My name is Shelley. I'm one of the chiefs and I'm happy to introduce our talk today. We specifically reached out to the gastroenterology department on this topic because there's been a lot of audience requests for it. So very excited for the talk today. And before I hand off to our introducer Dr Wadhwani. I wanted to point out the QR code here on our first slide. You can go ahead and scan that now on your on your device. Um but if you miss it it's okay because I will be posting the link in our chat a couple of times during the talk for any questions that come up. If you could please just drop them in the Q. And A. And we will save some time at the end to address some of your questions. Um Okay so without further ado I'll hand off to Dr Wadhwani to introduce our speaker for today. Thank you, thank you so much uh for those of you don't know me, I'm Sherrod Wadhwani, I'm one of the pediatric Cap Atallah gist. And I split my time between Oakland and san Francisco. Uh And it is my distinct honor and pleasure to introduce my friend and colleague Dr Nam Rata Patel Sanchez um NAMI as I know her, she recently completed her pediatric GI fellowship with us at UCSF Benioff Children's hospitals and during her fellowship she studied the link between non alcoholic fatty liver disease and pcos in adolescents with an adult Hepatology Ist Dr Monica Sarkar. She recently joined the faculty of Benioff Children's hospital. Oakland. And in her new role as assistant professor, she will have a clinical focus uh in non alcoholic fatty liver disease, nutrition and shortcut. And her academic focus will be on quality improvement and medical education. She will serve as the liaison between the G. I. Division and the pediatric residency program. So please reach out to her if you have an interest in G. I. Or liver. Um and so now without further ado I'll turn it over to Dr Patel Sanchez to give her talk titled non alcoholic fatty liver disease and its association with polycystic ovarian ovary syndrome. Thank you Sherrod. Hello everyone. Yes I am Sanchez but Mommy! Mommy and I'm excited to be here to um have this talk again the title of the talk. Non alcoholic fatty liver disease and its association with polycystic ovary syndrome. And I wanted to tell you about it or disclosure that no one involved in the planning of presentation of this activity has any relevant financial relationships with the commercial interest to disclose. We have a few questions for you to quickly review and we will go over the answers at the end. Next question you can think about your answers and either write them down on the side or just remember what you thought about again or review them at the end. Great. Just wanted to quickly introduce myself. Um I am from the suburbs of Chicago namely Burr Ridge Illinois. I did my undergraduate studies at Davidson College which is now currently best known for um being where the M. V. P. Um Steph curry went to college and I didn't know him while I was there. Um I then went to graduate school at Tufts School of Medicine and did was in the MD mph program there. I then moved to Chicago to do my residency at University of Chicago cuomo Children's Hospital to then do fellowship here um across the bay. UCSF Mission Bay and also got to do a few experiences over here in the Oakland side during fellowship. Um A couple of my hobbies include dancing by myself um cooking all types of food and then reading and I brought to say that I am okay on to the objectives of our today's talk. So first objective is that we're going to define and evaluate how to evaluate a patient for non alcoholic fatty liver disease. Using mass began guidelines the second one to identify which patients to screen for non alcoholic fatty liver disease. We're gonna identify which patients with polycystic ovary syndrome or Pcos to screen for nah fault. And lastly we're gonna list the different types of study designs to inform fatty liver treatment option. I'm gonna start with the case. So um we have a 15 year old with Pcos who presented within elevated A. L. T. Two G. I. Clinic her course um started that she got diagnosed um with Pcos the age of 13.5 with her having acne and dismay Maria. And then at 14 years old labs were done for that around at the beginning of her diagnosis and A. L. T. Of 28. Um Otherwise labs were mostly okay except the triglyceride level was elevated at 205. These were fasting. Um She was prescribed oh cps. But they cause mood changes so she stopped them but she continued to see endocrine followed closely with endocrine over six months um 1 15.5 years old. And we can all just notice that she developed a parenthesis negro can so had because I did to repeat labs and found that her A. L. T. Shot up to 163. Um And her A. S. T. Went up as well was along along with her total cholesterol 2 to 19 A. Total cholesterol level of 2 22 and an LDL level elevated to 1 33 hemoglobin A. One C. Stayed um below. Um Sorry that top line should also say hemoglobin A. One C. And that hemoglobin um hemoglobin A. One C. Um stayed you know sort of in the um look not had not yet really got prediabetes status. Um Then she would refer to G. I. With this elevated A. L. T. Um concern. And so G. I work up was pursued importantly um the other areas or other diagnosis of chronic hepatitis were ruled out. So that includes infectious um ideologies and activities and then the autoimmune um work up was negative against autoimmune hepatitis type one and type two. And then metabolic work up ruled out Wilson's disease, thyroid disease, celiac disease and one and two trips and efficiency. So we can say for this patient that they have traveled. What is natural. So natural is um as defined by the North American Society for pediatric oncology. Hepatology and nutrition is chronic halitosis in Children less