Chapters Transcript Pediatric Lipidology: When to Start? Course: 19th Annual Irwin D. Mandel Advances in Cardiovascular Risk Reduction: Improving Treatment for Patients with Diabetes And so kind of we're gonna back it up and go to primary prevention and why we really care. So these are my learning objectives. I want to start out with a couple of clinical cases, and these are really demonstrative of patients that I see in my lipid clinic. The first is a 13-year-old male who was screened because of a family history of hypercholesterolemia and premature heart disease. Dad has high cholesterol, had an MI at 41, paternal grandmother has high cholesterol and had coronary stents placed at 52, and he's a 15-year-old brother with hypercholesterolemia who's currently on a statin. Second case is an 8 year old female who was screened due to increasing BMI over the past 2 years. Dad's overweight, mom has had gastric bypass surgery, maternal uncle has hypertriglyceridemia, but there's no early heart disease in the family. This is, uh, you guys know this, that heart disease is a leading cause of death for men, women and people of most racial and ethnic groups in the United States. One person dies every 36 seconds in the United States, and that's about 655,000 Americans who die from heart disease every year. And why do I care as a pediatrician and pediatric cardiologist, and why should you guys care? Well, we now know that atherosclerosis begins in childhood and it seems like, well, kind of duh, but it wasn't that long ago that we didn't know that. So I want to start with just a couple of landmark studies. So the first one is the Korean War autopsy study, which was published in 1953 from JAMA. There are about 300 cases of soldiers who were killed in the Korean War. The average age of the last 200 that they had was 22 years. In over three quarters of the hearts, there is evidence of coronary arteriosclerosis from fibrous thickening, about a third of them, to large arthromatous plaques causing complete occlusion in about 3%. However, at least 2 decades passed before studies were started in the pediatric population looking at cardiovascular risk factors in the young. I want to highlight two of these studies. The first is the Bogalusa Heart Study. This was a comprehensive school-based epidemiologic study of a biracial community in Bogalusa, Louisiana. Autopsies were performed on 204 young people aged 2 to 39, who died primarily by trauma and for whom antemortem risk factor data were available, and that's 93 of them. This first figure shows the prevalence of fibrous plaque lesions in the aorta and coronary arteries. This was all 204, and you can see that there is a consistent trend toward a greater prevalence of coronary artery lesions with increasing age. Figure 2 shows the effect of multiple risk factors on the extent of atherosclerosis in the aorta and coronary arteries in children and young adults. The risk factors that they looked at were elevated BMI, elevated systolic blood pressure, elevated triglycerides, and elevated LDL cholesterol. The values shown are the percentages of the inomal surface covered with lesions in subjects with 012, and 3 or 4 risk factors. As you can see, once again, as the risk factors increased, so did the percent of inomal surface involvement. And regardless of age, in participants with zero risk factors, the percent of intima surface covered by fatty streaks was 1.3%, and those with four risk factors, the percentage was 11%. The extent of fatty streaks in the coronary arteries was 8.5 times greater, and fibrous plaques 12 times greater in those with 3 or 4 risk factors compared to those with zero. The other study I want to highlight is the P-Day study, which is the pathobiological determinants of atherosclerosis in youth. In 1985, a group of investigators organized a multi-center cooperative study looking at the relationship of cardiovascular risk factors to atherosclerosis in teens and young adults. They had about 3000 sets of coronary arteries and aortas from people ages 15 to 34. Risk factors that they looked at with VLDL cholesterol plus LDL cholesterol, HDL cholesterol, smoking, glycosylated hemoglobin, adiposity and hypertension. And I'm just kind of showed you one of the graphs, but they all look fairly similar. High serum VLDL plus LDL cholesterol, low HDL cholesterol, hypertension, and hyperglycemia were all associated with more rapid progression of atherosclerosis from fatty streaks to raised lesions in the abdominal aorta and the right coronary arteries. These studies really showed us that cholesterol begins in childhood. There is a synergistic effect with the number of cardiovascular risk factors and the risk of atherosclerotic heart disease. It helped to give justification for not just identification of risk factors in Childhood, but treatment of risk factors. And I love this quote in one of the articles