Hello, good evening. Thank you for joining us for this session on lipids, cardiovascular health, nutrition, and obesity. I'm Anastasia Amaro from University of Pennsylvania, and it is my pleasure to introduce Dr. Michael Villa. He's a clinical endocrinologist and an associate professor of medicine at the Icahn School of Medicine at Mount Sinai. Dr. Villa has been committed to lipid metabolism and nutritional sciences since college. He completed undergraduate study at Cornell University, where his honors thesis focused on omega-3 fatty acid metabolism. He attended medical school at NYU, residency at Brown, and endocrine fellowship at Mount Sinai. He is board certified in endocrinology and nutritional sciences. He is currently co-directing fellowship program at Mount Sinai. He has authored over 50 articles and chapters on topics in nutritional, biochemical, and metabolic science. He served as a chair of the nutrition committee at his institution, as well as the director of the metabolic support service since 2008. He has served as section editor of the lipids, obesity, and nutrition section of the American College of Endocrinology self-assessment program for the past five years. Dr. Marra, thank you for the introduction and welcome everyone to tonight's session on the ASAP live board review. And this, as Dr. Marra mentioned, will be on the lipids, cardiovascular health, nutrition, and obesity. But to recognize those who made this possible, Dr. Elias Siraj has been the editor-in-chief and director of the ASAP and co-directing this most recent iteration of ASAP with Dr. Geeta Gopalakrishnan, who's been the chair of the fellows education subcommittee. So I'd like to thank both Dr. Siraj and Dr. Gopalakrishnan for their support and continued leadership in making this endeavor possible. And tonight, myself and Dr. Amaro will be presenting some of the questions and going through questions and explanations and cases for board review in this topic. As far as disclosures, I have nothing to disclose. Dr. Amaro gets a little bit of funding that she's disclosed here. And just to go over just logistics, if you have questions, you can type questions in at any time into the question box and you can vote on questions that other people put in. And there will be a Zoom poll that opens when we get to the multiple choice question. And you can select your answer. That should be pretty straightforward how to do. And we'll answer try to address questions that anyone asks at the end of each case. And so here's the first case. Let's get right to it. So a 21-year-old man is seeking consultation for lumps on the dorsal aspect of his hands. His medical history is not significant, but his family history includes coronary artery disease. His mother had a myocardial infarction six months ago at age 49 years and received coronary artery bypass grafts. His maternal uncle had a myocardial infarction at age 51 years. His father died in a motor vehicle accident at 22. He has no siblings. He does not use tobacco, drink alcohol, or use illicit drugs. He follows a healthy diet. On physical exam, his heart rate is 72, blood pressure is 120 over 80, and body mass index is 26. He has tendon xanthomas on the extensor tendons of his hands. There's no corneal arcus, no xantholasmas, or tuberous xanthoma are found on examination. His renal, hepatic, and thyroid studies are normal. And so when you see a board question like this, I think it's good to break down. There's a lot of talk here. There's almost nothing extraneous put into a board style question. And so when you see a lot of talk about family history, of course, it should make you think of something familiar. So here's the fasting lipid panel. Total cholesterol is 330, triglycerides 140 milligrams per deciliter, high density lipoprotein 55 milligrams per deciliter, low density lipoprotein 230 milligrams per deciliter, so high. And non-HDL cholesterol also high at 275 milligrams per deciliter. And so what mutation is most likely responsible for the patient's lipid disorder? Is it a gain-of-function mutation in proprotein convertase substituent kexin 9, PCSK9, a loss-of-function in PCSK9, a mutation in the low-density lipoprotein receptor, or a mutation in the epilipoprotein B gene? You can go ahead and enter your vote. All right, so here's the results. So about a quarter of you said a loss-of-function in PCSK9, 63 percent LDL receptor, and 13 percent epilipoprotein B gene. And so let's go through this case. These are all good answers. So I think we recognize that this is familial hypercholesterolemia. And there's a few clues in the case. One is the young age of the patient. The second is the family history. And most notable is the physical exam, as well as, of course, those very elevated LDL levels. This is a common condition, and it's underdiagnosed. It's very commonly missed. Sometimes LDL is only subtly elevated, or sometimes it just gets pushed to the side and not recognized. It is one of the most common, if not the most common, genetic condition with a prevalence of 1 in 200 to 1 in 500. And this is for the heterozygous state. Heterozygotes with this condition have it not quite as severe as those who are homozygous, which thankfully is less common. But in both cases, there's clinical ramifications of having this. And these are inherited conditions where LDL catabolism is inherent. There's four main genes that have been identified in this condition, and three of them were answers that were given. The LDL receptor, a-folipoprotein B, PCSK9, and the LDL receptor adapter protein. In fact, this is how we diagnosed PCSK9. Inactivating mutations of PCSK9 led to a clinical benefit. Patients with that condition had very low LDLs. People with activation mutations of PCSK9, patients had very high LDL cholesterols and high rates of coronary disease. So that's how we discovered this pathway. And it's good to understand the pathway of LDL metabolism that we know these days. So here's a cartoon. If you think in circulation, these LDL particles, which are recognized, identified by this ApoB protein on the surface. LDL receptors on the surface of the parasites will bind to the ApoB and the LDL particles and internalize it to take it out of circulation and metabolize. If there's a defect in the protein, ApoB itself, or a defect in the receptor, then this process is inhibited. Additionally, if there's a defect in this associated protein, it's inhibited as well, although that's pretty uncommon. And then PCSK9, which is in circulation just outside in the extracellular space outside of these parasites, also is important. It will bind to the LDL receptor and target it for internalization