than 18 years old, not due to metabolic genetic disorders, infections, use of psychogenic medications, ethanol consumption or malnutrition. So novel really is the full spectrum of disease. That's why I put in the middle there um and imitates any fatty infiltration liver. In the absence of these other um other causes fatty infiltration is typically defined as fat greater than 5% of the liver. Um when done by imaging or direct quantification sometimes by histological estimation, nah fall is diagnosis without specific changes to suggest data hepatitis. Um It can be with or without fibrosis. Nash is non alcoholic Seattle hepatitis and that's often what we find when there is an elevated A. L. T. They tend to they're going to meet the definition of nash because there is the hepatitis um there's actually two types of nash. So there's type one which is when the most of the inflammation and injury is in zone three. Um And this can sometimes have associated with ballooning. Um Type two is when most of the information is um portal two predominant and it was initially thought that Type two was child type and type one was adult type. But over time over the past 10 years really realized that um Children can present with both types and then um patients can go on to develop fibrosis. Again not always do they have hepatitis first. Um But oftentimes the state of hepatitis maybe undetected or excuse me. Um It may be that the patient is found to have the fibrosis even without having been found a dynasty of hepatitis. Um Just because of when they were screened. Um And the fibrosis can be perry portal portal or sinus auteuil. And always concerned when we find bridging fibrosis and then those patients will go on to develop cirrhosis. Um And oftentimes in adulthood can go on to develop a cellular carcinoma. I drew some green arrows here to indicate that um a lot of this early at the top is reversible. So this is the area where we really want to address which is why we really strongly suggest screening um for national baffles um because fibrosis is reversible although it's difficult to reverse but it is reversible. And then nash is most certainly reversible. And apples also most certainly reversible. We can get kids with fatty infiltration back to having a healthy liver because the health deliver is very um Such a young age easy to regenerate screening and evaluation at this time A. L. T. Is the only recommended screening test fine asked again um The upper limit of normal um is different from maybe a lot of times what you see in the results that you get back from the lab. So it is 30 for Children 12 and under. But Fortin girls it is 22 14 boys. It is um 26. So biologic girls greater than 12. It's 22 and biological boys. It's teen boys, it's 26. We really recommend screening um kids at least um starting at 9 to 11 years old should be all Children that are obese for me to be M. I greater than 95th percentile or overweight Children with A. B. M. I. Between 85th and 94th percentile with risk factor including central capacity, insulin resistance, prediabetes or diabetes, dis lipid e mia sleep apnea or family history of baffled as those have been seen to be a risk factor for developing field. Most certainly you can get A. L. T sooner. If your if a child has to be your obesity or signs or known hypo pituitary is um after initial screening. Oftentimes providers to ask what next? Um So it's important that it is continued to be repeated. Um And so if normal you recommend repeating every 2 to 3 years again sooner. Risk factors are present just like was done in our case. Right so the provider noted the synthesis negro cans. Worried about insulin resistance and then repeated labs and found um the significantly elevated A. L. T. Um if the A. L. T. Is greater than two times normal. Um So 44 14 girls, 52 13 boys. And it should be repeated again in three months and if it continues to be elevated it should be further evaluated. It can refer to G. I. And we're happy to further evaluate those patients and if you get a result greater than 80 then it should be further evaluated immediately. Um pediatric non alcoholic or metabolic associated fatty liver disease unfortunately has become the most common pediatric chronic liver disease. There has been around a threefold increase in prevalence between the 1980s to 2000s. Right now, our population studies done within the past 10 years found that Um it's affecting around all about 7% of all Children um in the general population when looking at just a pediatric obesity clinic, it affects around a third of Children. Um and it's Children that develop pediatric um nah fold compared to those who develop adult nah fold later on in life have an increased risk of morbidity mortality. And now novel has been found to be the fastest growing indication for liver transplant in young adults. And is the leading indication for liver transplant in adult women. The second leading indication for liver transplant in all adults. So it is a very morbid disease and something we definitely need to address. And oftentimes transplant is due to either development of a sailor carcinoma cirrhosis or cardiovascular disease. So how do patients develop baffled? Um There is both a genetic and an environmental component. Environmental component. Um There have several genetic risk factors for Nashville have been identified um conducting genome wide after conducting genome wide association studies. Multiple single nucleotide polymorphisms um have been for around the one that is most um notable is uh the snips and padding like fossil like pays domain containing protein three or P. N. P. L. A. Three. And these variants have been bound to increase psychogenic activity by gain a function and that um in that protein and that promotes triglyceride and fossil lipid