Corinn Cross, MD (Host): Welcome to Children's of Alabama Peds Cast. I'm your host, Dr. Cori Cross. In recent years, endocrinologists at Children's of Alabama have seen a drastic increase in the number of young patients with severe hypertriglyceridemia. This is an extremely elevated triglycerides. Levels that can pose serious health risks if left untreated. To address this, Dr. Ambika Ashraf was selected to join a group of leading national experts in developing a new framework and a new tool for managing this condition. Today we are lucky enough to have Dr. Ashraf here with us to discuss the challenges of hypertriglyceridemia both in patients and clinicians, and to explain how this new framework and tool can help.

Thank you so much for joining us.

Ambika Ashraf, MD, FAAP: It's a pleasure to be here. Thank you.

Host: It's my understanding that the prevalence has greatly increased. What are you seeing?

Ambika Ashraf, MD, FAAP: That's a great question. High triglycerides is becoming increasingly common in youth. When I started medical school more than 30 years ago, elevated triglyceride was not a topic that was taught in pediatrics because it was considered to be a problem affecting adults between 30 to 40 years of age when they gained weight.

So now 30 years later, I'm seeing elevated triglycerides more and more common in children. Especially, what I'm noticing is that it is associated with obesity, insulin resistance, sedentary lifestyle, high sugar intake, diabetes, and some genetic predisposition and certain medications. So if you really look at the United States data, triglyceride in elevations,

they go up sharply with higher body mass index, which is obesity. So if you take all children, it's seen in 10% of all adolescents. Whereas in children with obesity, the prevalence is anywhere from 24 to 60%. That's at least one in four children with obesity are impacted. So that's a huge number. I also want to point out that I'm seeing a wide spectrum in terms of age and severity.

For example, I remember a newborn who presented at 36 days of age due to abdominal colic, and when pediatrician was drawing blood, they saw milky serum and that child's triglyceride was 36,000. As you know, normal in that age group is less than a hundred, so we see a wide spectrum. Obviously that patient was very rare.

She had a genetic condition called FCS Familial Chylomicronemia Syndrome. But I also want to point out that severe triglyceride elevations, more than thousand are seen in some children who present with diabetes. So I'm seeing a wide spectrum in terms of age, presentation, and severity.

Host: Now, what about high cholesterol? How does that play in?

Ambika Ashraf, MD, FAAP: So high cholesterol. High cholesterol, now we are seeing large number of children have high cholesterol. Cholesterol is very different from triglyceride. Cholesterol is predominantly genetically determined, whereas triglyceride, there's a significant component of metabolic syndrome, obesity, weight gain, those type of things.

So cholesterol is much more common.

Host: So cholesterol, as you're saying, is then much more genetically predisposed. But triglycerides are much more lifestyle and body dependent.

Ambika Ashraf, MD, FAAP: In general. Yes, that's correct. Whereas there are genetic causes of high cholesterol, which is in fact one in 250 children have heterozygous familial hypercholesterolemia. So it's much more common. It is not related to body weight or obesity.

Host: And then how often should pediatricians be checking triglyceride levels, and what age should we start doing that for patients?

Ambika Ashraf, MD, FAAP: So that's a great question. So in reality, the national universal screening is between nine to 11 for lipid disorders and also repeat the level between 17 to 21. That's for all children, and the purpose of doing that universal lipid screening is to assess familial hypercholesterolemia. Totally different condition, but we also see patients with high triglycerides at that time.

If a patient has any risk factors like obesity, insulin resistance, or family history of heart disease, then you can actually call something called selective screening starting from age two. So checking for triglycerides is not universally accepted. However, when we do lipid screening, we also identify patients with hypertriglyceridemia.

Host: How difficult is it for clinicians to manage elevated triglycerides, and do they need to really refer this out?

Ambika Ashraf, MD, FAAP: That's a great question. So yes, you are right. Hypertriglyceridemia is difficult to manage. I would say there are at least four reasons for it. First of all, it's a very heterogeneous condition, meaning it's not just one cause. So when you see a lab value of triglyceride, it reports triglyceride as one thing.

For example, you just see a triglyceride of 400 or 600. However, there are mainly two types of triglyceride that circulate in the blood. One type is called VLDL produced in the liver, and the other type is called chylomicron that comes from dietary fat. However, our lab does not differentiate what type of triglyceride is causing the elevation, and also it could be due to genetic factors.

