Good evening, everyone, and welcome to another edition of the ACE Self-Assessment Program Live program. Tonight, we're going to be reviewing board review-style questions on the topics of lipids, on cardiovascular health, nutrition, and obesity. And so just welcome, and thanks for joining. Before we get started, I'd like to thank, one, Dr. Elias Siraj, who's been the editor and chief of the self-assessment program at ACE for the last five years or so. And I think he's been a continual great resource and supporter of the program. And I'd also like to thank Dr. Geetha Gopalakrishnan, who's the chair of the Fellows Education Subcommittee, who's really made these kind of programs possible. And I'd like to thank them for all their support. It is my pleasure to introduce Dr. Michael Villa, who is the editor of the Lipid Cardiovascular Health, Nutrition, and Obesity section. He is an associate professor of medicine, fellowship program director in the Division of Endocrinology, Diabetes, and Bone Disease at Mount Sinai Beth Israel in New York. And I am Anastasia Amaro here in, well, glad to join from Philadelphia. I am medical director of Penn Metabolic Medicine, a space for non-surgical weight management. Great. Thank you. Thank you, Dr. Amaro. Here are disclosures before we get started. And one more point before housekeeping is this is an interactive session. So please feel free to ask questions. The best way is to type them into the Q&A box within the Zoom program here at any time during each case. And, you know, I'll be presenting the cases, and Dr. Amaro will help, you know, get organized with questions. And when we get to the point of the Zoom poll, you know, each question will open. You know, please select your answer. And then questions from the audience, of course, will be addressed, usually at the end of each case. We have six cases tonight, so let's get started. The first case, a 54-year-old woman with type 2 diabetes, hyperlipidemia, and ovarian carcinoma. All right. Was admitted with small bowel obstruction secondary to metastatic ovarian cancer. She had a three-day history of nausea, vomiting, abdominal pain, and inability to tolerate oral intake. Her calorie intake was insufficient even before admission, and she lost weight. She had not had a bowel movement in the past five days. Abdominal imaging results were consistent with a small bowel obstruction due to carcinoma. A nasogastric tube was placed, and she had an average daily range of 1 to 1.5 liters per day. On physical exam, she appears thin with poor muscle mass, and she had 2 plus ankylodema. On testing, her albumin was 1.9 grams per deciliter. Aspartate amino transferase 36, alanine amino transferase 34, alkaline phosphatase 57, total bilirubin 0.8. Thyroid tests were normal, and her hemoglobin A1C was 6.7. She had lost weight during the admission, and she's now 150 pounds, and her height's 70 inches. She was started on total parenteral nutrition on day eight of her hospital admission, and the TPN formula included 1,800 calories per day, 50% carbohydrates, which were 265 grams, 30% fat, 54 grams of fat, and 20% protein, 90 grams of protein per day. On day 15, one week after TPN was started, testing showed an AST of 115, ALT of 112, alkaline phosphatase of 190, and total bilirubin of 2.1. Clinical evaluation reveals parenteral nutrition-associated liver disease. Here's the question. Which of the following changes would you recommend to improve the parenteral nutrition-associated liver disease in this patient? You can read through the choices. Change the source of lipids from soybean to lipid-based, soy-based lipids to fish oil-based lipids. Discontinue lipids and TPN. Discontinue the TPN and start dextrose intravenous fluid, or change the TPN infusion cycle time from 24 hours to 12 hours while maintaining the current TPN format. So go ahead and enter your votes. All right, great. So there's a good mix of answers here. Let's go through the explanation for the question. So this is a question about parenteral nutrition, which is not something that we always think about in endocrinology, but it's actually an important part of endocrine. It's a fundamental, provides a fundamental understanding of nutrition and metabolism, and it is still part of the ACGV curriculum for endocrine fellows. So it's good to know about it. And it's good to know about the complications that can occur, and, you know, liver disease is one of them. So parenteral nutrition can cause both cholestasis and hepatosteatosis, and often these things kind of occur together. There are multiple factors that contribute to the etiology of these conditions. What do you find clinically? Well, elevations in immunotransferase levels and bilirubin levels and alkaline phosphatase. And if you were to look at histology, there would be, you know, the classic changes in food hepatic steatosis, steatohepatitis, and cholestasis can be seen. And here's a lot of the factors that lead to all three of these conditions. As we were saying, they kind of occur simultaneously. There's a lack of enteral feeding, and so there's reduced, you know, substances within the intestine. Often there's short bowel. As a result, there's reduced intestinal mediators that affect metabolism and function of the liver. So there's glutamic acid and creatine, cholecystokinin, bile acid, FGF-19, and many other factors. In addition, there can be bacterial overgrowth within the intestine itself, leading to inflammation within the portal system. There's some deficiencies that are specific in malnourished patients, such as choline or taurine deficiencies. And there's high rates of dextrose infusion, of course, or contribute to fat accumulation and hepatic disease. And the use of soy-based lipids also contributes to that. And here's just a picture that I've taken just showing a lot of these mechanisms that you can see. A lot of the mediators just depicted here in the cartoon, such as FGF-19 or cholecystokinin, that are important in reducing inflammation within the liver. There's potential for bacterial overgrowth. And eventually, this can lead to fibrosis and even cirrhosis if this is left to continue and left untreated. And so this can be a serious complication of TPN. One of the most important is the dextrose infusion. And the recommendations these days is to keep dextrose less than 5 milligrams per kilogram per minute of body weight. And here's just a study of infants, because I picked this because it's relatively recent, receiving TPN because of intestinal failure. Those that went