synthesis and parasites and parasites. And so Children with my sagacity for P. And P. L. A. Three um had an increased risk of baffled with An odds ratio of 28. It's very high. Um and the homo sagacity um for Fibrosis was even stronger in Children compared to adults. Um importantly this allele is the most frequently present in Latino patients. Um and namely mexican american mexican patients which is what we've also seen in population studies that baffled is most prevalent in latino boys namely those with a mexican descent and less prevalent although quite prevalent in those with european background or asian background and a quite a low prevalence amongst the african american community, black community which is why genetic studies were really pursued um since it felt like an only environment could not explain the prevalence of nah folds. Environment does have a huge impact. Um It has been found that a sedentary lifestyle and increase fructose consumption um have an increased risk of naff old. And it was also found that patients with increased visceral at capacity. So for every five centimeters every five centimeter increase in waist circumference increase the odds of developing developing hepatic cirrhosis by 1.4. Um was also found that apple is strongly associated with insulin resistance, metabolic syndrome change and like a genesis and oxidative stress namely started with obstructive sleep apnea. Many studies have been done to look at the association of polycystic ovary syndrome and now raffled. Um You know as we as I discuss before now it has become the leading indication for trance liver transplant an adult women. It's very important to conduct these studies to see where there is an association and PCOS is known um as a manifestation of insulin resistance. Um So a meta analysis was done in 2018 and found 17 studies that did compare um for sorry, 17 studies that looked at the relationship between Pcos and baffled and overall they found that patients with Pcos had 2.25 times the odds of baffled and three F. O. B. So there is definitely a relationship and adult women. A study of 102 women with biopsy confirmed Naff aled was performed and it was found that Nash was found in 76% of women with Pcos compared to 66% without pcos. So there was a 10% increase in prevalence. And those with Pcos um compared to those without pcos um had a higher proportion with more advanced disease with severe ballooning and fibrosis. Also, very importantly, those with advanced fibrosis. Amongst those with advanced fibrosis, those of Pcos were five years younger than those without Pcos. So the disease snaffled when it develops in patients with PCOS, it comes earlier and more severe. Few pediatric studies have been done and general, they've mostly been small studies. A retrospective chart review in 2009 looked at 39 adolescents with Pcos and found that 15% of them and elevated at A. L. T. Possibly concerning for nah fault. A cross sectional study done in 20 and 13 found that an imaging that fatty liver was found in two out of 30 adolescents with Pcos. A large cohort um Study um done in 2016 in Australia. So, through the rain study, which is a large cohort study established in 1989 that follows um Children um through their adulthood and looks at comparison um You know, looks at pregnancy, childhood adolescence and adulthood. Um so it is a ongoing cohort study. They found that in 32 girls with pcos that 37.5% had nah folds compared to 15% Of around 100 girls without pcos. Um so they found that to um there was a 2.5 times increase risk. However the diagnosis was made by ultrasound only and ultrasound has low um sensitivity and specificity since many other chronic liver diseases can cause hypoxia ketosis. Um So there was that limitation. Um importantly they also found that girls with PCOS and baffled had similar insulin resistance scores and add capacity to boys with baffled when looking at um markers of both insulin resistance and at capacity. So that may explain some of the relationship. We conducted a study to look at a larger population. Since you know those studies were done in All the number of patients were less than 40 and we felt that it would be relevant to do a much larger scale studies. So um the primary aim of our study was to evaluate national prevalence and overweight and obese adolescent girls by pcos status are secondary aim was to evaluate whether risk factors for novel differed by pcos status. We collected data from the electronic medical records of both many of Children's hospital and san Francisco as well as here in Oakland. And um patients were included. Our study sample was adolescent females aged 12 to 18. They had to have at least one encounter with an I. C. D. Nine or 10 code for overweight or obesity. Our cases were diagnosed with Pcos by I. C. D. Nine R. I. C. D. 10 code and we compared them to age matched controls, patients were excluded if they had a prior diagnosis of a genetic or metabolic disorder or other chronic liver disease If they had self reported heavy alcohol use if there was a history of parental nutrition or the use of medications, a failure with hypoxia ketosis which are some heart medications, chemotherapy, methotrexate, he cortical steroids and heart therapy. And um they were also excluded if at the time of A. L. T. Collection they were found to have an acute infection or evidence of gallbladder disease such as colds, cystitis or cholangitis. The data was collected um Through as a hand review of all the charts by yours truly. So an individual trained and pediatric pediatrics and pediatric gastroenterology. Hepatology, nutrition all into an online database called Red Cap. So why did we use an I. C. D. Nine I. C. D. 10 code for Pcos to be our diagnosis. Um It was PCOS is a clinical diagnosis. So we really relied on