and degradation. So if there's active PCSK9, that breaks it down. So defects in any of these things can lead to familial hypercholesterolemia, but the number one cause is the LDL receptor. So the majority here got it right. The LDL receptor, mutations in the LDL receptor represent 90% of cases of familial hypercholesterolemia, although all of these other mutations can lead to the same. And so what's nice is nowadays you can order a genetic panel from many commercial labs that include all of these genes into next-gen testing to screen for mutations in any of them. So you may not need to think about it, but it's always good to know the mechanisms and which one is the most common. Within the LDL receptor itself, there's over 2000 described mutations, and there's five different categories that can affect the binding itself or just the transport of the receptor to the cell surface, how quickly it's internalized, how easily it's recycled, or even how much of it is expressed. So all different types of mutations which lead to differing severity of this disease. If there's no LDL receptor expressed whatsoever, LDL levels can be very, very high in the 500s, and there's a high rate of very premature coronary disease in that group. Sometimes it's more mild, or it's just a diminished binding to the ECOV protein or the LDL particles, and that leads to just mildly elevated LDL, but still leads to high LDL. And so how do you diagnose this? Well, you should suspect it in someone who has high LDL cholesterol higher than their age. So in children, we've got 160 milligrams per deciliter or higher, or adults, 190 or higher. And especially if there's early family history of early coronary artery disease or in patients themselves with early coronary disease. And because it's heterozygous, it can be inherited in an autosomal dominous form because there's symptoms and signs develop when people are heterozygous. There are a number of criteria, clinical criteria, that are used to help with the diagnosis. It's good to know one of them I use, the Dutch lipid criteria, which assigns different points to different categories of family history, clinical history, physical exam, and LDL cholesterol. Or if you happen to have genetic testing, then, you know, if the test is positive, you'll get eight points and have definite familial hypercholesterolemia. But we can go through this. Just the family history, of course, looks at whether there's premature coronary disease, which is counted as less than age 55 in men, a first-degree relative is more men, or women who are less than 60 with coronary disease as a first-degree relative, you'll get one point for that. Or if there is children of first degree, children with LDL cholesterol of the greater than 95th percentile, or another relative with a tendon xanthoma, you'll get points for that too. Patients who have themselves premature coronary disease or premature cerebrovascular disease, points can be assigned for that. But the biggest points come from the physical exam or from the LDL cholesterol levels themselves. Physical exam presence of a tendon xanthoma gives six points, so it's almost pathognomonic. And that, in addition to an elevated cholesterol, we usually clinch the diagnosis of familial hypercholesterolemia. And of course, the severity of LDL cholesterol, if it's very high, greater than 326, you know, that's pathognomonic. If it's moderately high, it's very suggestive, you know, somewhat high and less suggestive, but in combination of these somewhat high levels and the rest of these findings can help aid in the diagnosis. And of course, genetic testing is possible. Here's some examples, and the published examples are always extreme. In practice, it's not always quite so obvious or clear, but you can see xanthomas on the Achilles tendon. This is a good place to look. And it's suggested in many patients, especially patients with premature coronary disease, to examine their Achilles tendon to feel for lumps and palpable lumps is a sign of this condition. Also, on extensive surfaces of the hands is another common place for these, or sometimes on the internal surfaces as well. It can appear anywhere, but the hands and the Achilles tendons are good places to look on exam. Also, the corneal arcus is common, although this can develop in people as they age, but if it's seen in someone under the age of 45, this is suggestive of this condition and, you know, should be part of the physical exam. So, genetic testing is available, as I mentioned. It's good to treat early and diagnose early. Why? Well, if you think about it, LDL cholesterol goes up in everyone as they age. In children, regardless, they often have very low cholesterol, regardless of their, you know, lifestyle. They often usually do. But if they have this inherited, you know, impaired metabolism of cholesterol, that leads to elevated cholesterol higher than it would be. And for longer periods of time, their bodies, their vasculature is exposed to these elevated levels of cholesterol, which leads to the development of premature coronary disease. Almost a quarter of patients with this condition will have demonstrable atherosclerosis in their 20s and, you know, symptomatic and, you know, clinically important by their 40s. So, it's important to recognize early so you can treat early and aggressively. And then the other benefit, of course, is that because this is inherited as a Mendelian inheritance, you can identify, you know, first-degree relatives and family members that are also at risk for this condition and should be screened. So, that is essentially the end of the first question. Is there any questions from the audience? Thank you. I don't see any questions. And thank you for a great review of physiology and clinical manifestations. I have a question. Do you mind giving us a few bullet points about treatment? What do we need to know for the board? Treatment. I mean, a lot of people focus on what they can do with lifestyle to lower cholesterol, but lifestyle won't help very much at all in this condition. So, the things you can do is a moderate or even high-potency statin, such as atorvastatin 20 or 40 milligrams, or rosuvastatin 10 or 20 milligrams daily. So, high-potency statins. Or one can consider PCSK9 inhibitors. About a year to a year and a half ago, there was a trial in New England Journal where they treated young patients starting at age 5 with PCSK9 inhibitors that showed clinical benefits. It's not surprising that it shows benefit in lowering cholesterol, but it was tolerability and benefit in the young age group for the long-term that is striking. So, either moderate or high-potency statins or