on to develop steatosis had a higher rate of glucose infusion than those that didn't. Now, these are infants. In adults, we like to keep it 5 or less. It is a continuum of risk. So it's not that there's a magic number at 5. But the lower the level, the better at reducing hepatic fat content and hepatic disease related to TPN. So for one, we like to keep the dextrose infusion rate slow. So, for example, one of the questions was to change to a dextrose infusion. And that might exacerbate things. Another one of the answers was to cut the TPN time, infusion time, in half. And that, of course, would double the dextrose infusion time and may exacerbate parenteral nutrition, fatty liver disease, as well. Now, let's talk about the lipids. So most of the lipids, at least in the United States, that are used in TPN are soybean oil derivatives, probably because it's the least expensive. And it's been in use for a long time in TPN. And unfortunately, soybean oil is inflammatory. It's high in omega-6 fatty acids, as well as triglycerides. And it has phytosterols that are somewhat inflammatory. And all of this is associated with both cholestasis and with steatosis of the liver. In contrast, a fish oil-based lipid is high in omega-3s, which are anti-inflammatory. It's lower in omega-6 polyunsaturated fatty acids. Also, fish oil has an increased concentration of vitamin E. Now, vitamin E, outside of TPN use, has been demonstrated to reduce hepatosteatosis. And one surmises that perhaps the additional vitamin E in fish oil contributes to its reduction in liver disease associated with parenteral nutrition. And so it is associated with improved liver function and a reversal of hepatic disease progression. So this is the right answer. Change to fish oil-based lipid emulsification. And then here's just one study showing that. There's a number of small studies. A lot of the studies in TPN are small. So here's a small study of 15 adults that were on parenteral nutrition for at least a month. They all had short bowel syndrome. All of them went on to develop parenteral nutrition-associated liver disease, proven by biopsy. And they were changed from a soy-based oil to a fish oil-based lipid formulation. And then underwent histologic evaluation again. So here's the cholestasis score at baseline during disease. And then one month after baseline, you can see a reduction. Same thing with steatosis score of histology. And then here is just I may like to say typical findings. I think maybe these are some of the better findings. But regardless, before you could see a lot of fat distribution within the liver. And you could see markers of inflammation and lymphocytes and cholestasis within the biliary system. And then after one month later, you could see resolution of all of this. So there's a significant improvement in liver disease in changing from soy-based oil to fish oil-based lipid formulations and TPN. And so just to summarize, to reduce the risk of parenteral nutrition-associated liver disease, you should avoid a high dextrose content of TPN, keeping the rates less than 5 milligrams per kilogram per minute. We should think about the infusion time because that can affect this rate. So doubling the infusion time is not a good option. Adding lipids will help allow to give less dextrose because, of course, you're giving calories as lipids. And, therefore, you can give less calories as dextrose, less reliance on dextrose as a calorie source. So giving lower dextrose will help. And instead of stopping TPN in someone who's severely malnourished, that was one of the answers. One of the answers that was incorrect was to stop TPN. But because this patient was so malnourished with ongoing small bowel obstruction and weight loss in the hospital, it's reasonable to continue TPN. So stopping TPN could be detrimental to the patient and would be better off continuing with a fish oil-based lipid. So that's the end of the first question. I don't know if there are any questions from the audience. I don't see any questions, but I'd like to spend an extra five seconds of your time on discontinuation of TPN. Probably not for the board purposes, but from clinical practice, do you ever hold TPN? If you don't have the proper composition available, would you rather hold it? Not hold, I mean, but discontinue lipids in TPN? Yes, it's certainly reasonable to discontinue lipids in the TPN, but at the same time, without raising any of the other components. So you can run TPN without lipids. So they call that a two-in-one formula as just amino acids and dextrose. And that's another reasonable way to go, especially if colon stasis is the main driver of liver disease in the patient. But you certainly can do that. And you can also reduce the amount of TPN or even hold it for a day or two. But the idea that it's important to resume nutrition when feasible and be mindful of calorie deficits that might be developing within the patient. Thank you. Yeah, I don't see any questions. I'd like to offer you to read the next question to give you a break. Sure, go ahead. And then you'll proceed with the explanation. All right, case number two. A 61-year-old gentleman with HIV controlled on triple therapy presents with an additional pretreated low-density lipoprotein level of 210 and reports intolerable myalgias on statin. Receiving azetamide therapy 10 milligrams per day, he tolerated it well, but his LDL decreased to 170 milligrams per deciliter only. He has a positive paternal family history of hypercholesterolemia and premature coronary heart disease. The patient underwent a coronary artery and calcium scan with a score of 210 units, which is ATF 80 percentile for an American man of his age. His cardiologist told him that if his LDL cholesterol level was not significantly lowered further, he would be a coronary risk equivalent within 10 years. His primary care physician has tried low-dose statins and every-other-day dosing with hopes to ramp up the dose. But each time the patient stops treatment because of muscle aches occurring within the first weeks of starting statin therapy. The patient is now seen in consultation regarding the usefulness of a pro-protein convertase PSK9 inhibitors in his case. So the questions. Although no randomized controlled trials evaluating the use of PCSK9 inhibitors have been conducted in this population, which of the following options describes the optimal recommendation? A, PCSK9 inhibitor is not indicated as the coronary calcium score is not adequate to interpret the extent of atherosclerotic