providers who were experts with that to be able to make that diagnosis to make the diagnosis. Um And so and there really is one I. C. D. Nine I. C. G. 10 code for Pcos compared to many other diseases where you can choose between you. It's really just one code. Um There are three different definitions for pcos. There's the Rotterdam. Um Which allows women to have just two of three following characteristics which is clinical and or biochemical hyperandrogenism, ovarian regulatory dysfunction and then polycystic ovaries on imaging where the um pcos society requires the hyperandrogenism and then the patient can have either one or two of the dilatory dysfunction or the polycystic ovaries on ultrasound. Where as the last definition, the National Institute of Child Health and Human Development requires both hyperandrogenism and auditory disfunction and does not consider ovarian morphology. And since there were three different definitions um So it being debated the clear definition. We really relied on experts namely endocrinologists, adolescent medicine um adolescent medicine experts and pediatricians to make the diagnosis. Um In terms of diagnosis for baffled we based it on um the definition through nasty again. So it was we called suspected baffled for patients who had a. L. T. Greater than 40 for just two times upper limit of normal at least twice. Or they had a. L. T. Greater than 80 once. Or they were found to have hepatic status imaging with negative work up. They were called confirmed snaffled if they had a biopsy performed or hip attacks ketosis was found on cross sectional imaging which has higher specificity and sensitivity compared to ultrasound. Um Such as um including M. R. I. Or C. T. Again with negative hepatitis chronic hepatitis work up. Type two diabetes was defined as a global U. N. C. Greater than equal to 6.5 hypercholesterolemia was defined as a total cholesterol greater than 200 LDL greater than 1 30 or less than 35 hypertrophic gardenia defined as a level greater than 1 30 greater than go to 1 30 hypertension. And we relied again on a diagnosis in the chart. So getting to our results. So um this is a chart comparing characteristics of our uh pcos population coverage or non PCS population. And um overall so you can see that there are no differences in age, PM I. Percentile or B. M. I. Z. Score no significant differences. There was a significant difference in race in that the patients without Pcos there was a higher percentage of patients who are black compared to patients with Pcos. There also um was a lower percentage of other uh patients identified as other in the non pcos group compared to the PCS group. Importantly when looking at the other group, around 3/4 of them identified as Latina. However when comparing those that identified as Latina there was not a significant difference. Um There were no significant differences in the level of A. L. T hemoglobin, A one C. Or glucose. When looking at lipid panel there was a significantly higher triglyceride level median triglyceride level in the P. C. O. S. Population. And um also in the Pcs population there was significantly higher percent of the population that had insulin resistance hypercholesterolemia and hyper triglyceride. So we found that patients with Pcos the prevalence of baffled was around twenties or 19.1% compared to 16.8% amongst the patients without Pcos and there was no significant difference. So you know, we really the population, the prevalence of baffled was very similar um in the pcs population compared to the non pcos population. And that went for those with suspected baffled those with confirmed snaffled and also those with an elevated A. L. T. That you know um maybe become snaffled. There was really no significant differences. We adjusted our models for asian BMR percentile and then that which did not affect the problems risk ratio. Um So again really no significant differences. We were curious because we were curious because as before, you know, we we saw that meta analysis done in adult women, there definitely is an increased prevalence of baffled and patients with Pcos. So we decided to further investigate, you know where maybe which patients might be the ones that have the higher risk. Uh We found that when stratify ng patients by um type two diabetes status. Those with among patients with type two diabetes mellitus. Those with Pcos were 2.5 times more likely to have nah fold. Um And there was no difference, significant difference in in patients without type two diabetes. So a this is definitely a risk factor for patients with Pcos to develop snaffled. We did not see the same difference in prevalence when stratify ng by academia hyper Trackless ride e mia insulin resistance or hypertension. We then um stratified by ethnicity and race since they do have such a strong component in the risk for baffled. And when stratified by Latina. Um And non latino. We did see a big difference in prevalence risk ratio. So the top line you can see that amongst Latina patients um There's really no difference in um snaffled prevalence if the patient had Pcos or did not have Pcos. Although they did have very high prevalence of scaffold around a quarter of patients in both groups had baffled. Um but when looking at the patients who did not identify as Latina, there was a 2.4 um prevalence risk ratio. And so 2.4 times more likely to have a baffled if pcos was present compared to patients who did not have pcos. So um again that would be important when um you know could be very clinically relevant when looking at your patients with Pcos. Um And then when you know looking amongst just patients who identified as white, the patients who had Pcos had four times uh prevalence of baffled if they had Pcos compared to those without pcos. And then looking at the