Good morning, everybody, and welcome to the ASLD webinar, our webinar today about Natural History of Naphaldean Nashian Children, Knowledge Gaps, and Interventions. I am Samar Ibrahim. I'm the Medical Director of the Pediatric Liver Transplant Program at Mayo Clinic. I'm one of the moderators. My co-moderator is Dr. Rohit Kohli, Chief of the Division of Pediatric Gastroenterology and Nutrition at LA Children's Hospital and a professor of pediatrics. Our first speaker today is Dr. Jeffrey Trumer, who is a professor of pediatrics at UC San Diego and the Director of the Fatty Liver Clinic, Rady Children's Hospital, San Diego. And his talk is titled, Natural History and State of the Art in Monitoring Progress of Naphaldean Children. Good morning. Thank you, Dr. Ibrahim and Dr. Kohli, for this opportunity to give this presentation. I was asked to talk about, in many ways, the future, the natural history and monitoring progression. My disclosures are grants to the university and a consultancy. None of those are relevant to today's presentation. So the natural history of disease refers to the progression of a disease process in an individual over time in the absence of treatment. And so the CDC has this diagram here, which is classic for, say, an infectious disease, stage of susceptibility and exposure, a stage of subclinical disease where there are pathological changes, onset of symptoms, the, quote, usual time of diagnosis, the stages of clinical disease, and then recovery, disability, or death. For Naphalde, where in this loop people get identified has to do a lot with whether they have screening or not. And so where in this state we're talking about the natural history may really be variable. With respect to longitudinal data on changes in histology, there are really very few studies. So to start with, in Indiana, they had a case report of a child with two years of follow-up who had NASHIT diagnosis and went on in two years to progress to cirrhosis with portal hypertension, ascites, and esophageal varices. Several years later, there was a case series of 18 patients in Arizona with a mean follow-up of 2.3 years that had a follow-up biopsy. And in those individuals, 17% got better, 44% stayed the same, and 39% got worse. In Minnesota, there were five patients that had repeat liver biopsy after a mean follow-up of 6.4 years, with one that stayed the same and four, 80% of them, that got worse. Now moving from those case series, there are the placebo arms of double-blind randomized controlled trials. Of course, being in the placebo arm of a clinical trial is not the same thing as the absence of treatment. The two largest pediatric studies have been done by the NASH CRN. The first was TONIC, and there were 47 children in the placebo arm that had a liver biopsy after two years per protocol. And then CINCH, and there were 75 children in the placebo arm that had a liver biopsy after one year of follow-up by protocol. And Dr. Zanthakos just recently combined these children into one in this very large publication. And one thing that was noted was that resolution of disease in that one or two-year time period was very uncommon, only 2.4%. With respect to change in NASH or fibrosis, seeing improvement was common. About half had improvement. And worsening was also common, a little over a third, 44 or 36%, had worsening of NASH or fibrosis. With respect to morbidity, very limited longitudinal data on morbidities. I'll show one representative study that we've just published where we followed 160 adolescents with NAFLD over a mean of four years and looked at depression in blue and anxiety in red and saw that both of these conditions increased over time, and depression in particular did so more than would be anticipated despite being an adolescent age group. And notably, when one's ALT elevated over time, that was significantly associated with a greater odds of developing depression. Longitudinal data with respect to mortality is very limited again, but we go back to the study in Minnesota with six-point years of follow-up for 66 patients with NAFLD, and 6% of them died over this time period. Moving from there to Georgia with 44 children with NAFLD who had a mean of four and a half years of follow-up, and over that time frame, 7% of them died. So very similar numbers of deaths, although relatively small sample sizes. Moving from natural history to monitoring NAFLD, the main tools are liver chemistry and imaging. So monitoring disease looking at liver chemistry, Kim Newton has just published in Hepatology a paper where we developed models for three different histologic outcomes looking at improvement. The first of those is NAFLD activity score, because that was the primary outcome in the CINCH trial, and here we see that GGT was the best marker, but