disease in someone with HIV and not warranted given the high cost of this medication. B, compared to levels of the general population, PCSK9 levels are much lower in HIV-infected persons, suggesting that PCSK9 inhibitors may not be useful and shouldn't be prescribed. C, since there is no information about PCSK9 levels in patients with HIV, you suggest ordering the level and prescribing the inhibitor if the level meets the criteria. And D, compared to levels in general population, PCSK9 levels are higher among those with HIV and even higher in those with HIV and CHV co-infection. And given this patient's intolerance of statin, PCSK9 is a reasonable option. All right, great. Great. Let's talk about this question, and I think this is another important concept in lipidology and nutrition. I think one that most of us understand that people who are living with HIV have a high risk of cardiovascular disease. There's just one meta-analysis showing those with HIV compared to those that don't have an increased risk, which I think we know, and it's a multifactorial etiology. There's systemic inflammation. There's metabolic diseases that occur. And then there's important changes in lipid metabolism, so we should talk about that. The other thing that we should understand, I think many of us do, is the role of PCSK9 in mediating lipid metabolism or LDL metabolism, lipoprotein particle metabolism. So as we all recognize, there are LDL receptors that are on the surface of hepatocytes that bind LDL that's in circulation, and then these are internalized. And within the hepatocyte, in endosomes, the LDL is then liberated from the receptor. This is metabolized, and the receptor is recycled to the surface for continual use. Now, to help regulate this, there's a protein that's within circulation, though it's mainly in the perisurface plasma, and it binds directly to the LDL receptor. This is a PCSK9 protein. It's an endoprotease, and it will bind with the receptor along with LDL. When that's internalized, the combination of these, this leads to a degradation within the lysosomal pathway of the LDL receptor itself, so this helps to recycle LDL receptors and downregulate their expression. But as a result, PCSK9 activity will reduce the ability of the liver to take LDL out of circulation, releasing LDL in circulation. And, of course, inhibitors that have been around now for several years of PCSK9 prevent this from occurring and can help bring down LDL levels substantially. Here's just data from two major trials of the two different available PCSK9 inhibitors, ebulicumab and allericumab. And you can see in patients who are maximally treated with statin therapy, LDL cholesterol levels were achieved around 90, and those continued on placebo maintained there, whereas there was a substantial, almost 60-point drop of LDL cholesterol in both groups, and this was maintained over several years of therapy. And more, you know, equally or even more importantly is the reduction in cardiovascular events by about 15% in both different medications over the study time, over the three to four years of follow-up of these two studies. So there's a significant improvement in LDL cholesterol in the general population. We'd like to, as the question points out, this hasn't been specifically studied in the HIV population, but we'd like to think that it would be just as helpful in this group. And so a PCSK9 inhibitor would probably be helpful for this patient who is not tolerant to statin. So that's a reasonable option. But one interesting finding, this is now a few years ago, this was a study done looking at patients' healthy controls compared to people with HIV, compared to people who have HIV and hepatitis C co-infections, the levels in circulation of PCSK9. And interestingly, those who have HIV, especially those with HIV and hep C, have an increased level of PCSK9. And it's not clear how much this contributes to the increased risk of cardiovascular disease, but it probably does contribute somewhat, we may think. And treatment, therefore, may be warranted with this. And so just a few points about this question. You don't need to check PCSK9 levels is not a good clinical assay or even a clinical practice of measuring this level as far as giving therapy. Therapy often is very helpful, even in patients who have inherited conditions that affect lipid metabolism. Coronary artery calcium scores is also a very useful surrogate marker to look for atherosclerotic disease, less invasive way. And the high cost of PCSK9 inhibitors, while this is certainly a problem, it is offset by the prevention of cardiovascular events. And so option A is not correct. So, all right. So, well, we've made it through to the second question. I know, I don't know if you have any comments or questions from the audience. No, no, we're good. Good. So it's an interesting finding that there's increased PCSK activity in people with HIV. All right. I can read the third piece. Okay, sure. A 41-year-old asymptomatic woman is evaluated in your clinic for an abnormal lipid profile and moderate hepatic steatosis. Her BMI is 26, blood pressure is normal at 115 over 78, and heart rate is 72. Her medical or surgical history is non-contributory. And the patient also noticed that her father had fatty liver, no known coronary artery disease, and to her knowledge, she doesn't take a statin. Her laboratory findings, LDL cholesterol is 31, HDL cholesterol, 50, triglycerides, 48 milligrams per deciliter, and ALT is 38 with the current normal range of 1 to 40 in the lab. At this point, you suspect familial hypobeta lipoproteinemia and order ApoB protein measurement, which comes back at 25 milligrams per deciliter. Normal is considered less than 100. Hers is quite low. Which of the following options are accurate? Are accurate for describing the most likely form of this patient's familial hypobeta lipoproteinemia? It's option A, homozygous ApoB defective form of familial hypobeta lipoproteinemia, deficiency of fat-soluble vitamins and failure to thrive. B, heterozygous ApoB defective form of FHBL, hepatic and muscle insulin resistance. Similar to that seen in patients with non-alcoholic fatty liver disease. Heterozygous ApoB defective form of FHBL, hepatic and muscle insulin sensitivity. Similar to that seen in individuals with the same BMI and normal intrahepatic triglyceride content. And D, heterozygous 3p21 form of familial hypobeta lipoproteinemia, specific gene not yet identified. Okay, great, so there's a lot to it. Interesting. Yeah, so a lot of good answers