PCSK9 inhibitors. Some of the other cholesterol-lowering agents can be considered, like benbedoic acid, or I suppose these other two are not tolerated, but really the first two are top choices. And treatment early and controlling cholesterol early can really change the quality of life and the cardiovascular risk in these patients. And that's made a big difference since the discovery of statins for the last 40 years or so. So, great. Great. Thank you. I think we can move on to the next question. All right. Sure. All right. So, question number two. A 47-year-old woman comes to the primary care office requesting assistance with weight loss. She's been struggling with excessive weight all of her adult life. She has been advised to lose weight because of right hip osteoarthritis that requires hip replacement. Her medical history also includes a five-year history of type 2 diabetes and glaucoma. Her medications consist of orlistat, metformin, semaglutide, canagaflozin, and oxytocin. She's tried different dietary plans without durable weight loss. She monitors her calorie intake and exercise at six days a week. Her family history is significant for obesity and type 2 diabetes in both parents. She denies tobacco or alcohol use, and she works as a school teacher. So, this is not an uncommon scenario. People who are frustrated with weight loss and are trying in the ways that they can are taking medicines. On a physical exam, her heart rate is 65 beats per minute, and her blood pressure is 148 over 85. Her weight, or her height, excuse me, is 5 foot 4. Her weight is 270 pounds, giving her a body mass index of 46.7 kilograms per meter squared. She is noted to have neck acanthosis nigricans. She does not have cushingoid features or thyromegaly. Hemoglobin A1c is 7.5 percent. Thyroid, liver, and kidney function test results are unremarkable, and she's interested in bariatric surgery. She seeks recommendations for optimal surgery. So, the question, compared with Roux-en-Y gastric bypass, which of the following is accurate for sleeve gastrectomy? A, sleeve gastrectomy is less commonly done, causes more weight loss, and has more complications. B, sleeve gastrectomy is more commonly done, causes more weight loss, and has fewer complications. C, sleeve gastrectomy is less commonly done, causes less weight loss, and has fewer complications. Or, D, sleeve gastrectomy is more commonly done, causes less weight loss, and has fewer complications. All right, good. So, I think the polls got it right. Let's go through the data. So, you know, it's good to know about these options for metabolic surgeries. They have a huge impact on the life and on the metabolic risk of patients and complications of diabetes and complications of obesity. I think we'll all recognize the qualifications for these surgeries. A person has to have a body mass index greater than 40, or a body mass index greater than 35, with other complications, including diabetes or high risk for diabetes or hypertension. For those who have lower body mass index, this has been studied, whether or not bariatric surgery is as beneficial. It's less beneficial when there's, of course, the risk of surgery. That's not indicated. It's not covered in this group. People with a BMI that's still considered obese, but less than a BMI of 35. It's good to know about the four major surgeries that are done, four major procedures. The Roux-en-Y gastric bypass, where the stomach is divided into a small pouch, and there's an anastomosis with a distal ilium. It's not quite to scale. The duodenum, jejunum, and the proximal ilium are bypassed, and this drains the stomach remnant, drains, and this eventually drains into the anastomosis. So, there's a restrictive and malabsorptive physiology that develops. Gastric banding, where a band is placed around the stomach to create a small pouch so that it's really a restrictive procedure. This band is adjustable, and so that more or less fluid can be infused into this, which may tighten the band or loosen it, but no actual resection is done. There's the sleeve gastrectomy, where part of the stomach is divided and resected. I think this was originally designed as a restrictive procedure, but it turns out many of the humoral effects of this procedure are what drive its metabolic benefit. And then there's the biliopancreatic diversion with or without duodenal switch, where the stomach is also divided and a large part of the intestine is bypassed, where a very small amount of distal ileum is re-anastomosed to this divided stomach, which creates a lot of malabsorption and is much less commonly done, but can be done because it's the greatest amount of weight loss. This is the latest publication on just the rates of various different surgeries since the 1990s, when these procedures became increasingly popular. It started off, there was even the vertical gastroplasty procedure that really fell out of favor because it had a lot of complications and didn't work so well for weight loss. The Roux-en-Y gastric bypass took off in the late 90s and the early 2000s. It started off as an open procedure, and then in the early 2000s, it became more popular as a laparoscopic procedure. Around this time, centers of excellence were developed and the laparoscopic technique allowed for fewer surgical complications in the immediate phase, and at the same time, with the centers of excellence, there were fewer longer-term complications as well, but there's still some complications. The Roux-en-Y gastric bypass became the most popular. The laparoscopic adjustable band was introduced around this time, now about 20 years ago, a little less than 20 years ago, and became popular. It was not as invasive, but then it was recognized that the weight loss with the adjustable gastric band was much less, and there was a lot of gastroesophageal reflux and adjustments that were needed. Eventually, this procedure has fell out of favor because the durable weight loss was just not as strong as it was in the Roux-en-Y gastric bypass. And then more recently, you can see in the green here, the sleeve gastrectomy has taken over and has really become the most popular of the bariatric surgeries, and because it induces a fair amount of weight loss, not quite as much as Roux-en-Y gastric bypass, but it's still a comparable amount, just a little bit less, and it has a significant metabolic improvement, and then has weight loss that's durable, comparably durable. There's fewer complications to this surgery, and so people tend to go with this. So that's the number one surgery done in the United States today for bariatric procedures, but there's still a fair amount of Roux-en-Y