that said, the best available information indicates that the earlier the risk factors are modified, the greater the potential for a beneficial effect and that's where we as pediatricians come in. Pediatric dyslipidemia is out there. The study looked at 1999 to 2016, about 1/5 of children and adolescents had at least one abnormal cholesterol level listed here. And then a little over a decade ago, probably due for some new guidelines, um, but they did put uh give out integrated age-specific cardiovascular risk reduction guidelines for children, and you can see kind of all the uh cardiovascular risk factors here and we're gonna focus on on this is lipids and lipoproteins and the big change for us was universal screening. And the rationale behind that was, well, yeah, early atherosclerosis exists like we've shown, we have effective treatment, and lipid disorders are common in children. So when the previous guidelines actually were published in 1992, it was not the obesity and overweight epidemic that we currently have, and they really used family history alone, and we, we kind of wanted to get away from that. Because screening with family history alone misses 30 to 60% of children with dyslipidemia for many reasons. You'd be surprised the number of parents that are bringing their kid with LDLs of 300 into see me and they don't know their cholesterol levels. So, that's one reason family parents don't know their lipid levels. Um, we have parents who don't know the other side of the family. We have kids who are adopted, and then we have parents who are just too young. They have maybe not developed heart disease. They're 30, and maybe they're gonna have a heart attack at 40, but we don't know that yet, so they don't have heart disease, so using that as a screening doesn't work. So now, how are we gonna do this? When and how are we going to screen for dyslipidemia in children? We really don't recommend screening less than age 2 years, um, largely because, uh, breast milk formula, and whole milk generally is gonna make the LDL higher. So you screen, you give me a, a toddler with an LDL of 128, and I, I, you know, I'm gonna say they're probably fine. So I really, generally, we don't want to screen less than age 2 years. Lipid screening ages 2 to 8 years. So there's gonna be no routine screening, but we're gonna measure a fasting lipid panel. I don't care. You can grab a non-fasting one. I, I, as I kind of discussed earlier, it's fine, but these are the guidelines so I'm putting out there. Um, and they say twice, at least give me one, cause I know poking a kid twice can be hard, honestly. So just getting one at least. If once again, so family history, so apparent. Has a known, uh, high cholesterol or premature heart disease in 1st and 2nd degree relatives. That's less than age 55 years for a male or 65 for a female pertains to you guys. So anybody type 1 or type 2 diabetic, I will be honest, I am sometimes surprised at who gets sent to me in lipid clinic. I'm seeing more and more of the type ones who've had type 1 diabetes for 10 years and have not had their lipids checked and they're now 16. So, um, I think this is really important that we are screening these kids at a young age. Um, anybody with hypertension, any obese child, um, secondhand smoke exposure, and then the later ones are kind of should be taken care of by the subspecialists. So then it's universal screening. We're gonna say one time between ages 9 to 11. So if no one, if there is no high risk, you've none of these high risks, you've got to a healthy child, um, we should screen once between 9 to 11. And why did we choose that time? In general, the LDL cholesterol is stable. Between 9 to 11, now with puberty, the LDL cholesterol can dip up to 20%. So I would say for a girl, I'd like to err on the side of checking them at 9. For a boy, I think we're fine with checking it at 11. And as well, we often start statins and other medications around age 9 or 10, so it's also a good time to check. We actually would maybe start a medication if needed. So if we grab a non-fasting lipid panel, if the non-HDL cholesterol is over 145 or the HDL is less than 40, the guidelines say get two more fasting lipid panels. Once again, at least give me one. Let's check it again. Let's make sure that those um numbers are correct. Um, and then always repeat. I mean, I do like to see a repeated one because we can have, um, you know, some lab error and whatnot. Um, so if the LDL is over 130, the non-HDL is over 145, a low HDL or triglycerides, um, are elevated, then I want you to get a repeat one. They say between 2 weeks and 3 months. Depends if it's not super crazy high. I don't know, give them 6 months, 9 months, it's fine. Um, certainly, if something's quite elevated, I would want you to recheck sooner. Um, lipid screening in the teenage years, generally no routine screening, but certainly, if