here. A lot of people picked answer choice B. And this is, you know, a condition that I think most of us don't think about that often. But I'm gonna use this question as an opportunity to talk about this not so uncommon disease, familial hypobeta lipoproteinemia. First of all, you know, and as the question implies with the family history, it is an inherited genetic disease. It's autosomal dominant. And it's defined by a low LDL cholesterol and low apolipoprotein B, ApoB, which is lower than the fifth percentile. So very low levels. ApoB is a protein. It's synthesized in the liver. That's important in the production of lipoproteins. A nascent, very low density lipoprotein particle allows this part to be produced within the liver and then released into circulation. And so that's, you know, this disease allows us to highlight, you know, a lot of lipoprotein metabolism. So of course, here's this cartoon, shows the liver here in the center that produces LDL particles that have ApoB 100 on the surface protein that allows, you know, what is the deficit in this condition. And it's a truncation of this protein. Interesting from the same gene is synthesized ApoB 48, which is what is synthesizing chylomicrons of the intestine is synthesizing chylomicrons, you know, from dietary fat. And, you know, the deficit doesn't extend to this protein. And as a result, people are able to eat and digest fat. There are, you know, more severe conditions where ApoB 48 is also involved. And in those patients have failure to thrive and lipid deficiencies, lipid soluble vitamin deficiencies from early ages. So in this case, when an adult with the lipid profile described, it's a deficit in the ApoB 100 only, and that leads to reduced VLDL cholesterol. And as you can see from the metabolism and pathways in this cartoon, you know, lipoprotein lipase helps degrade triglycerides within the VLDL cholesterol forming IDL and eventually LDL particles. So with deficits of ApoB 100, there are low levels of all of these low levels of triglycerides that are fasting as VLDLs, low levels of LDL cholesterol as well. And if you measure ApoB 100, which you can do, that shows, that will show very low levels as well. All right, and so familial hypobeta-lipoproteinemia, generally it's a heterozygous, and most of the time it's asymptomatic, but it can come to clinical attention by, you know, mild liver dysfunction and hepatosteatosis that is seen, and also by very low cholesterol levels. You know, there's two different forms, but the form that's due to the ApoB protein truncation occurs one in 3,000. So it's not so, not so uncommon, but it often gets overlooked because cholesterol levels are low and hepatosteatosis is relatively common. There are three forms altogether. So there's the ApoB form that's inherited a truncation of ApoB. There's also a susceptibility locus on chromosome 3p21 that interestingly does not lead to hepatosteatosis. And then there's a separate locus somewhere that's not fully understand. So that's the third case. And so here's the 3p21 familial hyperbeta-lipoproteinemia is not associated with hepatosteatosis. So option D was incorrect. And the other question, the other part of this question was, what is the association of the hepatosteatosis that occurs in familial hyperbeta-lipoproteinemia and possible insulin dysfunction or insulin resistance? Here's a nice study that was done by my colleague, Dr. Amaro, a few years ago, where it's really a nice project where she did hyperlinsolemic euglycemic clamps in patients who were lean controls, in patients who were overweight or obese with classic non-alcoholic fatty liver disease, as well as people who were overweight and obese who did not have fatty liver disease. And then in the fourth group, people who were overweight or obese but had familial hyperbeta-lipoproteinemia. Of course, in that group, patients did have hepatosteatosis. And if you see where the insulin resistance shows or the insulin sensitivity, the greatest sensitivity, of course, was in the lean controls, and the worst was in the patients who had obesity or were overweight with non-alcoholic fatty liver disease. But interestingly, the familial hyperbeta-lipoproteinemia group had an insulin resistance very similar to patients with normal intrahepatic triglyceride content. So patients who, it seems that it's not simply the fat content within the liver that leads to insulin resistance, but a more complex cascade of events leading to insulin resistance and contributing to insulin resistance in this scenario. So the answer that familial hyperbeta-lipoproteinemia does not contribute to insulin resistance in the liver or the muscle, this is the correct answer. So, okay. And that leads us to the end of this question. If there's any further questions from the audience or any comments, Dr. Morrow, if you have any. Thank you. Thank you for including my study in this. It was my fellowship project, and it taught me to understand the difference between the importance and possibly actually inert nature of triglycerides in the liver themselves. And it is very likely that there would be some active, metabolically active metabolites such as diacylglycerol that would eventually, that can induce the inflammatory cascade, but not in this case. So the presence of triglycerides in the liver itself is not necessarily directly proportionate to insulin resistance. And probably would like to add that, even though I anticipated there could be a question about treatment approach, and really there is no treatment, there are no guidelines. It is suggested that people with familial hyperbeta-lipoproteinemia are somewhat protected from cardiovascular disease. So they truly don't have to be on a statin, but still consider other risks. Thank you. Thank you for sharing. All right. All right, well, I guess we're about halfway through. I guess we can go on to case number four. All right, 54-year-old woman is scheduled for surgical neck exploration and laryngectomy for the recurrence of laryngeal squamous cell carcinoma. She was initially treated with external beam radiation to the neck three years ago when she was first diagnosed. Over the past six months, she has lost 35 pounds, which was attributed to increased dysphagia and reduced appetite during this time. Despite strong support of family members and friends and the large supply of oral nutritional supplements at home, patient is unable to meet her nutritional needs with oral intake. Her current weight is 93 pounds and her height is 65 inches, giving her a