It could be due to secondary causes. So you may think, why does it matter from a clinician standpoint; because management is different. If it is due to too much liver production of triglyceride, which is VLDL, we need to recommend reduced intake of carbohydrate. Whereas if the severe elevations are due to chylomicron, that's from poor clearance of dietary fat, that's usually due to reduced activity of a enzyme called lipoprotein lipase. In that case, we need to decrease the dietary fat intake. So these are two separate entities and certain genetic conditions like FCS or acquired condition like MCS can cause that. So that's one reason.

Host: Now wait, so if you were to manage a child like this and you were to send the labs, do you have specialty labs then that separate out the chylomicron and the VLDL?

Ambika Ashraf, MD, FAAP: So actually no. So that's where we really need to understand what causes elevated VLDL, what causes elevated  chylomicron. So to make it simple, that's what we did when we did the publication. We tried to categorize, we made it easy for the practicing clinicians how to identify when you see a report. So what we recommend is mild elevation is called less than 400. Moderate elevation is called less than 800, and so if you have mild to moderate elevation, that's almost always related to increased liver production of VLDL. You have to restrict carbohydrate, reduce dietary intake of sugar, whereas severe elevations are always due to reduced clearance.

So that's where we need to restrict the fat intake.

The second reason you were asking about why is it hard for managing high triglyceride for clinicians? Because guidelines are not consistent. Classification is different. Mild, moderate, severe triglyceridemia is differently classified by different professional organizations and also lots of pediatric management is extrapolated from adult guideline, and the point I really want to make is management is different depending on the type of triglyceride and severity.

So when the triglyceride, let's say severe is what we call when the level is more than thousand. And very severe is more than 2000. And the reason this is very different is there is a risk of pancreatitis because if you have very severe triglyceride, triglyceride is basically fat, each in the first instance I was talking about a neonate who had milky serum, so the blood becomes so thick, milky viscus, it can clog blood vessel.

And also when the triglyceride level is more than 2000 medications do not work. So most conditions, we think as the severity increases, we can use some magical medications, but here we have to resort to extreme dietary fat restrictions, something put the children as NPO or nothing to eat by mouth and put on IV fluid and insulin.

So that's why this is very hard to manage elevated triglyceride, especially very high triglyceride, and to make the matters more complicated, genetic testing is not always definitive or readily available, so that is why the distinction matters, because management is different, but we don't have the necessary tool.

So between multiple etiologies, inconsistent guidelines and diagnostic uncertainty, one size fits all does not apply to elevated triglycerides.

Host: That makes sense. And so you, referred to it a little bit. You and a mentee developed a framework, basically to help clinicians, I think, manage this condition. It was published in Current Atherosclerosis Reports. Can you tell us a little bit more about the framework and the scoring tool? So I think the scoring tool is what you just referred to, right? The less than a thousand, 2000 that is the scoring tool, correct?

Ambika Ashraf, MD, FAAP: Little bit different. So I would say our, yes, my mentee and I worked together. We recognized how confusing it is, triglyceride management. So first of all, we wanted to give clinicians a clear stepwise approach. So this is where, this was centered around three key factors. So first, we categorized management based on triglyceride level, mild to moderate, severe.

Then we tried to attach it into based on underlying mechanism, mild and moderate, related to overproduction of VLDL in the liver and severe, impaired clearance of triglyceride, or is it both? Both increased production and decreased. Then we tried to align each category with actionable management goals. For example, mild to moderate elevation and because we are trying to tackle the cardiovascular risks such as preventing heart attack and myocardial function and fatty liver.

So this is where we tried to focus on lifestyle secondary causes, such as diabetes, medications. And in this category, we clearly outlined the management strategy as sometimes using statins if needed. And then when we go to the moderate category, which is more than 400, but less than a thousand, the risk of pancreatitis increases as the levels go up because of the blood vessels clogging. Here in addition to the lifestyle, you can also think about medications like fibrids, omega-3 acids control the secondary causes, like diabetes, encourage weight loss. And then when it comes to severe hypertriglyceridemia prevention of pancreatitis is the ultimate goal because as the triglyceride goes up, more than a thousand pancreatitis risk is 5%.

As the level is more than 2000, the risk is almost 10 to 20%, and pancreatitis can be life threatening. So this is what me and my mentee did. We kind of classified it in such a way that it's easy for clinicians to cut through ambiguity, like they can quickly identify the category, understand the mechanism, and take right action steps.

Whereas when I talk about the tool, that's a broader sense because we realized, so until now, what we were talking about was classifying all types of triglycerides. So then we realized there is a severe category of high triglycerides, which people really struggle with. So the tool I'm really proud to say I have been part of this team that developed what we call the North American Familial Chylomicronemia Syndrome Score or NAFCS score.