gastric bypass. And so when you're making medical decisions, you should always weigh the risks, benefits, and options, and it's good just to have a chart of comparison. The amount of weight loss that's expected from each of the surgeries, Roux-en-Y gastric bypass, about 30% to 35% of the excess body weight, laparoscopic sleeve gastrectomy, a little bit less, 25% to 30%, so almost, but not quite as much as Roux-en-Y. The adjustable gastric banding is, in the literature, gives around 20% to 25%, but that's really very optimistic. Eventually that tapers off over time, and so the number is less, and so this has fallen out of favor. The bilio-pancreatic diversion with or without duodenal switch has a greater amount of weight loss, but there's a lot of complications and a risk of malnutrition and malabsorption. There's less complications with the sleeve gastrectomy, and a moderate amount of complications with Roux-en-Y gastric bypass, and these include dumping syndrome, they include malabsorption, and various anastomoses or fistula formation, although those are less common these days. Due to the references, are there any questions? It looks like there might be one. Yes, there is a comment about some more recent evidence suggesting a similar weight loss with the both procedures, Roux-en-Y and sleeve gastrectomy. I think that's true. I think it's a comparable amount of weight loss. It's hard to compare different studies and to say are these equivalent or not, but they're very similar amounts of weight loss, and I would agree with that. They have similar rates of improvement of metabolic procedures as well, of metabolic conditions as well, and so one could consider, and I think that's why we do consider the sleeve gastrectomy more commonly because of the similar amounts of weight loss and improvement with less complications. However, there are still practices that will offer, especially in patients who have a very high degree of obesity, body mass index of 45 or 50, will not offer the sleeve gastrectomy as readily and be more focused on Roux-en-Y gastric bypass just because of the longer history of that procedure that's being used, but I think there are similar amounts and that should be taken into consideration. Another consideration, people with obesity, just by social networks, tend to know other people with obesity, and as a result, they tend to know people or even have family members who've undergone one procedure, usually it's Roux-en-Y, and it may or may not have had complications, and so that can also guide which way they'll decide more so than what the science or what you decide, but of course, the decision between you and the patient should go with what the science says. Hopefully, there's a comment here. If the patient is diabetic, I recommend Roux-en-Y. Roux-en-Y improves diabetes. Sleeve gastrectomy does as well, so I think it's hard to know what the boards will say. A lot of it has to do with what the question writer may think, but usually, there'll be clues in the question, and I think these days, in a patient with a BMI in the 30s with uncontrolled diabetes, a sleeve gastrectomy is a great choice. Roux-en-Y is also a good choice, and hopefully, the question on the boards is clear which one they're angling for. They may say Roux-en-Y, and someone with a greater degree of obesity is the biggest clue that I would look at. Thank you. All right, good. I guess we can go on to the next question. Yeah, case three. All right. A 48-year-old man presents to the clinic for recommendations on his weight. He reports that he's always struggled with his weight and has had intermittent fluctuations when he attempts to diet, but unable to remain compliant over the long term. His medical history is significant for mixed dyslipidemia and hypertension, which are managed with atorvastatin, 40 milligrams, and hydrochlorothiazide, 25 milligrams daily. He's a current smoker with a 20-pack-a-year smoking history. His father died of a myocardial infarction at age 57. He reports that although he's motivated to start improving his eating habits, he finds it difficult to adhere to strict dietary restrictions for long periods. In addition, he reports that he works in a factory and has one hour for lunch daily, and is not allowed to snack while on the factory floor. Notable measurements obtained during the visit include weight of 238 pounds, height 5 foot 11 inches, body mass index of 33.4 kilograms per meter square, his waist circumference is 42 inches, blood pressure in the clinic is 133 over 82, and the remainder of his examination findings are normal. In addition to encouraging physical activity, which of the following recommendations is most likely to benefit this patient? The DASH diet, the ketogenic diet, intermittent fasting diet, or Mediterranean diet? All right, good. So we have answers in each category, which is good, I think. You know, the board's exam questions about diets are always tricky because there's a lot, a lot of times there's more opinion than there is science about diets. But there is some science. We're going to go through that. I think, well, let's go to that. There we go. So first, I think we all recognize that it's not really a diet. It's a lifestyle, something that a person has to be able to do over the long term. And we should have goals that are achievable. I think a lot of patients come in with really unachievable goals, at least in my practice, they come in wanting to get back to their college weight or lose, you know, 50 pounds or something like that. That's just not something that's going to be able to be met by most people. Some people can, I suppose. Most cannot. In most studies, people lose 5% to 10%. And sometimes even despite continued healthy diet or healthy lifestyle, regain. But still a 5% to 10% weight loss in someone with obesity is very meaningful. Metabolically helps reduce the risk of diabetes, hypertension, coronary disease, etc. And so achieving that goal, however you do it is really very admirable. And so, you know, the classic teaching, a low calorie meal plan with a deficit of 500 to 1,000 calories a day is how you can do this. But what's the best lifestyle or dietary pattern to allow a patient to do that? Because, of course, we want them to stick with it. And so let's go through each of these. The Mediterranean diet, which we think is the answer to this question, is recognized now for probably about 70 years. In the 1950s, it was recognized that people around the Mediterranean had low degrees of cardiovascular disease. And so the diet study into this style of diet has been undertaken. The diet itself has about 30-35% of its calories from mono and