there's new cardiovascular risks, certainly they're now diagnosed with diabetes or now they come in and say, oh yeah, dad had a heart attack two months ago, yeah, then this child needs to be screened if they have not yet been before, especially. And then we're gonna do one more lipid screening between 17 to 21. So you have an otherwise healthy child, once between 9 to 11, and then once again between 17 to 21. I think getting one before they go to college is a very nice time to do it. Um, and then it's the same guidelines for ages 17 to 19. Once you get to the 20 year old, it's your adult. Guidelines, so more the, the, as you say, the cut points, you get a higher non-HDL cholesterol, so we only gonna repeat a lipid panel if the non-HDL is over 190 or a low, low HDL and then certainly we give up to an LDL of 160 or greater um to repeat or a non-HDL over 190 and triglycerides up to 150. And these once again just to highlight the lipid levels in children and adolescents. So, um, an LDL cholesterol less than 110 is what we consider normal. um, over 130 is gonna be elevated, and non-HDL less than 120, we consider normal over 145 is gonna be elevated. Triglycerides, we give up to 100 for up to age 9 and um 100 less than 130 for um up to 10 and over, and then HDL less than 40. And you guys, I'm assuming know these guidelines, um, these cut points. All right. So now I'm gonna take you back to the clinical case. This is that first young man that I saw with that strong family history of heart disease. His exam was completely normal. He had no xanthomas. So we did take an average of two labs because once again, they were, you know, quite abnormal. His total cholesterol was 444 mg per deciliter. HDL is very normal at 64. LDL cholesterol was 366. Remember, our normal is less than 110. Um, triglycerides were normal and a non-HDL of course was quite high. Um, liver tests were fine. Um, I'll put in the end, his lipoprotein little A was also checked. I'm not gonna get into that here. I know it's gonna be coming up later. His LP little A was also normal. So this represents um FH um he clinically has it um based on his lipids and um the family history. um FH is an autosomal co-dominant inheritance, about 1 in 200 to 250 incidents, and about for heterozygotes, about 1 in 160,000 for homozygotes, um, there are many different mutations. The most common one that I see in my clinic is LDLR. We do genetically test. Um, and I recommend it generally, especially in patients who are on the border to help us decide if we're gonna treat or not. Um, and sometimes we'll use it because other family members don't know if they have it, so, you know, we'll test the child and then we can then test the parents and then any other children. Um, so heterozygotes usually LDLs of 160 or greater. I've seen some with um LDLs of 140 and 150. So if you have a strong family history of early heart disease and the LDL is 148, I think it's certainly worth it to um genetically test. The reason we care is, um, as you guys all know, if left untreated, um, about 80% of men by age 60 will have heart disease, and about half of all women. Homozygotes, I'm not going to get into right now, but certainly they're one of the few um in pediatrics I would say is a lipid more um emergency urgency in terms of treatment. Um, these kids have LDL cholesterols over 400, and usually, honestly, well over 60-700. Um, uh, these people will die by age 30 if they are not treated. Um, statin Zia, PCSK9 inhibitors, vannaumab, they need aheesis. There are other drugs out there as well. It's, it's a very different disease from heterozygous FH. Um, and for us as adults, probably see, so some signs that we might see that uh clue us into FH. So as pediatricians, we don't generally see tendons and thomas. Um, in my homozygote, I might actually see that, but in general our heterozygotes were not, but I'll often say to to feel the parent, especially the parent was treated late, you could. Often have them feel their Achilles tendons. Sanallasmada, um, I don't see this in, in pediatrics and it's really low specificity. Um, but corneal arcus actually is something that, um, you all might see once again, I don't see it in my heterozygotes, and I've actually not seen it in, um, my homozygous FH patients. I'm sure, um, some of you guys have seen this though. So, in pediatrics, um, somewhat different than adults, I feel like is, is, there's a much more focus on diet and lifestyle, um, you know, especially when we have uh 4 and 5 year olds coming in, 3 year olds, you know, we, we're not general and take away the homozygos. We're not putting these kids on, on medications. And even the older kids, often we are doing diet and lifestyle first. Um, so I think it's a, it's a little different than, than in the adult world. I was The concern is. It's up there. Oh jeez. Oh, so yeah, sometimes we got to do that, you know, um, so the