BMI of 15 kilograms per meter square. Her other medical history includes hypothyroidism that she developed six months after radiation therapy and hypertension. She previously smoked one pack of cigarettes per day for 25 years, but quit 10 years ago. She has mild emphysema and only rarely requires rescue inhalers for symptoms of wheezing. Her oral medications include levothyroxine and amlodipine, as well as opiate medication for pain. Two weeks before her scheduled surgery, the patient is admitted for nutritional optimization and gastric feeding tube is placed. Laboratory tests before admission show iron deficiency, anemia, and other laboratory test findings are as follows. Fasting glucose, 71 milligram per deciliter, sodium 136, potassium 3.6, magnesium 2.1 milligrams per deciliter. The reference range is 0.85 to 1.1. Oh, I'm sorry, 2.0 to 2.6 milligrams per deciliter. Phosphorus 3.1, creatinine 0.4, and albumin 2.8 with the reference range 3.4 to 5.4 grams per deciliter. So in my view, everything is on the low side. And the question is what would be the most appropriate approach when initiating nutrition therapy for this patient over the next 72 hours? A, cover patient's full energy requirements and add a protein supplement. B, cover patient's full energy requirement plus additional calories for weight gain. C, cover less than half the patient's energy requirement and provide vitamin supplements. D, cover patient's full energy requirements and correct iron deficiency. All right, so another mixed answers, but a lot of the crowd picked the answer C. And let's go through this question. So this is a question about refeeding syndrome. And it's an important concept to understand. Caused by electrolyte and fluid shifts that occur in someone who is essentially starving when it's really nutritionally depleted and who's suddenly given exposure to nutritional therapy and something that's malnourished. And this was first recognized, you can see here about 72 years ago, it was recognized in prisoners of war and other aspects of war that lead to malnutrition where refeeding individuals led to adverse outcomes and even death in some cases. And so refeeding syndrome occurs because with the addition of nutrition, patients who had compensated and who had been depleted of electrolytes, there's sudden shifts, the induction, by glucose shifting into cells, the induction of insulin leads to reductions in serum levels of phosphorus, magnesium and potassium potentially. In addition, there can be micronutrient deficiencies, very commonly thiamine deficiency with leading to various forms of beriberi. And often there's multiple deficiencies. And who's at risk? Well, people who have severe malnutrition risk. So anyone with greater than 20% weight loss of their baseline over six months, people who have severe chronic disease, such as a malignancy, or those who've had a history of poor intake for months or at a time in a very low BMI, less than 16 kilograms per meter squared. And so here's just a cartoon of what may happen. You're in a starvation state, there's low insulin and high glucagon. There's a lot of gluconeogenesis that occurs and depletes and consumes lean body mass, depletes protein and other stores. There's proteolysis as a result. There's loss of lean tissue and muscle mass. And there's a decrease in the electrolytes within cells. And as glucose is added, and it's through insulin mediated glucose uptake, glucose travels down its concentration gradient. And the first thing that occurs when it enters cells is phosphorylated to glucose 6-phosphate. So that consumes phosphorus. In addition, glycolysis is instituted and even the citric acid cycle is instituted. All of this consumed phosphorus, and especially the formation of ATP consumed phosphorus. So this can lead to very low levels of phosphorus in circulation. Thiamine is also required in both glycolysis and in the citric acid cycle. So depletion of thiamine, sudden depletion of thiamine can lead to symptoms of beriberi or Winnicke-Korsakoff syndrome coming about. And then at the same time as phosphorus, potassium and magnesium to a lesser extent can be affected, although those are less common. So the most common electrolyte abnormality is hypophosphatemia. And when that's severe, that can lead to muscle weakness and paralysis and even diaphragmatic paralysis due to respiratory failure and death from that. The refeeding syndrome, even in mild states, is associated with either hospitalization that's unexpected or transfers to ICU for long hospitalizations and an increase in six-month mortality. So it's certainly associated with adverse outcomes. We'd like to avoid it. How can you avoid it? Well, it occurs very early in time of refeeding. So the best way to do this is to identify patients who are at risk and prescribe nutritional therapy that makes sense. So you treat with reduced energy intake, which is option C, which is what most of you chose. You give fluid restriction and vitamin supplementation as well as electrolyte replacement and monitoring during this time. It's important, careful monitoring of electrolytes and those three that I mentioned, phosphorus, potassium, and magnesium, and repleting those as needed. It's good to give empiric thiamine especially, as well as just general micronutrients, which are likely to be deficient in these patients with severe malnutrition. Eventually, we'll want to get diet and calorie intake and protein intake up to the person's goals, but this is something that you have to have a tempered approach. It's good to give maybe 50% of the target or less and slowly increase to about day 10, day seven to day 10, getting to the target levels of calorie and protein intake to avoid refeeding syndrome. So options A and B were incorrect, as I said. And what about iron? So iron actually has an interesting effect. If you give someone who's depleted of iron, a new supply of iron that can reduce red blood cell production and they consume even more electrolytes, which is worse than hypokalemia, and there's a higher rate of hypophosphatemia that's been reported with early iron therapy. So even in patients who are deficient in iron, it's best to hold off giving iron until nutritional therapy has been started and several weeks into therapy, and it's reasonable to give iron at that point. It's not a common thing that we see these days, thankfully, but it's something to look out for. In any type of malnutrition, whether it's bariatric surgery with severe weight loss, whether it's patients with eating disorders