-H-F-R, I may need to give, think about optimizing them with methyl folate.

I closely follow the ones that are abnormal. They don't check every one of these every time. And of course I ruled out all the other stuff. I am going to be mindful that this, as I work on the liver, the diabetes may be improving and the cardiovascular disease may be improving and the kidney disease may be improving.

[00:50:00] I realize that, that those small lifestyle interventions may be going a long way. Um, take a look at this cheat sheet. When you get a chance, it's basically looking at the, at risks based on the lab. So your insulin oxidize, your insulin is kind of, uh, looking for a risk for fatty liver. When it's high, that oxidized LDL is starting to look for a, there's, there's a, a risk of mash along with a LT high, a ST high, um, that is going to be pushing more for, oh, man, do they have mash?

And then do, are they, so, so, so, so now they have inflammation plus fat, and then are you starting to get fibrosis? That's where the fib four come in. That's where. The, the, the liver, um, um, that's where the, the, the ELF is gonna come in as well. So our educational objectives were to understand the prevalence and health implications of non-alcoholic fatty liver [00:51:00] disease.

And we got a bonus. We not only went over prevalence and how prevalent it is, but we also went over a little bit of that identity change or name change. It's now maed. We were to review the latest theories of pathogenesis of fatty liver disease, and we did that. You have insulin resistance, you have elevated fructose and elevation of uric acid.

Um, you also, you also, we also have, um, advanced glycation end products and small intestinal bacterial overgrowth and iron overload. Just to mention a few. We were our, our next, our third objective was to recognize, or the guidelines, and we did that, the pathway check, the guidelines of of, of monitoring and when to refer and when not to refer.

If that ELF is high, you're gonna. You're, you're gonna, or if that fib four is showing fibrosis, you're gonna wanna refer to hepatologist and the last list of create a personalized laboratory workup for the [00:52:00] patients. And we did that. Um, thank you very, very much for, for tuning in. I hope you tune into more of our content.

And with that, it is time for some questions.

Trish AI: Awesome. Great job. Thank you Dr. Elman.

Yousef: You are welcome.

Trish AI: All right. Um, so I learned a lot from your talk. Thank you so much for reviewing that. I think it's, uh, refreshing to have a holistic, uh, in-depth approach for understanding why it happens and addressing those root causes.

Um, so I think we have a deep appreciation and we, we have a lot of, in similar. A lot of similarities in terms of finding those root causes and then going to down the path of the progression of that condition, which is kind of what our cardiometabolic approach achieves. Um, my first question is that it's not about just finding fat in the liver, it's about who's going to experience adverse events from it.

Um, I love [00:53:00] that you had mentioned that the disease is not always linear. Is that something that you've seen commonly in practice?

Yousef: Yeah, absolutely. So the, when they have fatty, because the liver is the center of metabolism, uh, including the packaging of LDL, including if there's an inflammatory process that's happening, we know that when people have atherosclerosis, that it's not just LDL, it's tiny LDL, it's, it's the A POB being elevated.

So multiple of these atherogenic particles, it's the inflammation and a lot of that's all happening in the liver. So absolute, uh, absolutely the having. Having that fatty liver should now tell us, this person has cardiometabolic disease. And the liver tells me, I'm, I, I focus on the liver because we don't want to overwhelm them too much.

But what I found is as the fat in the liver starts to decrease, their cardiometabolic disease starts to improve.[00:54:00]

Trish AI: That's awesome. And I mean, definitely speaks to the interconnectedness of those conditions.

Um, so you mentioned a lot about the FibroScan and the ELF test now in the A A CE and the A SLD guidelines, they, they say either or, but what's your experience and, and why you use both?

Yousef: Sometimes one of them is falsely high. So if we're not getting a biopsy or if the patient's decla declining a biopsy, I'm gonna look at both.

Because if, if one of them is high and then the other one is low, versus both of them are high, if both of them are high, I'm gonna say biopsy

 I wanna, I want to see both markers. Both of them are not perfect, but they're both great tests.

Trish AI: Mm-hmm. Awesome. All right. Well, thank you so much for your perspective today.

I think this is gonna hold a lot of value. And if anyone had any interest in going deeper into Maslow, do you have any additional opportunities for them to learn from you?

Yousef: Absolutely. We actually have a course, so I have a course, um, under [00:55:00] FMP Essentials, functional medicine practitioner essentials.com. We have a blog, we have a maed course, we have a community, we have a mastermind.

We have a group of people that are into, uh, providers or practitioners that are into lifestyle medicine. And we have a full over 10 hours on how to deal with ma.

Trish AI: Awesome. So this is really only just a, an appetizer to the main course if, if you really wanted to dive deeper. So thank you so much for, for this.

I think, uh, it'll hold a lot of value for prep for providers. 

Yousef: My pleasure. Thank you.