patient that identified as asian. Um Only patients with Pcos were found to have fatty liver disease compared to patients without pcos. And so this was a significant difference in prevalence. We then look to see you know what other comorbidities um These patient groups had um And the to guide you through this graph. So the orange. Our patients without either Pcos or fatty liver disease. The darker orange are patients with Pcos without fatty liver disease. The dark tan, our patients with um out PCOS but with fatty liver disease only fatty liver disease. And then the the bars in Tan are patients with both PCOS and fatty liver disease. And you can see um that we compared the patients with Pcos without snaffled to patients with PCOS and baffled and there were significant differences and comorbidities. Um Almost every co morbidity um Namely Type two diabetes to slip academia hypothetical academia and insulin resistance. And so you know, patients that go on to develop fatty liver disease are also developing these other comorbidities. And therefore our patients that have higher morbidity overall, there were not significant difference differences in the patient's um the one that had natural. So the ones in tan patients with snaffled comparing with Pcos without Pcos. In conclusion, we found that Pcos did not increase the risk for fatty liver disease in overweight and obese adolescents overall. Um even after limiting. Confounding by restriction. Mashing and model adjustment. Um But in long Latina patients mainly those that identify as white and asian Pcos may increase the risk for fatty liver disease but was not statistically significant. We did find that in patients with type two diabetes snaffled was two times 2.5 times more prevalent than those with pcos. And we also found that patients with both pcos and baffled were more likely to have anemia anemia. Type two diabetes and insulin resistance therefore overall higher mobility than those with pcos without baffled. So in patients with PCOS it's important to continually screen for snaffled especially if they have risk factors of type two diabetes to slip anemia or hypertrophic gardenia. And perform further evaluations of elevated LTs. Multiple limitations to our study. It was a single center. So the study was only done at many of Children's hospitals which are also a tertiary care center. And so you know to rely on referral basis um as a single tertiary care center in California we had a predominantly latino population Um was around 50% of the patients that we studied versus the you know general US population in which is around 26% of youth. It is although you know we are the Latinos are the fastest wearing group among youth. So it may be that our study um you know it's becoming more reflective what the US publishing may become. Um We used I. C. D. Codes again for the reasons I had discussed earlier but those can have limitations since it did exclude a lot of patients that maybe did not receive those I. C. D. Codes especially those that did not receive an I. C. D. Code for overweight or obesity. Um We performed a cross sectional study versus a cohort study. The reason we decided to do that was because um to have a confirmatory diagnosis of an apples do need to perform a liver biopsy which is the gold standard. However it's controversial um whether these kids need a liver biopsy or not, since we are able to often make the diagnosis as a diagnosis of exclusion. And so there was never really able to make a time point that patients were diagnosed with the disease at this time. Um And lastly um we this study was a chart review and so there were many patients, especially those without Pcos that never had screening performed for nah fold. And so we were. That may have led to some selection bias and um also you know patients that were prescribed um oh cps or Metformin for their P. C. O. S. It was very hard to determine compliance at the time of the laboratory tests. Um and therefore that may have affected the results. To review the different types of observational study designs. Um We discussed that we performed a cross sectional study looking at one time point versus a prospective cohort study were starting um at a point and continuing to follow them over a certain amount of time. Um We also thought of about performing a retrospective cohort study looked at patients. Now I look back at their exposures. Um but again very hard to do a cohort study um in this population. Um And then um we did not do a case control study where you would actually look at the outcome. So whether you know looking comparing patients to snaffled for those without baffled and looking at P. C. O. S. Status. So I'm looking at the outcome and then the exposure um rates. So we uh you know just wanted to note that we did the cross sectional study. Um The different treatment options for baffled. So many studies have been done. Looking at the treatment options for fatty liver disease. There are nearly two categories that we can go into. So the first category is lifestyle modification um Two large R. C. T. S. Or randomized controlled trials were done and found that reduction of sugar sweetened beverages. Those with fructose decreased um capacity in Children. So that is a strong recommendation that we discuss with patients. Another RCT was performed. That looked at aerobic exercise resistance exercise compared um compared to aerobic exercise resistance exercise and no exercise. And found that either type of exercise is more likely to reduce hepatic that than no exercise. And um you know important that um exercise either type of exercise can improve insulin sensitivity irrespective of weight loss. Also many cohort studies have been done um that have found a reduction in A. L. T. And psychosis after a lifestyle modification