guidelines, these are what they, they kind of recommend. I think it's, it gets a little nutty. I don't want parents and people like they come in, you know, they're like measuring and counting the grams, and I, that's what makes me really nervous with these guidelines. I usually like to say. Um, one fruit and a vegetable to every meal and snack. Remember, I've got kids, we're, you know, we're snacking, you know, it's, it's a little different than adults, maybe not. Um, but, uh, 2 to 3 g of fiber per serving or sliced, and we aim for less than 2 g of saturated fat per serving. Um, we also really encourage mono and polyunsaturated fats and really wanna make sure cause we get a lot of kids that come in that are growing and they're put on a very low fat diet by their parents, and that's also of concern. So we also have to meet with our dietitian. Um, I think it's really important cause I started to see sometimes kids with weight loss, um, which, you know, once again, different than in the adults, we often don't want our kids to be losing weight as they're growing. So, um, for a high LDL cholesterol diet, we're really gonna focus on a low saturated fat, sorry, for high LDL cholesterol, uh, focus on low saturated fat. We always work on soluble fiber as well. Psyllium, so Metamucil, goes over somewhat with kids, um, often not. Sometimes the teens will try it. Um, so I got to, you know, warn them about this potential side effects, but also really talk about the different foods that we can do to work on um soluble fiber. All right, so let's switch over to clinical case two. This was the um the 8 year old young lady who had had increasing BMI. Um, so her BMI was at the 122% of the 95th BMI percentile, so she was in a severe obese category. She had normal blood pressure, um, and just an innocent murmur on exam. Her total cholesterol was 213 with a quite low HDL cholesterol of 27. LDL cholesterol was 140, triglycerides were 229 with the elevated non-HDL cholesterol of 186. Remember ours we like less than 120. Um, everything else looks good. I always check thyroid functions, hemoglobin A1C, all that was actually normal. So most likely this was combined to slipidemia of obesity. Once again, we're seeing this a lot in our clinic. Um, I'm sure you guys probably see it too in the adult world, um, characterized in general by high triglycerides, low HDL, and normal to mildly increased LDL cholesterol. We generally focus on diet, um, weight loss stabilization, and exercise, but we do pharmacotherapy as well, um, if needed, and if, uh, kids are not able to, uh, implement diet and lifestyle changes. And similar for high triglyceride, very similar dietary changes that we would do really working on limiting the simple sugars, so. Um, for kids, I also ask what they're drinking throughout the day at school. So we have a lot of kids that get free, um, breakfast and free lunch, and, um, for them, a fruit and a vegetable is, is a fruit juice, is considered their, their fruit. So we have a lot of kids that are actually drinking quite a bit of, of, of juice and chocolate milk. Um, so the parents will tell me that they don't get soda and no juice at home, but then when you find out that they're eating most of their meals at school, it's, you know, it's a problem, so we do have that discussion, um. With the kids, I think it's important to take that when you're taking a history for kids. And then also, as you know, so we got the diet, the drugs, and the doing, so we're gonna do, um, so physical activity is very important, maybe not just chewing fast. So all children and probably adults, but uh 2 years of age and older should just in 1 hour of enjoyable moderate to vigorous intensity activities daily. Um, during COVID, this was actually a huge problem as, as you know, um, a lot of our kids, um, uh, went up into the overweight and obese category due to the increased sedentary time, sports were canceled and they were on the screen in school for certainly more than 2 hours a day. So it was a, it was a big issue. And uh this is my daughter coming in in in 2nd there doing what she loves, so she's a bike racer and um I think just encouraging kids doing, um, you know, doing what they love is really important. Um, and then drugs. So when do we consider medications and we're gonna focus initially on the LDL cholesterol. So in children, I generally start between ages 8 to 10 after intensive diet and lifestyle changes for up to 6 months and depending on the risk level, and we're gonna talk about risk level in a minute. Um, the LDL cut points vary depending on the risk level and statin is first line therapy. In 2019, the AHA published a statement on cardiovascular risk reduction in high-risk pediatric patients. Um And as you can see for for you guys, the type 1 and type 2 diabetics consider high risk. Also homozygous FH and stage renal disease and a few other things. In the