polyunsaturated fatty acids. It has a high intake of vegetables and fruits, nuts, legumes, fish, etc. There are a number of published studies with the Mediterranean diet, and it shows reduction in total cardiovascular cancer-related mortality and reduction in developing type 2 diabetes. In contrast to this, the DASH diet, Dietary Approaches to Stop Hypertension, which is a fine diet. It's also similar. It's high in fruits and vegetables and low-fat dairy. It also has a low-fat content. It has red meats, which is perhaps a different—I guess it's low in red meats and in sweets. It's been shown in scientific study to reduce systolic blood pressure, and you can see by a small amount, 5 millimeters over 3, but that's a fair amount, and diastolic blood pressure by 3. And there's an average of 5-kilogram weight reduction. But the hard endpoints in the DASH diet aren't really done in scientific study. They're not published studies on that. So if you're going to compare and say which one has better data to support the use, the Mediterranean diet has better data. The ketogenic diet, which is truly ketogenic, has 90% of the calories from fats, very little bit from proteins, very minuscule amount from carbohydrates. This was popular a few years ago. It's still popular. People talk about it going keto. It's very hard to sustain. It's very hard to even generate ketones. It's benefits of this diet help reduce seizures and intractable epilepsy in children, and there may be some benefit in cancer. The question, of course, is this very strict ketogenic diet sustainable? And the other question, the other potential diet is intermittent fasting. There's several different variations of this, whether you fast for one or two days a week or fast for about 16 hours a day. The idea is that you are fasting and then switch your metabolism to lipid metabolism, and this allows for better, more efficient calorie use and leads to improvements in metabolic resistance. There are a number of published studies with short-term benefits. Another question is this sustainable or beneficial? One study that everyone should know is the Danziger study. Now that's 17 years old from 2005, and this was a randomized trial of people with either overweight or obesity, and they were randomized to one of four diets. Older diets, because the study is a bit older, the Atkins, which is a low-carbohydrate diet, the Zone diet, which is very similar to the DASH diet but has some meditation, Weight Watchers, which is a calorie counting, so it's a low-calorie diet, or the Ornish diet, which is a vegetarian diet. Four diets, and patients were assigned to that for a year, and how much weight did they lose in a year? You can see the spread for each one, Atkins, Zone, Weight Watchers, Ornish. Not much weight loss, about 1 to 2 kilograms on average over 12 months. But what's interesting about this study is each person rated how well they stayed on the diet, so on a scale of 1 to 10, how adherent were you? And you can see that those who were the most adherent lost the most weight, and it didn't matter which diet they followed. What mattered was that they adhered to it, and so the take-home from this study, to me at least, is that it has to be a dietary pattern that a patient's going to follow. It has to be something patients like, and they're interested in doing, and that they can do over the long term, because that's what's going to make improvements for the rest of their lives. The other aspect, of course, is how beneficial are these diets? So here's one of the famous studies of the Mediterranean diet. This is done by Shai. It was carried out in Israel in a factory. So people go to the factory and have lunch there, and lunch was the biggest meal. And of course, they continue this at home, but the biggest meal of lunch was given to them, so they could really control, in this study, what people were eating. And they randomized people with a body mass index greater than 30 to one of three groups, either a low-fat diet, a Mediterranean diet, or a low-carbohydrate diet, and they followed them for two years. And you can see this is the amount of weight loss. Everybody lost weight, but the low-carbohydrate and Mediterranean diet had the most weight loss. In the extension of this trial that went on for up to six years, the Mediterranean diet group had the most weight loss. And I didn't show it here, but they also had reductions in LDL cholesterol and improvement in insulin resistance. The biggest study with the Mediterranean diet is the PREDIMED trial. This trial is controversial because it was retracted, but then it was reprinted. But let's go through it. It's 7,000 adults. People either had type 2 diabetes or they had three risk factors and increased body mass index. And they were assigned either to a low-fat diet, a low-calorie diet, or the Mediterranean diet. Now, the Mediterranean diet, there were two groups. One that was supplemented with extra virgin olive oil. They had to drink a little bit of extra virgin olive oil each day. Or they were supplemented with nuts, so they had to eat a little bit of nuts each day. And or it was the low-calorie diet was the control group. And it showed improvement with the Mediterranean diet in weight and in cardiovascular risk and cancer. I'll show you that data in a minute. But then it was retracted. And there was a lot of questions. One was, well, this study was done in Spain, you know, wasn't the control group actually following the Mediterranean diet. But they went through and analyzed this questionnaire of what people ate. And it turned out they weren't. They were actually following this low kind of westernized low-calorie diet. The one argument was that the data in cardiovascular benefit was driven by stroke. That's true, but strokes are not so great. And second, there was also a reduction in other cardiovascular events. Another criticism of this trial is that it was stopped early. It was stopped early because the benefits seemed to be very strong. And so the steering committee decided to stop the trial early. But one criticism is, well, maybe that inflated the benefit. And then the fourth criticism is that some analyses just seemed implausible. There was a cancer risk that was reduced by 50%. But it turns out in other studies of the Mediterranean diet, there's also a reduction in cancer risk. So perhaps that's not such a problematic criticism. Some real criticisms was that there was a problem with randomization. About 20% of the people in the study were not randomized properly. So it was redacted. But then they reanalyzed the data, correcting for this, and republished it. And they still had a reduction in