or certainly patients with chronic disease, such as cancer patients who cannot eat, such as the one presented here. Any audience questions for this? No, no questions. I thought it was an important case. Like you mentioned, really a case came to mind that were post-bariatric surgery with a severe malnourishment that almost got to the stage. Not exactly, but it got me thinking at some point. So thank you. All right, sure. Yeah, it's good. It's a good teaching point. Thank you. All right, case number five, probably my favorite because that's what I do every single day. A 40-year-old woman who has been receiving treatment for obesity is having a follow-up visit nine months after starting subcutaneous semaglutide 2.4 weekly in addition to lifestyle modification. Her body mass index at the start of the therapy was 34 kilograms per meter square. She had mild hypertension treated with HCTC, and you counseled her about the cardiometabolic benefits of losing 10% or more of her weight at that time. Since then, she has introduced recommended changes to her diet, slightly increased physical activity, tolerated semaglutide well, and lost 11% of her weight. Her current BMI is 30. Her blood pressure has been normal in the past three months without hydrochlorothiazide. She is happy with her progress and wishes to stop semaglutide now. Which of the following describes the best approach to therapy and counseling at this time? A, discontinue semaglutide 2.4 because clinically meaningful weight loss has been achieved. The patient's weight will remain stable after discontinuation of semaglutide. B, continue semaglutide 2.4 milligrams weekly. Discontinuation of semaglutide at this time will result in approximately 7% weight regain in the following 12 months and increase in systolic blood pressure. C, discontinue semaglutide because 10% weight loss has been achieved and there is no significant difference in systolic blood pressure in subjects who discontinued semaglutide and those who continued semaglutide after 20 weeks of therapy. And D, continue semaglutide since the ideal body weight has not been achieved. All right, good. So two different answers were picked and we'll go through this question too. A lot of voting for answer B, some for answer D. And so this has become, as Dr. Amaro pointed out, a common practice in modern times. You know, the medical therapies for weight loss and there've been a number of guidelines that have been issued. This is just the ACEs guidelines that were put forth in 2016. I just wanna read a few points because even though they're a few years old, a lot of the concepts that they highlight are still very relevant and should be thought about in the treatment of obesity. And, you know, I'll just read through this. The addition of pharmacotherapy produces greater weight loss and weight loss maintenance compared with lifestyle therapy alone. The pharmacotherapy for overweight and obesity should be used only as an adjunct to lifestyle therapy. So that's a good point. Everyone really should be doing their best to improve their lifestyle in the ways that are available to them. Pharmacotherapy should be offered to patients with obesity when potential benefits outweigh risks for the chronic treatment of their disease. That's important, the chronic treatment. You know, while still controversial, I think many groups view obesity as a disease. And if you view it that way, then it makes sense for the chronic treatment, the chronic therapy, just like you would with hypertension or hypercholesterolemia, consider therapy for the long-term because that's where it seems to be most successful. Short-term treatment for three to six months using weight loss medications has not been demonstrated to produce longer-term benefits and cannot be generally recommended based on scientific evidence. Those were ACEs guidelines. The Endocrine Society has similar guidelines and so does the American Heart Association, American College of Cardiology and Obesity Society. Though they're starting to get a little bit old, 10 years ago, the Canadian Medical Association came out with more recent guidelines, but they all say about the same thing. We consider medical therapy in appropriate patients, but should be considered over the longer term. And specifically with some of the newer agents like semaglutide, which we should all really be familiar with some of the trials, including the Step 4 randomized trial that was published in JAMA about two years ago now. But in this trial, they started with 900 patients with a body mass index, one or two with an elevated body mass index above 30 or greater than 27 with one comorbidity. And they were given weekly semaglutide for 20 weeks. Everybody was given this. And of those most responded, of the 804 of that group that responded and that lost at least 5% of their body weight, they were randomized at week 20 to either continue semaglutide or to change and continue placebo. And these are the results and they're not surprising, but as you can see, here's weeks zero through 20 when everyone in the group was given semaglutide and weight loss about 10% of body weight was achieved a little more than 10% by week 20. And then of the group that was switched to placebo, there was a weight regain. Now they didn't get back to by week 68, which means a little less than a year, almost a year later. I didn't get back to their baseline weight, but they did certainly climb up in weight. Whereas the semaglutide group that continues semaglutide continued to lose weight and then plateaued about 60 weeks just beyond a year into the trial. So highlighting the longer term therapy that makes sense. But in addition to weight, they also looked at waist circumference, which had this kind of a similar pattern, weight circumference decreased and continued to decrease in the semaglutide group whereas it started to re-increase in the placebo group. But I think, and when I view weight, I don't just look at the weight. I think most of us look at the metabolic disease that occurs. And so the risks, whether it's hypertension, sleep apnea, diabetes risk, cardiovascular risk, those are the things that we really wanna prevent in addition to this, the weight of the patient. And so if you look at at least one of these, they looked at in this trial, it's systolic blood pressure. And of course it decreased in everyone as people lost weight. But then almost immediately, as soon as people stopped and switched to placebo, you can see the systolic blood pressure went back up and almost back to