moderate risk category, the heterozygotes, um, and then they separated out severe obesity from obesity. So in children, severe obesity is defined as a BMI of 120% or um over the 95th BMI percentile. Um, which is in line with class 2 obesity in adults, which is associated with increased, uh, cardiovascular morbidity and mortality. So they did separate that out and I think it's important, um in this population. So now we're gonna sta um how we're gonna do this by risk level, how we're gonna initiate statins. So in a high risk category, so once again, our diabetics, our LDL cholesterol cut point is gonna be 130 or greater for starting a statin, and we're gonna start a statin along with um TLC simultaneously. In the moderate and at-risk, the cut point is 160 or greater, and the basically the big difference is how much time we're gonna spend on um diet and lifestyle changes. So, I will be honest, certainly not with my diabetics, but certainly in the at-risk category, you know, if their LDL is at 162, and they have no other risk besides whatever it is that brought them in, if it's their obesity, I will work with them a little bit longer, probably than the 6 months. Um, so I think it's just, once again, these are guidelines, they're not the rule. um. Statins approved for children, um, are listed. I generally start with atorvastatin 10. Um, on occasion, I'll start with simvastatin, and on some occasion, I'll start with Resuva 5. pravastatin, I generally don't use, and I really don't use lovastatin, but it just maybe, um, depending on how you were taught. We always start with the lowest dose, probably a little different than adults. So we don't, you know, I don't put them on 40 mg, you know, the kids, I mean, they're, they're always start out at 5 or 10 mg. Um, we don't generally have to push their LDLs quite as low as you guys do in the adult world. And also, I think it's important because the last thing I want is for them to have any side effects. So these are kids that maybe need to be on, they're gonna need to be on some sort of medicine for their whole life. And the last thing we wanna do is have pushed up the statin to say a 40 mg and then they get, oh maybe I've gotten some So myalgia or something, and now I'm statin intolerant, you know, then it becomes this whole thing, the parents don't want to put them on it and now you might have set them up for a lifetime of not being able to be on a statin. So I, you know, we're, we, we have to balance things in pediatrics. And then what about statin safety and efficacy in pediatrics? I'm going to flip through this very pretty briefly because actually they all look pretty much the same. Um, this was in 2002 with 173 heterozygous FH children who were on simvastatin. For nearly a year, there was a significant reduction in all parameters except HDL cholesterol and AOA1, uh, and similar to atorvastatin. And Pravastatin, this one also showed that after 2 years, um, the CIMT was looked at and showed a trend toward regression in the treated versus a trend toward progression in the placebo group. And similarly with resuvastatin, um, there was initially they did 12 weeks and then another 40 weeks, and there was no difference in safety measures. In 2019, this is a really nice uh article in the New England Journal of Medicine from the Netherlands. They had um 86% of patients with FH from this original cohort from 20 years before they had participated in a placebo-controlled trial of Pravastatin. That's the only in the Netherlands can we have 86% of people with 20 years out that you can find. Um, there have been no serious adverse events, no difference in LFTs or CK levels at follow-up. They had data on cardiovascular events and deaths from CBD were available on nearly all patients. And the mean LDL cholesterol and treated patients decreased from 237 to 160, which still isn't, I mean, certainly a decrease, but certainly wasn't even Huge decrease in my 32%, but it's not as low as I think we would want. Um, that being said, there was a very nice, um, you can see this Kaplan Meyer curves of those treated with statins versus their parents who did not start statins until much later in life, and you can see their event-free survival and freedom from death was significantly different in both groups. And I think that this really makes a case um for not just the lower the better, but the younger the better. This was another study that looked at um resuvastatin treatment for 2 years. Um, uh, the baseline mean CIMT was greater for heterozygous FH patients compared to their unaffective siblings, but by 2 years on medication, the difference in CIMT was no longer significant and once again supports the value of early initiation of statin treatment. I wanna make sure just to touch on um treatment of hypertriglyceridemia because we do see quite a bit of this in our clinic. Um, we have definitely plenty of heterozygous