knowing only baseline GGT tells you almost nothing. Knowing just GGT at the end of treatment tells you a little bit more, but when you combine those two, knowing both baseline and the follow-up value, you get an area under the curve that's now 0.79, and then adding in other clinical variables increased that significantly, approaching the range of clinical utility. So moving from NAFLD activity score to pediatric or zone 1 NASH, there ALT functioned best, and you can see knowing baseline ALT to the week 52 ALT to the combination of just those two values to those with just a couple other markers increases to an AUC of 0.91. And then finally for fibrosis, ALT was also the best marker, and once again moving from baseline to week 52 to the combination with other clinical variables. And so the area under the curves you saw there were in the development groups using the data of all participants in CINCH, and then in each one we also used tonic as an independent validation set. And here you see, again, for NAFLD activity score, this is approaching clinical utility. For improvement in pediatric NASH, this actually was excellent, was 0.91, and the validation set was 0.92. And for fibrosis, again, approaching clinical utility, 0.89, not quite as good on the validation set, 0.82. But when you look at these, you'll see they're better than you get in most of the imaging studies. So looking at imaging to monitor disease, first we have to think about what tools we're going to use. Ultrasound, it turns out, is not worth considering as a monitoring tool because, frankly, it's not even good enough to be a diagnostic tool. The one study that evaluated this by taking a population at risk for NAFLD, a group of adolescents with obesity attending a tertiary care clinic, did ultrasounds on all, and the ones that had positive tests had liver biopsies. And here we see that only 40% of those with positive biopsies actually had NAFLD, the red meaning not NAFLD and the green meaning NAFLD. And you see none of the grade 1s, about half of the grade 2s, and it was only when you got to grade 3 that they actually had NAFLD at a high rate. Moving from ultrasound to CAP based on trans-analystography, this really doesn't diagnose NAFLD at all. The accuracy rate is about 70%, and here you see CAP compared to MR spectroscopy, proton density fat fraction. And you can also see why it struggles to be an adequate diagnostic tool, because here at the cutoffs, both of PDFF and of CAP, you see there's a lot of noise sliding slightly higher or lower as to how many people are going to be in the misclassification category. You also, when you look at this first band of those individuals with enough steatosis to be consistent with NAFLD, this 5 to 10 range, you also see that almost the full range of CAP scores are present in this band as well. So moving on to MRI to both look at liver fat and liver fibrosis, we'll look at both MRI, PDFF, or proton density fat fraction, which is not the same thing as hepatic fat fraction that you will see in many papers and is still done in some studies. Fibrosis is a technique that actually takes into account a lot of the confounders that conventional MRI does not, and this is a semi-automated analysis for steatosis. MRE or MR elastography is a measure of stiffness, which is not a direct measure of fibrosis, but they are related. Currently the versions that are in use are two-dimensional, although there are three-dimensional methods that are being used in some research studies, and importantly, this is still a manual analysis. The MRI Rosetta Stone study looked at 174 children who all had liver biopsies with equal numbers of people in each steatosis grade, and you see, although there is long tails, a fairly good difference between steatosis grade by liver MRI PDFF value. Here's really the best way to think about it. This heat map, there's a probability from the dark green zero and this dark orange 95%, and you can see at each transition from no steatosis to grade 1 to grade 2 to grade 3, there is some noise, not unexpectedly, but certainly at the margins it's quite robust. More recently, we published the steatosis study, and we looked to see how stable a measure this is over a 12-week timeframe without intervention, and so each individual, you see their PDF value at baseline and at 12 weeks, and here when they're plotted the difference, it is most individuals were anywhere from a couple points higher to about 4.5 points lower, again, over a 12-week period without intervention, so this begins to give you a sense of how much of a change would be needed to be meaningful. We also looked at MRI PDFF in the SINCH trial in a subset of individuals who had MRIs and looked at whether the histology for steatosis was better, the same, or worse, and