baseline by the end of the trial, even though the patients hadn't gained all the weight back. So there's a metabolic impact of taking semaglutide in this case of weight loss medicines that may impact insulin resistance and metabolic consequences. So blood pressure in this instance went back up. Whereas in the treatment group, their blood pressure continued to remain low. And so it's reasonable to continue, even though the patient had a substantial amount of weight loss over the short term to continue semaglutide over the longer term as the majority of our group had answered. But there is one other point is about achieving ideal body weight. That's not been an endpoint of any of the OVC clinical trials of weight loss medications, or even in lifestyle medications. Weight loss, it's currently recommended to try to achieve reasonable goals. I think achieving an ideal body weight can be very daunting and frustrating for patients because it's really unachievable for most patients to get down to ideal body weight. But just setting an achievable goal of a five to 10% weight loss, which is metabolically meaningful. And in almost every study that's been done, whether it's in the Diabetes Prevention Program, the STOP, Non-Insulin Dependent Diabetes Trial, Lookahead Trial, CEQA Trial, PREDIMED Trial, Finished Diabetes Prevention Trial, Ducting Diabetes Trial, all of these trials have seen substantial reductions in various metabolic diseases, such as diabetes, cardiovascular endpoints, or other endpoints associated with metabolic syndrome. A substantial reduction in these endpoints despite achieving only about a five to 10% weight loss. So this is a kind of a target that's, one is achievable, it's reasonable, and it's metabolically meaningful. So I think that's the goal that we'd like to strive for. And I think that's the end of the question. I'd like to hear your thoughts on this question, Dr. Amaral. Yeah, you covered it all. I think I have really been doing this in the patients, in the exam rooms where we talk with patients about what ideal body weight means. And it means very little at this point. And I explained how we go away from the concept of ideal body weight. We have a very strong evidence for the percentage weight lost, but not for achieving ideal body weight. So I kind of discourage people from thinking that way. Oops, I think we have a question. If patient does have to come off semaglutide, what have you found best to maintain weight loss? Excellent question. Yeah, this is a good question. And I think it's, you know, I don't know what is, I mean, you know, what, you know, certainly, you know, emphasize a continuation of a healthy lifestyle. One can consider one of the other therapies. I guess the question, you know, what is important here is what caused the patient to come off semaglutide. Now, some people aren't able to tolerate this medicine. Usually the intolerance occurs early on in therapy, but if it happens to be later on where patient's been on semaglutide and they do have to stop it, or perhaps due to intolerance, or perhaps due to costs, or maybe insurance changes, then if it was due to, you know, you could consider, if it was due to side effects, you could try considering some of the other GLP-1 or GLP-1 and GLP-2 analogs, if those may be tolerated. You could consider some of the other therapies if it's due to costs that can be either prescribed as generic medicines, such as fentamine topiramate, or perhaps naltrexone bupropion, some of these older therapies that still exist in combination pills, but I often prescribe them separately because in those cases, they're generic when it's prescribed separately, and I continue with these therapies. And they show a significant weight loss still, and improvements also in blood pressure intolerance over a long time. I think the longest study in the combination of fentamine and topiramate goes about six years, so there's certainly room to continue this therapy over the long term. Thank you. You pretty much answered the second question as well. Do you use off-label topiramate for weight loss? And I probably concur that I do that, too. Yeah, and probably in that scenario where the patient has to come off a semaglutide topiary and comes back with increased cravings, especially evening cravings, topiramate would definitely be on my list of things to discuss. And while I'm fortunate to be at a tertiary center where I can also offer patients participation in clinical trials, so that's another tool that we have here. So we guide patients into clinical trials. Yeah, you have to take advantage of any tool you may have. And so I think these are reasonable choices. I think on the board exam, off-label use is usually discouraged, but at least in practice, these are certainly good options. And I support that, too, absolutely. Yeah, I'm pretty sure all the board questions will be strictly based on the guidelines and all the names will be all the, it will be Wegovy and not, ozempic semaglutide 2.4 and not 2.0 if we're talking about weight loss. So please be accurate about that, probably even selecting the right answer. All right, thank you, I think. Few minutes left, and I guess this is, I think the last question here is relatively short, so maybe we can get through this before the time's up. All right, an 11-year-old boy comes to the clinic for routine well childcare. At five years of age, he had surgery to repair a coronary artery anomaly, and on subsequent pediatric cardiology evaluations, the artery has been visualized and remains patent. He has otherwise been healthy, participates in school and physical education without concerns, and is not currently taking any medications. He is 11. His family history is positive for a great-grandfather who died of heart problems in his early 50s, so premature heart disease. His parents report being concerned that he averages two hours of screen time per weekday and four to five hours per weekend day, and that he tends to snack on chips during the screen time. His physical examination findings are completely unremarkable. He has BMI at the 70th percentile for age and sex. Which statement about lipid testing for this child is most consistent with current American Heart Association and College of Cardiology cholesterol clinical guidelines? A, the coronary artery repair history compels a lipid screening. The family history warrants a lipid screening. The excessive screen time warrants, necessitates a lipid screening. And D, he is at an age at which universal lipid screening may be of