FH but probably I would say we get more of the hypertriglyceridemia. Um, so I think this is important. So, Um, for those with moderate hyperglyceridemia, basically triglycerides up to 400 with a normal non-HDL cholesterol. Basically, you want to treat with uh therapeutic lifestyle change, reassess in 3 months, and treat periodically. We are not going to be putting these people on medication. Anybody with more severe triglycerides, over 1000, um, confirmed on repeat testing, we're certainly gonna initiate um lifestyle change and um pharmacotherapy. But this is the group that I think I see the most of, um, these kind of, you know, pretty significant hypertriglyceridemia, triglycerides of 7 800, or really these triglycerides of like 250, you know, the LDL is 140, the HDL is 32, kind of like the girl I showed you. So you have this elevated non-HDL and that's when you're gonna use those risk categories that we had talked about before. So someone with that in the high risk category. And someone with this you are going to start treatment with therapeutic lifestyle changes and pharmacotherapy. So they talk about omega 3 fatty acids, which I don't find really work much. So we've been using a lot more of the phennofibrate, noting that certainly there are no like randomized clinical trials in children, phenofibrate. There are some case reports and some um case theories that seem to be quite safe. So I will say that's one of the problems we have in pediatric medicine is that we don't have a lot of trials in, in children. Um, in the moderate risk category, you're gonna basically do 3 months and then the at-risk category, you're gonna do 6 months. Um, treatment goal is triglyceride less than 150, and honestly, I'm happy with triglycerides of less than 200 or 250, and many people really want to get that non-HDL down. So, um, concluding here, looking back at clinical case one, that was our patient with severe heterozygous FH. In children our LDL, um, treatment goals less than 130 or 50% of starting, which honestly in this patient would be way too high, especially with that family history. So I would get them down lower. And we did do genetic testing. He had a, a single pathogenic theory in the LDLR gene, put them on a tour of a 10. Um, dropped his LDL to 200 to over 20 to 165, a tour of 40 and we kept him at an LDL of 122. Could be argued, um, that we should have gone less than 100 LDL cholesterol, and it's something that we actually discussed, um, actually after this, and he is actually on ZD now and his LDL is at 89, um, but this I did this before that. Clinical case 2 is obesity-related to slipidemia. So this young lady, they increased physical activity, they removed the soda from the house and she stabilized her weight. So when kids, once again, they're growing, so we can have weight stabilization with an increase in height and that decreases their BMI, um, and 3 months later, still a little improvement, um, but still, you know, some dyslipidemia. So we started on 2000 mg of mega-3 fatty acids. Parents did not want to start a prescription drug, so we sometimes have to, you know, OK, fine, we'll try some fish oil. Um, and I, you know, did it, did it work? I don't know, I probably think it's her physical activity really that probably helped a lot more in kind of changing in diet, but her LDL dropped to 125 or triglycerides normalized, so. So in summary, um, screening, we're in the universal screening once between ages 9 to 11 and again between 17 to 21, and then at risk, kind of whenever you find out the risk, I would just do it. Um, for medication therapy, so if they're age 8 or 10 years of age or older, and the LDL is 160 or 130 or greater based on risk category, we're gonna consider statin therapy, and we're gonna consider omega 3 fatty acids or other pharmacotherapy, which I probably prefer, um, certainly for very high triglycerides and then for that kind of significant hypertroglyceridemia or the moderate hypertroglyceridemia with an elevated non-HDL cholesterol, depending on their risk category. I think the take-home points from my talk would be premature atherosclerosis is preventable, at least from my standpoint, from the pediatric primary prevention world. Uh, the number of cardiovascular risk factors acts synergistically in the development of fatty streaks and fibrous plaques. We want to screen early for at-risk children. Diet and exercise are generally started before medication therapy, but we have safe and effective medications to treat children when needed. And super important and once again, also different from the adult world is we have to work with the families on a therapeutic plan is acceptable to everyone and will be successfully implemented to achieve um the treatment goal. Thank you very much. Published December 7, 2023 Created by Related Presenters Julie Brothers, MD
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