program. Um So that can be like programs at Y. M. C. A. Or participating participants or you know in a group where they discuss diet changes actually changes and are part of a group that can help motivate them to really improve their lifestyle And then when comparing different types of diets. This was done um Most the low calorie versus low fat diet were done in adults. And it found that both diets were effective. So no specific diet but any diet didn't help improve A. L. T. And hypoxia acidosis. But when looking in mice um when just doing a low fructose diet that was found to be in effective. Although that type of diet is very hard to emulate in humans. Um So it has not yet been performed but just a loafer just i it can be effective then you know the questions always like is there a medication that we can give or help these patients along a very um breakthroughs trial the tonic trial was done um you know about 10 years ago now and a within the past 10 years and it was a three arm study that was placebo controlled and all patients got lifestyle counseling. Then a group um Some got metformin and some got vitamin E. And when looking at the patient's after six months they found that there was no difference in A. L. T. Reduction. The patients on vitamin E. Had some histological improvement are vitamin E. Is not recommended because we're unsure of the long term effects and worried about the possible robotic effects that vitamin E. Can have. And so vitamin E alone is not recommended for the patient population um at this time for patients with an apple at this time. Um Other um other medications supplements that have been looked at include fish oil um and also dial and they have found them to not be helped more than placebo. Probiotics are still being uh studying however um thus far and I think conclusive and then a bariatric surgery is often discussed and there's very limited data in adolescents. Um We have seen known a lot of adult studies that any weight loss can improve nah fold. And so the likelihood is that bariatric surgery would help these teenagers. However given all the risks of bariatric surgery. Um and the limited data is not yet recommended. Um But you know that's I think I can always be discussed on a patient by patient basis. It is important to note that A. L. T. Is considered the only usable noninvasive marker of histological improvement. So that's why A. L. T. Is often the lab that is followed in these studies and not always biopsies are performed. It's back to our case at the beginning um excitingly the patient, she joined the valuable team and started uh bike riding with her dad. She removed sugar sweetened beverages from her diet. And she also increased her vegetable intake. And when we repeated labs she had brought her A. L. T. Down to 22 which is very exciting and she brought down all of her cholesterol levels. And total cholesterol level is now less than 200 tribal start level less than 1 30 A normal HDL level um and an LDL level less than 1.30. So she did a great job and you know, all improved with lifestyle modification. I want to acknowledge. Um My P. I. Monica Suncor who I actually quoted her study earlier um and she is a wonderful mentor who is doing great work in looking at women's health in liver transplant um and is doing a lot of continuing to do work in the area of looking at the Association of PCOS and baffled. Um Emily Pareto, who is a wonderful pediatric hematologist um and really helped with um with the research aspect of the study, Patrick Asai, who focuses on pediatric obesity and watch clinic um and Mission Bay. Um My wonderful scholarly oversight committee, Maya Lodish, who is a pediatric endocrinologist, Marissa Raymond flesh, who is an adult medicine doctor and James Baron who is a pediatric Gi. And research and also the program director of the fellowship. And then I want to thank Suri for helping me get the study cohort together and it's a great pediatric rheumatologists really want to thank and recommend the department of epidemiology and biostatistics. Um I took a few classes through the sugar program, which I'm always happy to discuss with folks and all the professors and teaching assistants were available even after I was done with the class to help answer my questions as I gathered um and analyzed the data. Um The the the study was funded by NIH Teaching Grant um which supported me in doing my reserve contract. I left time for questions. Thank you so much. That was amazing. We do have a handful of questions. So um I think I'll start with this one regarding a different medicines because you were recently talking about that towards the end. Um Have you seen any of the newer weight loss medications used in teenagers for example, than the glue tied tied um Naltrexone buPROPion, things like this orlistat. Do you recommend them for patients who are unsuccessful um with lifestyle changes or and or do they help with not fold? Great question. Um Some of the little glue tied and some glue tied some of the diabetes medications um recently have been seen in adults to be helping patients with baffled. We don't recommend them at this time, but they have been seen in adults to be helping orlistat or the other weight loss medications. I think it I think it really depends on the patient's motivation. Um Again, you know, it's it hasn't yet been seen in Children specifically that weight loss um improves fatty liver, but it's more than likely it does since many studies in adults have shown this and if patients need the help with orlistat, then you know, I would say that's a per patient basis. It was not recommended by Nasa began specifically that any of these weight loss medications be used. Um But um you know, I think it could help a lot of these patients if they need that support, but we found that even