benefit. I like how this question was constructed to test actually test-taking skills. Yes, there's a lot of test-taking, unfortunately, on the boards, but hopefully this review will help you through that. So let's talk about this question. So they asked specifically about what the guidelines say. And so the latest, the 2018 American Heart Association, American College of Cardiology cholesterol practice guidelines, they do include universal screening and it is just based on age. So once between ages nine and 11, and then once between 17 and 21. And this is to look for moderate or severe lipid abnormalities. And so that's, so the answer, correct answer, it's based on age. And it's moderate quality evidence, you know, in this guideline. And the rationale is really to look for undiagnosed or familial hypercholesterolemia, which is a very common inherited condition that often can go unrecognized. So it's underdiagnosed, its prevalence is somewhere between 100, one in 200 and one in 500 of the heterozygous form. And in this condition, there's compared catabolism of LDL cholesterol. There's a reduction in clearance of LDL cholesterol. Four of the genes, four genes have been identified that contribute to this. And these are the genes, the LDL receptor, which is by far the most common. The apolipoprotein B, so we talked about that earlier when it was truncated, it can lead to familial hypobatal lipoproteinemia. There's point mutations or there's other slight mutations in the apolipoprotein B, that can lead to a misrecognition of LDL particles and lead to familial hypercholesterolemia. The PCSK9 gene itself, when there's an activating mutation of this, this can lead to familial hypercholesterolemia. And then there's an LDL receptor associated protein also that can be associated. And here's just a cartoon showing, again, the LDL receptor at the surface, there's PCSK9 in circulation and LDL particles in circulation. So defects on this LDL receptor associated protein, so defects, and then you can see the APOB100 on the surface. These defects can lead to familial hypercholesterolemia and elevated LDL. So by far, it's 90% of cases are from the LDL receptor. And then APOB is the next most common, these others are quite rare. And then of the LDL receptor, there's different mutations, over 2000 mutations that have been described. So various different mutations exist and how the severity contributes to the severity of the condition. Ligand binding, surface transport, receptor internalization, recycling, or expression. And one thing interesting about familial hypercholesterolemia, one, it leads to high cholesterol, which we don't think about treating. But even if you compare it to people who don't have familial hypercholesterolemia and look at the, in this case, it's the odds ratio of coronary disease, at all levels of cholesterol, it's the people who have familial hypercholesterolemia have a much higher risk for coronary disease, even at the same level. That's seems, it's an interesting point. And here's a study just looking at children here, now at ages six through 18, looking at their carotid intermediate thickness compared to their siblings. So patients who have familial hypercholesterolemia compared to their siblings, already, you know, around age seven and a half, there's a significant increase in carotid intermediate thickness. Here's just another graph showing the same thing. Familial hypercholesterolemia, intermediate thickness is greater than those of their unaffected siblings. And if you think about it, you know, LDL cholesterol is very low when we're born, and then it increases with time. So if you, this is the healthy controls of what LDL cholesterol may do. And this is the line of patients who have familial hypercholesterolemia. And at all ages, cholesterol is a little higher. You know, you could see, it's essentially double, here starting around age four, age six. And so the area under this curve is what's important and leads to atherosclerotic disease. So if you start a low dose statin, you know, here, this is kind of, you know, very young to think about a statin age 11, you can change this trajectory. On the other hand, if you started even earlier, you know, to, I guess, wait until age 18 or age 20, there's a higher exposure time of high LDL cholesterol. And so over a lifetime of a patient, this can lead to early atherosclerotic disease. So that's why diagnosing early and consideration of treatment early makes sense. Sorry. And even, you know, so statins have been shown to be beneficial in this population, though it's still controversial when to start statins. And then also lately, this is an article in New England Journal a few years ago, looking at PCSK9 inhibitors that show benefit in the pediatric population. And so this patient would meet, just based on their age, age 11, meet screening recommendations. And the other responses, you know, coronary artery repair history, familial family history, and excessive screen time, all of these are associated with increased coronary risk. Though they don't specifically say this in the guidelines that this is not the reason to check, but they're reasonable considerations as well. And then you note that there was significant premature coronary disease for men under age 55 and women under age 60 within the family. And this can include parents and sibling aunts and uncles. So, good. All right, so, all right, well, thank you. I don't know if there are any questions with regard to- No questions. Do you know, by any chance, at what age is statin is formally FDA approved? I confess I have very little pediatric knowledge. Yeah, no, and that was one of the reasons to include this question. I know it's still approved in adults, so it would be hopefully of use. But I think, you know, and it's different groups have different recommendations, but it's usually in familial hypercholesterolemia, around age 16 or so, it's considered to start to help prevent, you know, atherosclerosis that's, you know, demonstrable in their 20s and may come to clinical attention in their 40s at earlier ages than would be otherwise. Thank you. Okay. Well, thank you all for joining tonight. It's been a pleasure going through these questions again, and, you know, thanks for coming. A few more sessions, I think monthly sessions of the ASAP. So, keep an eye out for those next month. Thank you. Thank you.

lipid disorders

cardiovascular health

nutrition

obesity

cases

abnormal lipid profile

surgery

semaglutide therapy

screening

familial hyperlipidemia