this is the change in MRI PDFF that was associated with those values, so better, the mean difference was minus 7.8, that had an AUC of 0.76, and a diagnostic accuracy of 63%. For those that got worse, it was an increased mean of 4.9 percentage points with an AUC of 0.83 and an accuracy of 83% in determining the histologic change. According to MRE, in the MAGNET study, here you see the elastograms, this is one for each fibrosis category and representative numbers, and when I said it's manual, it's just that, an individual actually has to go in and draw the liver and decide where is the liver and then decide which of these color map areas are valid measurements. So here we had different reading centers as well as an experimental automated reading, and those are the three different reads you see here. This is looking at no fibrosis versus any fibrosis, and you see the areas under the curves are good, not quite high enough for the classical clinical separation, but approaching that, and the separation between advanced fibrosis and none to moderate fibrosis, here you see AUCs that are much better and are in the range of clinical utility. Looking at the stability of MRE measurements, so again in the steatosis study, here we saw there was a greater change over that 12 weeks without intervention, person to person, and so numerically these numbers are smaller, but this is minus 0.5, this is plus 0.5, and again the scale is if this is normal and this is fibrosis, that that change over just those 12 weeks could push somebody into the considered to have fibrosis or not have fibrosis scale. So there is still some refinement needed for MRE to be a useful change measure, at least in the short run. Summarizing, for natural history there is documentation of morbidity and mortality. With heterogeneity, some children getting better, some getting worse, clearly natural history is very much a work in progress. I expect that over the next five years we will be seeing a lot more long-term outcome data needed to understand this. As far as disease monitoring, the things that we know well, ALT and GDT actually turn out to be very useful tools, and imaging, ultrasound is not valid. MRI, PDFF for steatosis really is the best validated imaging tool, and MRE for fibrosis I would put into the emerging category with great promise. Thank you. Thank you, Dr. Schwimmer. That was an amazingly succinct but packed full presentation, and we look forward to the emerging technologies, as you just mentioned. It's my pleasure to now introduce Dr. Shikha S. Sundaram, the Medical Director of Liver Transplantation at the University of Colorado School of Medicine Children's Hospital Colorado, where she's also an associate professor of pediatrics. She will be speaking to us today on interventions. Now that we know what the natural history and monitoring tools are going to be or are available to us today, she will tell us now about the interventions to stop the progression of NAFLD and NASH in children. Welcome, Dr. Sundaram. Thank you very much, Dr. Ibrahim, Dr. Coley, and the ASLD for this opportunity to speak about interventions to stop the progression of NAFLD and NASH in children. I have no relevant disclosures, and as we walk through these next 20 minutes or so, I'd like to discuss interventions to stop progression of NAFLD and NASH, including lifestyle interventions, bariatric surgery, dietary supplements, and of course, pharmacotherapy. So before we dive into interventions, I think it's important to think a little bit about the challenges that we face as we talk about interventions. Our goals are certainly to improve outcomes in these patients, to resolve NASH if we can, and to improve fibrosis. These goals, however, are complicated by the fact that we currently do not have an ideal biomarker. NASH activity is likely dynamic. The disease is heterogeneous in nature. Histologic interpretation from time to time may vary. The drugs that we may have may in fact only have modest potency, and as Dr. Schwimmer just shared with you, our understanding of the natural history of disease in children is really in its infancy, maybe toddlerhood. Therapeutics should in general be based on the physiologic basis of what we think is happening in NAFLD. So as we think about the normal liver progressing to have steatosis, it is likely important to target drugs or therapies on insulin resistance or lipid metabolism, as well as targets related to lipotoxicity and oxidative stress. As those affected by NAFLD move from steatosis to steatohepatitis, targets related to inflammation and the immune activation may be important, and targets related to both cell death with apoptosis and necrosis. And as some patients evolve into cirrhosis, targets related to fibrogenesis and collagen turnover will