patients who don't lose that much weight as long as they improve their sugar sweetened beverage and take that has huge strides and start any exercise that has huge strides. So some of the patients we follow are still with the B. M. I. Greater than 99th percentile, but they're A. L. T. Improves from, you know, the one above 100 to less than 30 just by changing not by losing weight but by changing their lifestyle. So, you know, I would say that weight loss is not the mainstay um for knowing that these patients are improving, but really just motivating them to make those lifestyle changes. I had a follow up question to that point um Is there a certain LP, like cut off or range at which you have seen, It's it becomes much more difficult to just do lifestyle changes alone. Is there like a number in your mind? No, I think it's I think it's gonna be patient, you know, it's really their motivation, you know, the other day, it just sort of had a really great family conversation because, you know, I'm sure many have seen our parents get a lot more nervous about it than the kids and they're still teenagers and feel like everything will be fine. Um And again, you don't feel natural right? Like a lot of times there's no symptoms associated, so they don't necessarily feel the motivation to change, but it's just getting everybody on a positive level, like it shouldn't be a fight or an argument in the family to get things to improve. Um And so when we see the numbers, we try to really just, you know, a special patients at our families, especially parents like, you know, 100 versus 200 is not concerning. I mean 506 100 it's very concerning because that sort of level of inflammation can lead to more scarring, right? If you're just that that inflamed of a liver more likely to develop. Um you know, the if the rest of them are likely to develop scarring, I don't know, we've ever found a cut off of where you get worried about it, but the higher the numbers for longer the time, the more likely you'll develop fibrosis. So that is something that we talk about with parents. But, you know, an increasing number just worries me that the that they're just developing more disease rather than improving. So, but I do try to really, you know, try to get parents and kids on the same team um and not let the numbers. Um even the wait, wait numbers or a l. T. Numbers affect that relationship and affect their motivation because even if they've changed and improve their lives down, maybe we'll see the numbers improve in some time. You know, maybe just require some time. And so I tried also to make sure that doesn't make patients lose faith. Thank you. This next question. Maybe while I'm asking you can go back to the slides on on the comorbidities, the hypercholesterolemia and Disl epidemiology to slides. Um The question is regarding where their specific cutoffs used for things like hypercholesterolemia and Disl epidemiology to I guess where did those cutoffs come from? If there was a source and we could just kind of take a look at that slide one more time. Yes here is the slide. I actually spent quite a bit of time trying to find different definitions. The C. D. C. Has a definition and also pediatric endocrine society. Um Just using those definitions at first and there was like 90 50 Percentile. Um but then to sort of because and then I was looking at what other studies had done and just to try to make them more similar to other studies I used the sort of standard instead of the 95th%ile because that can be affected by age. Um I standardize it to the these numbers which are the general definition when looking at justice Libya Denia and adolescence. Um Again I found it very hard to find a definition that work just for that patient population that was used in the literature. Um and sort of defined by the pediatric endocrine society. And I confirmed that with um dr lotus who was on my um scholarly oversight committee. So just consulted with endocrinologist. And the next question is regarding the P. N. P. L. A. Three um genetic predisposition in Children and obese Children who have not cold. Is it worth screening for this gene or how often is that done? Um I think it's I think it more so tells us that it explains why you know, amongst the patient populations that are more readily likely to drink high fructose beverages, Why we're seeing a difference based on race and ethnicity. Um And it just explains that difference um rather than but needing to be but I don't think it it's important to screen the patients because you're going to screen them for novels and I think that would be more relevant then screening the patients um for their genetic predisposition when they're younger. Thank you. Um Next question is so much of this is dependent on the diagnosis of overweight slash obesity based on B. M. I. Was B. M. I. Adjusted for ethnicity um with different growth charts and what is being done to improve the measurement of B. M. I. Um We um did include you know when doing the model adjustment had included ethnicity and then taken it out and found that really um it didn't impact and we felt like it actually was something we wanted to study and not control for. Um So we did not um we did not adjust for it so that we could study the different ethnicities or races. If we included it in the model, then we would have taken out being able to stratify for that. Um So we did not adjust for B. M. I. Based on ethnicity and in terms of the work being done um to look at that, I don't actually know there's many what is being done to look at B. M. I. Um in different ethnicities. I wonder um you know, how much it may change, like a couple of percentage points here and there and how much that would really affect. Um Our care for those patients. Next question is, you know, um this is such a