these cardiovascular events over time, over five years. So the Mediterranean diet, either extra virgin olive oil or nuts, they had similar. There was no difference between those, but certainly much better risk than the controlled diet. The Mediterranean diet seems to have the best evidence. And so we like it. That's why we made it as the answer to this question. But the real answer in real life is whatever dietary pattern that's healthy that the patient could follow. And I think there's a few questions here. Yes, there is a question that is related to the case. It is tricky since the question mentioned in the question, he can't snack at work. So intermittent fasting seemed reasonable. Well, that's true, although I think the question writer made it so that he had only an hour to eat, and so would eat lunch there. But it certainly could be reasonable if he could pull it off. If he could not eat during lunchtime and then not able to snack. Because for intermittent fasting to work, one pattern is to fast for 16 hours a day. And to do that, he may have to not eat lunch, depending on his routine, and it may or may not be plausible. It may work. I mean, he might be able to find a way to make it work. I think what they were trying to say is that it's not plausible because of his work. But I think you could make that argument. That's true. I think when we write the questions, when we go through questions, I think we need to pay attention to what exactly the question is asking. And with nutritional science, more than anywhere else, the question, which diet is best for the weight management versus which diet will benefit patients' metabolism the most, may actually carry different suggestions and different prompts. So, for example, intermittent fasting would be beneficial for insulin resistance, even without weight loss, as suggested by the study from Pennington Group in 2018. But then, on the other hand, there is a suggestion in the chat box about a recently published, last week published, study in the New England Journal of Medicine, I pulled it up here, where caloric restriction and intermittent fasting have been shown to be beneficial for insulin resistance and insulin resistance, I pulled it up here, where caloric restriction and intermittent fasting were not better than caloric restriction alone. And in their study, actually, it was not intermittent fasting, but reduced feeding for 10 hours on average to eight hours. Yeah, I haven't had a chance to look at that study. And so it's an evolving science is a new, still a new, relatively new dietary pattern that people have been proposing. And it would be interesting to see, but I think, you know, as you point out, it was improvement in insulin resistance that we see. And there's studies that show improvement even in diabetes glycemic control. And so I think it's, if you have a patient who's willing to do this for the long-term, that's, you know, something that you can consider, but it's very hard to find someone like that. In practice, I haven't found too many people who could sustain this for a long time. Yeah, yeah. And it is true, the other comment about reduced feeding time versus intermittent fasting, it's all about definitions, but I think reduced time feeding, RTE, that's reduced time eating is another way to, it's interchangeable with intermittent fasting for some of the patterns, but not for all. So yeah, we need to be careful about that as well. All right. Thank you. All right. So let's go to case four. This is a 38-year-old man who's seen for his first physical exam in 10 years. His medical history is unremarkable, and his only surgery was for extractions of wisdom teeth. He's married and has a five-year-old daughter who's in good health. He does not smoke. He consumes one alcoholic beverage per week. His family history is significant for coronary artery disease, and his paternal great uncle, who's sustained a myocardial infarction at age 67. No other family members are known to have cardiovascular disease. On physical exam, his blood pressure is 120 over 80. His body mass index is 27 kilograms per meter squared, and the rest of his examination findings are normal, except for a slight yellow hue of his palmar creases bilaterally. His laboratory tests show normal liver function, normal electrolytes, and a fasting glucose of 98 milligrams per deciliter. His fasting serum lipid levels are as follows. Total cholesterol of 320. HDL cholesterol, 63. It's a little bit high. His triglycerides, 309. His calculated LDL cholesterol, 196 milligrams per deciliter, and LP little a is 12 milligrams per deciliter. His primary care physician ordered a computer tomography coronary artery score, which showed a score of 47, and this range is zero to 300, but a normal score of zero for anyone less than 45. So this patient should have had zero, a little bit of calcium. A mutation of which of the following proteins is most likely to explain the findings in this patient? Is it apolipoprotein E, cholesterol esterase transfer protein, lipoprotein lipase, or proprotein convertase of psilunkexin type IX, PCSK9? All right, good, good, so we have a few choices, a few of all the choices, but APOE is the correct answer, and that's what the group chose. So let's go through this physiology. It's good to know these main proteins that are important in lipid metabolism. We talked a lot about LDL metabolism on the first question. This is now talking more about triglyceride metabolism, but it involves LDL as well, and HDL for that matter. So let's just go through this whole kind of schematic, just kind of simplified diagram of lipid metabolism. There's, in triglyceride metabolism, there's two main sources. One is the synthesis of chylomicrons from ingested fats in the diet that form these chylomicron particles that are high in triglycerides. And the second is the synthesis of VLDL particles by the liver that are also high in triglycerides. In both cases, lipoprotein lipase helps digest and degrade the triglycerides, making free fatty acids available for energy use and for storage within adipose tissue. And as this chylomicron, or as this VLDL particle is digested by lipoprotein lipase and forms these remnants, it's recognized by the surface ApoE protein, which helps it bind a number of receptors on the liver, including the LDL receptor, the LDL receptor-related protein, or heparin sulfate proteoglycan, which binds ApoE as well. And these either chylomicron remnants or VLDL remnants can be taken out of circulation. The VLDL remnants can be degraded further into intermediate-density lipoprotein, or eventually with even more hepatic lipase degradation and really removal