need to be targeted. So let's start with lifestyle interventions. There are some central questions that are often asked about lifestyle modifications, which include how much weight loss really improves this disease. We know that seven to 10% body weight loss in adults may significantly help disease, but this actual fact is unknown in children. We are often asked which diet specifically, what macronutrients should be recommended, and when we talk about exercise, what should be suggested, including the type, volume, and intensity. So let's start with diet alone, looking at a low carbohydrate diet versus a low fat diet. So Goss and colleagues looked at 32 obese children and they put them through eight weeks of a low carbohydrate diet, less than 25% of their total caloric intake versus a fat restricted diet, less than 20% of their total caloric intake. And they looked at hepatic lipid change. On the left-hand side here, you can see a carbohydrate restricted diet resulted in a significant decrease in hepatic lipid content and a decrease of about 24 points in ALT. However, after eight weeks on a fat restricted diet, there was essentially no change in hepatic lipid content and ALT only decreased six points. Ramon Corral and colleagues did a smaller study, but for six months, where they looked at the effect of a low glycemic diet versus a low fat diet. Bottom line, things looked about the same. You can see from the table here that whether patients were on a low glycemic or a low fat diet, they had a decrease in their BMI of 1.2 or 1.3. Their MRI PDFF, which we just heard a lot about from Dr. Schwimmer, decreased eight and a half to 10 and a half points. And their ALT also decreased 28 points in the low glycemic index diet and 11 points in the low fat diet, suggesting that either of these may be useful. Dr. Schwimmer and his colleagues did a very interesting study looking at a low added sugar diet. This low added sugar diet study was on 20 patients, all Hispanic males ages 11 to 16 who had histologically proven NAFLD and ALTs over 45. The low added sugar diet was based on study meals for the entire household that provided restricted free sugar to less than 3% of daily calories for eight weeks, along with two times per week phone calls. The primary outcome of this study was change in MRI proton density fat fraction or PDFF. And what you can see here on the left, low sugar diet versus usual diet. And in those on the low sugar diet, their MRI PDFF average changed from 25 to 17% versus essentially no change in average MRI PDFF in the usual diet. Similarly, when they looked at ALT on the right-hand side of the slide, on the low sugar diet, the average ALT dropped from 103 to 61 compared to essentially no change in the usual diet from 82 to 75. This study nicely suggests that restricting sugar can have a significant impact on disease. However, this may be difficult to do practically in most patients that we take care of. There has been great interest in the Mediterranean diet, and I will point out that there is no data in kits. However, if you're not familiar with the Mediterranean diet, it has significant fiber, PUFAs, and antioxidants with high daily servings of fresh fruits and vegetables along with olive oils and unrefined grains or cereals. Protein sources include weekly nuts, legumes, and fish. And if you're an adult, red wine. I'm highlighting four studies, again in adults, that look at the Mediterranean diet. Fraser looked at 250 patients that were randomized to either a diabetes diet, a low-glycemic diet, or the Mediterranean diet, and noted significant decreases in ALT on the Mediterranean diet independent of weight loss. Bizelto did a much smaller study and noted 25% decrease in hepatic fat by MR after eight weeks. And Nisgani noticed in controls versus on the Mediterranean diet over three to six months that again, there was a decrease in hepatic fat. And finally, Gelli in 46 patients noticed that there was a decrease in both hepatic fat, almost half the amount on the Mediterranean diet with concurrent decreases in AST and ALT. So this certainly in adults seems to be a good option, but I think that getting most children to eat the typical Mediterranean diet will be a bit of a clinical challenge. Exercise alone is a critical part of lifestyle changes and lifestyle medicine. What if we try to prescribe exercise alone? Well, DiPiano looked at 58 children with NAFLD based on abnormal ALT and hepatic steatosis on ultrasound, not on biopsy. Everybody got nutritional counseling by a dietician weekly and half the patients under the guidance of an exercise physiologist did aerobic training 60 minutes, three times a week for a year. And the other half did aerobic training 30 minutes, three times a week plus resistance training for 30 