serious disease. So there was a question about why why there's so little in terms of programs that support weight loss management. Um And and could you comment on that? Yes, I can comment on that sadly. So there were so many programs, I'm not sure if you remember like Michelle Obama that this was her big push. Um and her big project while she was first lady. And there were many grants and lots of programs, I would say like nationwide. I did a project in Illinois um through with the academy with a ap american pediatrics, looking at all the way to manage programs in Illinois. And I was doing that program and found that a lot of programs existed. They were funded and then lost funding and closed. And so it's really an issue of just funding and grants and so, you know, these, a lot of these places are sort of running on whatever funds and means that they have and um weight management programs are just they're no longer supported the way they were in um between 2008 and 2016. And so um the funds have run out and also it's been found that weight management programs are wonderful and they help through Y. M. C. But they're not, you know, we're not able to follow them long term. So there's a strong recommendation that they be done like as part of schools or something that can be more sustainable because they, you know, a lot of times the weight management programs are studied at the beginning of the program at the end of the program and maybe 23 months later if if, you know, if they even have that much means of research to do a 12 week follow up, which not all of them do and they continue to be helpful, but we don't we don't have any studies like six months or one year follow ups. Um I do know that there are some charter school programs that are looking into this. I worked at one of Harlem Children's Zone where they're tracking uh data and programming um as part of schools. And um you know, I'm not sure if that work is being published or when it will be published, but they are following them over time I think so. So I think school programming is the best way to go. But again, um finding the funds and the means I think has been the real big anger. Thank you. Um There was a question about vitamin D. Was was vitamin D. Looked at and any role in vitamin D. In this disease. So we did not look at vitamin D. Because it um you know, not every patient had that level checked and I was just finding that many didn't and then I didn't want to just exclude so many patients. Um It is it is part of the it is known that helping improving vitamin D. And all patients obese patients can be helpful. Um Whether it directly affects um fatty liver disease has not been found. But I think it's you know, looking for vitamin D. Deficiency in these patients um is very um important because a lot of times patients with obesity have vitamin D. Deficiency um I'm not I I'm not sure if I recommend like it to help heal or help their liver. Um But I do just recommend vitamin D. As a as a great vitamin to help the body overall on any of these patients. Um And so but the direct relationship has not yet been found. I mean we do see vitamin D. Deficiency in patients with colon static liver disease, but these patients are ones with hepatitis. Um And so not necessarily but um and it has been studied um And it's shown that vitamin D. Maybe helps but it's unclear if it's helping just because their overall improving their lifestyle. Um And it's confounded by that rather than just offering vitamin D. Thank you. There are also a couple of questions just to review the timeline of things. How often you follow the L. T. How soon after the lifestyle changes do you give them? I believe three months was mentioned. But can you talk about the intervals thereafter? Yeah I can go back to that. So um just get back to that slide. So um you know in patients that you get there first lt um you usually by the age of 9 to 11. If it's normal then repeated every 2 to 3 years. Again very okay to get an L. T. Sooner if you're very concerned with the obesity in the child. Um But if it's abnormal. So above any of the cut offs that are listed at the top that important to repeat with like in three months and if it continues to be greater than two times the upper limit of normal then you know refer to G. I. If you find that it's either improving or pretty extremely low. Is it just continue to recommend? And there's no um that in between maybe that in between normal and two times upper limit of normal. I would say it's up to your discretion. It's not like a very concerning number um that you would need to be referred to G. I right away. Um But you know, you may want to repeat it within a year or two if you are concerned about it and I almost repeat them annually. Um in the patients that I'm following um I'm gonna beat them every six months and the patient that I'm following and then if they get to be you know less than 30 started to be very close to 22 or 26. Then I start saying you know, maybe check it again in a year and again if it's normal and check it in 2-3 years. Awesome. Great. Well thank you so much. We came right up to nine o'clock so we'll make that the last one. I really appreciate your presentation today. Really educational and we thank you so much. Absolutely. I wanted to, if people have a quick second I want to stay, I did answer all the questions at the end so I'll just leave them up and people can leave as they go um Quickly. This answer was false. It's only in women. Um The next one is, And upper limit of normal, we found this 22 ultrasound is not for screening, it's just for I'm looking for disease but it's not a screening test for an apples. There is a genetic component and randomized control trials. Great. Okay, thank you for having me Sanchez, tune in next week. Everyone. Thank you.