This is for clinicians to tell apart, is this FCS or MCS multifactorial  chylomicron syndrome when triglyceride is severely elevated, like more than a thousand.

Host: And so the tool helps clinicians to make that diagnosis?

Ambika Ashraf, MD, FAAP: Yes, that's correct. So for example, if you have familial chylomicronemia syndrome, like the neonate I was describing, so this is because of a genetic disorder where the enzyme that breaks down the fat in our body, lipoprotein lipase is not working due to multiple reasons. And so these patients, it is important to make that distinction is because these patients cannot break down fat.

So they need to be on an extremely restricted, fat restricted diet from birth, and the usual medications do not work. So what it makes is we have now clinical trials for newer novel therapies that can target the LPL. On the other side, there is an entity called multifactorial Chylomicronemia syndrome, where you can have elevated triglycerides more than thousand.

Here, it is mostly due to secondary factors like obesity, diabetes, certain medications. So here we can actually try certain medications, we can treat their secondary cause, and the outcome is totally different. They both present like more than a thousand triglyceride, but the outcome is different. So this is where we came up with a score.

Host: And so can other pediatricians access this tool and framework? I know the framework's in the report is there. Is it stored somewhere online that they can access? How do they utilize it?

Ambika Ashraf, MD, FAAP: So that's very good, great question. I hope people who are listening can go back and look at it. So we do have it, the score is easily accessible. It's, there's also one page calculator, so they just start to Google NAFCS score. And it's really using simple things that we usually measure in the clinic.

Like for example, age of onset, body mass index, history of pancreatitis, whether there are other conditions like diabetes. Lab markers such as triglyceride cholesterol ratio, APO B, which is another component. So basically, for example, each of these get a point value and then you can come up with a total score, which will give a probability of having FCS.

So for example, a score above 60 confirms FCS. Scores between 45 to 59, that suggest it's very likely. So what it means is having elevated triglycerides, severely elevated triglycerides, more than a thousand, is a confusing gray area. This clearly translated into a number based guide, so you can recommend the right treatment at the right time.

Host: It sounds like it really does help you to figure it out, particularly if it's not something that you see often. And so as a general pediatrician, you're not necessarily an expert in this, so you need guidelines to understand what are the other factors that I should be looking at that might give me a clue as to what's causing this, what the underlying etiology is, and therefore how should I best address it?

Because if you just make the same dietary and lifestyle modifications to everybody, to your point, you're not going to get the same results. Is there anything else you'd like to add before we wrap up today? Because this has been so educational.

Ambika Ashraf, MD, FAAP: I would say the tool is really a game changer for both clinicians and families, so it releases a lot of stigma because we can really tell a family this is not a lifestyle failure. It's a genetic condition. That's incredibly validating. And for patients with a confirmed diagnosis, that opens the door to support groups, clinical trials and treatments designed for rare diseases.

And I also want to point out that if you remember one thing, mild to moderate elevation of triglyceride is from liver overproduction of triglyceride, which means we need to reduce the carbohydrate intake, cut down on the sugary drinks, fast acting, processed food, carbohydrate production, lifestyle.

Lifestyle is key here, and also mild to moderate elevations of triglyceride is the cause of heart disease later on. So they have, they increased the risk of heart attack, myocardial infarction. So because of that, you really need to be careful, whereas severe elevations cause increase the risk of pancreatitis.

So this is something to think about and how whenever you are dealing with any type of triglyceride evaluation.

Host: That all makes a lot of sense and it, it'll be interesting to see as this goes on and as people are utilizing the tool and the framework, how much more frequently we do do the labs early because we do test for cholesterol. We are testing for like high blood pressure and everything. We're seeing this all sort of start younger and younger, so our just our basic tests are becoming different at these just well-check appointments. So it'll be interesting to see as we are able to find these things earlier, how that changes the outcome. Because as we all know, dietary restrictions and modifications are easier to do when you're sort of starting in the beginning than when you're starting and it's been going on for so long.

It's so much harder to change that sort of habitual behavior. So this will be interesting to follow. Thank you so much for taking the time to speak with us today.

Ambika Ashraf, MD, FAAP: Thank you so much for this opportunity. Thank you.

Host: For more information, you can visit insidepeds.org and search up triglycerides. That concludes this episode of Children's of Alabama Peds Cast. If you found this episode helpful, please share it on your social channels and be sure to check out the entire episode library for other topics that might be of interest to you.

Please remember to subscribe, rate, and review. And thank you for listening to this episode of Ped's Cast. I'm your host, Dr. Cori Cross.