minutes, three times a week again for a year. And in these patients, it was noted that those who had a combination of aerobic plus anaerobic exercise had larger changes in ALT and more resolution of hepatic steatosis than aerobic training alone. There are many scattered studies that look at the combination of diet and exercise on pediatric fatty liver disease. And while we don't have time to go through each of these, this meta-analysis published in 2018 sums up 19 manuscripts in just over 900 individuals ages six to 18, half male and half female. In these studies, the diets that were prescribed were normal caloric between 13 and 1900 kcals with 50 to 60% carbohydrates, 10 to 30% fat and 12 to 20% protein. Exercise ranged from once a week to daily workouts but most patients received three to five times per week of exercise. And again, the duration of these studies was short with a month up to a full year. And I'll walk you through a few data points to show you that diet plus exercise on this particular chart favors decreases in BMI, decreases in ALT again with a similar chart and decreases in hepatic steatosis together suggesting that diet plus exercise can in fact improve this disease process. What about the intensity of lifestyle management? Does the frequency of visits and thereby accountability to a medical team impact outcome? Lam looked at a cohort of patients who either received yearly lifestyle visits or visits every three months and noted that those getting yearly lifestyle management visits had no changes in BMI Z-score or ALT whereas the population who were seen every three months had a BMI Z-score albeit mild 0.6 and an ALT difference that also decreased. What about the impact of the multidisciplinary team and can this optimize results? DeVore and colleagues at Cincinnati looked at a cohort of 39 pediatric patients with NAFLD who were followed every three months and noted that when they were seen by a gastroenterologist, nurse and dietician who all set goals, provided education and monitored progress that they could certainly decrease BMI Z-score and improve fatty liver disease. I'd like to switch gears a little bit to something that may seem a little bit more dramatic and talk about bariatric surgery. There are clear criteria by which to consider bariatric surgery and the adolescent population which include a BMI of 35 to 39 or 125th percent of the 95th percentile and comorbidities that include type 2 diabetes, sleep apnea, NASH, pseudotumor, Blount's disease, SCFIs, severe reflux and hypertension or alternatively a BMI equal to or greater to 40 with no other comorbidities. It's important to note that the guidelines suggest that this must be assessed by a multidisciplinary team who can target the ability and motivation to adhere of an individual patient to both pre and post-operative treatment recommendations. The two most common operations used in adolescents are the sleeve gastrectomy where part of the stomach is excised and removed leaving a sleeve or the Roux-en-Y gastric bypass where a gastric pouch is created, a gastrojejunal anastomosis created and the gastric remnant hooked up to the other part of the jejunum with a standard Roux-en-Y then created. We can learn a little bit about trends in these operations using the PCORI bariatric study. I'll start at the bottom where you can see the adjustable gastric band shown in blue. In the early 2000s, about 40% of the adolescent bariatric surgery was done by adjustable gastric band and you can see over the ensuing 10, 12 years that this has essentially fallen out of favor and is no longer used. Again, in the early 2000s, 45 close to 50% of bariatric surgery in adolescents was the Roux-en-Y gastric bypass and you can again see that over the ensuing 10, 12 years, this too has fallen out of favor and is now about 15% of the bariatric surgery that is done. And in contrast, the vertical sleeve gastrectomy which was only 10 to 12% in the early 2000s has become the bariatric surgery of choice and you can see now accounts for about 80% of bariatric surgery that is done. This data from the teen labs or longitudinal assessment of bariatric surgery data shows that patients who receive bariatric surgery, whether bypass or a sleeve gastrectomy in the first six months after surgery lose a significant amount of weight, 25 to 30% change from baseline. And while there is a little bit of rebound over the next two, two and a half years, for the most part, this weight loss is maintained. So what does this do to pediatric fatty liver disease? Well, the reality is, is that we know very little but this is a small but really excellent study that was published in 2017 by Manko and colleagues. They looked at 20 patients who had a sleeve gastrectomy, 20 who got the gastric balloon and got some