of almost all of the triglycerides. What's left is cholesterol as LDL particles. And then the LDL, then with the ApoE, it binds to the LDL receptor and is taken out of circulation in that fashion. And then cholesterol esterase transfer protein helps remove cholesterol and exchange with triglycerides in either chylomicrons, IDLs, or LDLs. And so these are the important proteins to recognize. And what happens in this condition, when there's, this is now supposed to be one of these remnant particles, whether it's a chylomicron remnant or VLDL remnant, when there's a defect in ApoE, and there are a number of defects that are in the population, it won't bind so efficiently to some of the receptors, the LDL receptor. That's overcome in a person's younger age by some of these other receptors, like the heparin sulfate proteoglycan receptor will still be able to bind these remnants to take them out of circulation. However, if there's a second hit of some kind, and that can be either obesity or insulin resistance, could be menopause, could be hypothyroidism. If there's a second hit that causes now this ApoE to not be so easily recognized, or actually there's a reduction in expression of this heparin sulfate proteoglycan, that leads then to high levels of these remnant particles. And that can lead to high triglycerides or high LDL cholesterol. And this is a condition called familial dysbeta lipoproteinemia. It's another familial condition that's common, relatively common, and it's undiagnosed. There's a high range in prevalence because we don't have a very strong definition of what constitutes this condition. So some studies show higher prevalence than others, but it's a fairly common and not unusual to see. It has to do with a defect in the hepa-lipoprotein E, which is the marker for these remnant proteins of triglycerides that then also carry some cholesterol. And these triglyceride-rich protein remnants, they're supposed to bind the heparin by these hepatocyte heparin surface receptors, heparin sulfate proteoglycans, LDL receptor or LDL receptor-related protein. If there is inefficient clearance of these particles, they're atherogenic and they can cause atherosclerosis. They can also cause high triglycerides, which then can lead to pancreatitis. So both of these adverse outcomes can occur. And what matters is which is the greatest impact, whether LDL is highest or whether triglycerides are highest. There are a number of APOE mutations that are in the population, and they are inherited in an autosomal recessive pattern and there's incomplete penetrance. So the family history, such as in this patient, can be negative. There's three actually different variants of this, and the variant, epsilon-2 variant, which can be inherited. It's inherited from both parents, can put a patient at risk. Patients can carry this without knowing. There's often an inciting event. So a second hit, as we mentioned, insulin development of insulin resistance or alcohol consumption or hypothyroidism or menopause. And with that, that can trigger this accumulation of these remnant particles, high triglycerides. And it's measured as high LDL, even though it's not by definition, if you ran this in ultracentrifugography, it would show that it's more these intermediate density lipoproteins or remnants. It's not actual LDL, but they're just the same. They're atherogenic. And so it's might as well count as LDL because they're atherogenic particles. Patients have high triglycerides and high HCL. HCL also has reduced clearance in this condition. And that can be one of the clues. The other clue that this is familiar with this beta lipoproteinemia is the yellow Palmar crease. The direct measure of LDL will show LDL may be smaller or may demonstrate lower levels. The Friedwald equation is not as accurate in this condition because these remnant particles are hanging around and they can disrupt the accuracy of this condition. There's the yellow Palmar creases and patients with lipid levels, they often are affected by their third decade with atherosclerotic disease by age 45. So how do you diagnose this? Well, you could just simply measure, look at panel and treat as accordingly. But if you wanna be sure that this is familiar however, this beta lipoproteinemia, one can do ultracentrifugation studies. You can also measure the epilipoprotein B to total cholesterol ratio. There's a low level of epilipoprotein B to total cholesterol. You could do genetic studies in HEPO-E. It's usually not necessary, but that's one way to diagnose for sure. Most important is how to treat. And treatment depends on the severity of the condition. Sometimes it's simply lifestyle modification to improve insulin resistance and reduce weight is simply enough. If it's a triglyceride driven condition, then treatment with fibrates is helpful. There aren't studies specific to this condition with some of the long chain omega-3 fatty acids, but it's reasonable that these would be beneficial as well. It's important to avoid bile acids question. It's not that anyone uses them these days, but some people do. These actually raise the LDL production and would be detrimental to these patients. PCSK9 inhibition is likely to improve this because of course that would help promote LDL receptor activity and remove these remnant particles out of circulation as well. There aren't any studies with PCSK9 inhibitors that I'm aware of to date, but likely they're beneficial. There are also a potential for antisense mutations of ApoB, but they haven't been studied in this condition as well. All right, so it's somewhat common condition. It can just masquerade as hypertriglyceridemia or high LDL cholesterol. It's worth recognizing, but more important, it's worth treating if in the case where you see. Any questions? It's a little unrelated to ApoB, but if we have a minute, would you comment on clinical utility of coronary calcium score in younger individuals less than 45? Yeah, I think this is a test that has been helpful in identifying people at risk for coronary disease that don't have some of the traditional risk factors. I think this particular board question was written to say, oh, the primary care doctor sent the patient because it's actually not recommended to do this study in someone less than age 45 because it's likely to be negative, even though in patients who are at risk, generally they haven't been around long enough for the enneathrosclerotic plaque to have calcified at that point and to show a positive test. So it's not really a useful test in people under age of 45, but you'll come across patients for which this is done. It's a more useful test in identifying