lifestyle medicine counseling and 53 who only got lifestyle medicine counseling. What I wanna do is draw your attention to the end of the slide where we're going to look at both fibrosis and an NAS score greater than five, which is often called definitive NASH. What they noted between time zero and time one in a nutshell is that there is significant improvements in NASH over one year. You can see here fibrosis with a fibrosis score greater than two was present in about 70% of patients who eventually underwent sleeve gastrectomy, which was the majority of patients, some with gastric balloon and some with lifestyle medicine. And then a year later at time point one, the vast majority who had undergone sleeve gastrectomy had fibrosis scores that had significantly improved. And similarly, when you look at an NAS score greater than or equal to five, about a third of the patients with sleeve gastric balloon or lifestyle had high NAS scores and a year later at T1 follow-up, you can see that all the patients who underwent gastric balloon and sleeve gastrectomy had significant improvements in resolution so that NAS scores dropped below five. What about dietary supplements? And I'm going to use the word dietary supplement to suggest something that you could pick up at your local health food store. First, let's talk about vitamin E, which is an antioxidant and we'll use the tonic trial, which again was mentioned by Dr. Schwimmer to help you understand this. If you're not familiar with the tonic trial, it was a randomized control trial of 173 patients, all adolescents with biopsy-proven NAFLD. They received either 800 units of vitamin E, 1,000 of metformin or placebo for 96 weeks. The primary outcome in this study was a sustained decrease in ALT. And if you look at the left-hand side of this slide, vitamin E is shown in triangles. And while initially it looks like there is a decrease, it is the standard error bars that suggest that the primary outcome was not met and there was not a sustained decrease in ALT nor AST. However, secondary outcome, the study really did look at histologic resolution. And of those on vitamin E, 58% had histologic resolution versus only 28% in placebo, which was significant and suggest that vitamin E may be a good option. Omega-3 fatty acids have also been studied a little bit with the rationale being the DHA may improve hepatic fatty acid metabolism by inhibiting lipogenesis and stimulating fatty acid oxidation. Two studies have looked at this. One by Nobile and colleagues, a randomized control trial over 24 months of either 250 or 500 milligrams of DHA versus 1,000. And they were able to show that subjects on DHA had decreased hepatic steatosis and ultrasound, improvements in ALT that persisted over the duration of the study. In contrast, in a shorter study, Jancic and colleagues did a randomized control trial, six months of omega-3 fatty acids, the DHA to EPA ratio of three to two versus placebo. And they didn't see any changes in ALT or hepatic steatosis and ultrasound. We would posit that this may be because of differences in the DHA formulation that was used versus a shorter trial. And certainly more studies may help us work this out in the future. What about probiotics? With the rationale being that gut dysbiosis may have a role in NACL pathophysiology. Two small studies help us look at this. Bajrou and colleagues did an eight weeks study of lactobacillus versus placebo. And you can see on the left-hand side that there was a significant decrease of about 40 points in patients who received lactobacillus as opposed to placebo. Olisi and colleagues did a small study looking at BSL number three versus placebo with their outcome being changes in ultrasound fat. And again, Dr. Schwimmer has mentioned the caveats and how good or not good this may be. On the left-hand side of this chart, you can see that of the patients with placebo, all of them had moderate or severe steatosis by ultrasound. And after four weeks of placebo, there was very little change in this. However, in the patients on BSL number three, who again had moderate or severe steatosis by ultrasound after four weeks on BSL, had shifts in their ultrasound fat to none or mild in the vast majority. I'm now going to shift gears to pharmacotherapy because we would all like to have a magic pill. Currently accepted endpoints for non-sorotic NASH, conditional approval by the FDA are two. One, the resolution of NASH with no worsening of fibrosis or alternatively, the reduction in fibrosis with no worsening of NASH. So I'm going to hit a few studies and a few drugs. I'll start with metformin, which is used because of its importance in insulin resistance. And again, show you results of the tonic trial, which I've already described. Metformin is shown under