people at intermediate cardiovascular risk who are older than that, who are in their 50s and 60s, who have one or two risk factors and have LDL cholesterol levels that level where you could consider treating, but might not. And it is a useful adjunct in helping risk stratifying those individuals. In the younger population, it's less likely to be positive. So it's unlikely. This is really, in a board question, when a primary care doctor does something, you know it's not the right thing. All right, you said that. Okay, all right. Well, I guess we have maybe time for one. We have five minutes left. We can go- Let's do one more case, yeah. One more case really quick and we'll go. So I'll try to read fast. So a 27-year-old woman with polycystic ovary syndrome presents for follow-up with concerns regarding weight management and dietary counseling. She'd initially presented with irregular menses, weight gain, and hirsutism after her first year of college. When she was started on a regimen of norel contraceptive and metformin at that time. Her menses are now normal and hirsutism has improved. At the time of diagnosis of TCOS, her weight was as high as 185 pounds, 84 kilograms, and she's been trying to lose weight. During the week, she works long hours and tends to grab something on the way to work, have a healthy salad from a local deli for lunch, and then have a late dinner when she gets home. On the weekends, she likes to go out to brunch with her friends. She's most sedentary during the day at work, but does go to the gym at least three to four times per week. Other than PCOS, she's healthy and denies other health issues. She's a non-smoker, does drink alcohol at least two times a week, one to two drinks per occasion. Her medications include norethindrone acetate, a final estradiol of one to 20 milligrams, and metformin, 2,000 milligrams daily with no known drug allergies. She's interested in trying intermittent fasting. All right, so here we are on intermittent fasting again. Which of the following would you counsel this patient regarding intermittent fasting? It can raise resting energy expenditure. It is safe and does not require a medication adjustment in the setting of having dysplasia, pre-diabetes, diabetes. It should be considered among other eating approaches as an adjunct to lifestyle modification to assist with weight loss, or it has been shown to be more effective than calorie-restricted eating plans. All right, great. So yeah, I think Ruth got it right, I think. Let's go through this. So, intermittent fasting, so intermittent fasting is a form of intermittent fasting. It's a form of intermittent fasting where you're not eating, you're not drinking alcohol, you're not smoking, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol, you're not drinking alcohol. Let's go through this. So, we talked a little bit about intermittent fasting on the last dietary question, but this is focused just on intermittent fasting. As Dr. Amaro mentioned, there are different methods and different ways. One is time-restricted eating, which we talked about as a 16-day plan. Another is alternate-day fasting or periodic fasting. There's tradition, you know, there are different religious groups that have done this for years, or more frequent than that, or less frequent than that. The physiology is that there's a shift in metabolism. People shift to metabolizing fat, which leads to ketone production, and this changes in energy and ketone production. There's reductions in insulin resistance, and this is maybe one of the best benefits of this strategy. It does not raise resting energy expenditure, so it doesn't change the way a person utilizes energy fully, so that's an incorrect answer, answer A. There are published trials at least up to one year that don't show a superior effect to calorie restriction, and so that's option D, so it's not better than calorie restriction. But diabetes medications should be adjusted due to this, due to most likely the improvement in insulin resistance, so answer B. Patients should be counseled that intermittent fasting should be considered as one dietary approach among others that can help in achieving calorie deficit, you know, 500 to 750 calories daily, which is what's needed for weight loss, and should be used in conjunction with lifestyle modification. That's still the current opinion. It's certainly a viable option for many people over the shorter term, but I think it's a reasonable option for people. And let me say, I think, you know, it doesn't affect energy expenditure, medicines. You know, when you look at the board question, you know, this one, you know, you should understand, of course, that does not, when you say it does not require medication adjustment, that is a clue that this may not be the best answer. And, you know, anyway. So that's basically made it through this question, too. Any questions or comments about intermittent fasting that we haven't gotten to? I think it was good. It was excellent. And it is very difficult to, I think, nutritional science, nutrition science questions are always the trickiest on boards, because just like you said in the beginning, it is oftentimes a matter of expert opinion versus strict evidence. And the evidence is very difficult to obtain considering how, how lengthy, cumbersome and expensive nutritional studies are. Yeah, absolutely. And necessarily there's often more than one change that's, that's done. So it's very hard to elucidate what is the mechanism and what is, what is going on in nutritional science. Sometimes as far as board strategy goes, you can tell, you can try to tell what the question writer feels is more important. Sometimes you can't, it can be hard, hard to judge, but it's always, it's good to understand that when, when one is asked, what is the best nutritional approach to a patient that is often an opinion driven question and try to understand what the question writer might be thinking. And there's some, some comments, I guess. Yeah. There was a question of how many cases we have left. I think, I think that's, I think maybe we'll quit there at eight o'clock is that this is a good, good place to stop. And thank you all for, for participating tonight. I hope, you know, I hope we all learn. I always learn whenever I go through these questions, something new. Thank you, Dr. Amaro for your, your contributions and, and to age. Great working with you, Dr. Thank you. Have a good night, everyone. Stop sharing.

lipids

cardiovascular health

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obesity

Dr. Michael Villa

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coronary artery calcium scores