the ALT chart as the dark squares. And what you can see is that the primary outcome was not reached, which was sustained decrease in ALT with metformin. Similarly, no significant and sustained changes in AST. Unlike vitamin E, however, in subjects who received metformin versus placebo, metformin, 41% resolved NASH versus 28% in placebo, which was not significantly different. Dr. Schwimmer mentioned the CINCH trial using cystamine for NAFLD in children. This was a trial of 169 children with NAFLD activity scores of four or greater performed by the Nash Clinical Research Network. Patients received either cystamine or placebo twice daily with a primary outcome from an intention-to-treat analysis being improvement in liver histology over two weeks. And the bottom line is that the primary outcome with a decrease in the NAS score of greater than or equal to two was not different between those receiving cystamine, 28%, or placebo, 22%. However, children receiving cystamine had significant changes in pre-specified secondary outcomes, including on the top left here, reduced mean ALTs, 53 versus eight in the cystamine versus placebo group, AST on the right, reduction of 31 versus four in the cystamine versus placebo group, and though not shown here, a larger proportion of patients who had reduced lobular inflammation. I'm now going to show you some data that speaks to agents that are in or about to launch into phase three clinical development. And I just want to give credit to my dear friend, Dr. Maru Ranella, who shared this beautiful slide with me. So, obatocolic acid initially seemed to hold great promise. It is an FXR agonist used to target lipotoxicity and oxidative stress. Many of us are familiar with the reverse trial. Of course, all of these trials have to have cute and catchy names, looking at 540 patients with compensated cirrhosis. And unfortunately, the reverse trial did not receive FDA approval to use this drug. We are now in the REGENERATE trial, which is a significantly larger trial of 2,000 patients thought to hopefully be completed as shown here by number two in the fall of October, 2022. Rosmeteron is a THR beta agonist that targets lipotoxicity. The trial for this is called MAESTRO-NASH. It's targeting 2,000 patients with stage two to three fibrosis. It's targeted to be launched here in this summer with final completion to be here in 2024, hopefully in the spring. Aramcol is a SCD1 inhibitor targeting fatty acid synthesis. And this trial, or the ARMR trial, looks at patients with NASH and fibrosis and hopes to be launched in the summer of 2022 and completed in the winter of 2024. Felipectin is a Glectin-3 inhibitor that targets fibrosis. And the study looking at this NASH-RX 500 patients is thought to be completed in quarter four of 2022. And finally, Senecrivirac, which is a CCR2-5 antagonist that targets both inflammation and fibrosis with a trial named AURORA to launch in October of 2021 with completion not to be finalized potentially until 2028. So certainly this shows you a smattering, and that's really all this is, of drugs that are in the pipeline that will be studied in adults. And it is certainly possible that as these are studying in adults, some of these will eventually trickle down and be able to be studied in pediatrics. So in conclusion, do we have interventions to stop pediatric NAFLD and NASH? I would say with caution that we currently do not have effective pharmacotherapy, but I think that we will continue to hear a lot about this. In yellow, we certainly have some dietary supplements on the horizon, most of which need further study, and probably the area in which we really have the green light are lifestyle interventions, which if you can get patients to do them, work in bariatric surgery for a very select group of patients. So thank you for your time, and I'll be happy to answer questions. Thank you, Sheikha. That was really outstanding, a very informative presentation. We can start by the audience questions. And the first, I think it fits most with Dr. Schwimmer's talk, is how to engage the primary provider and the pediatrician so we can identify those patient interests early on and prevent the development of fatty liver. And there is also some discussion about how fatty liver is missed out of the whole picture when a patient has obesity or diabetes. So on the primary care level, I think that it really is about pediatric gastroenterologists having those relationships with the pediatricians in their community and investing the time, energy, and effort to give talks, to build those relationships, to make sure they understand why we care about this so much. Obviously on a national level, the kinds of things that happen at societies and between societies. So certainly when NASPGN developed guidelines, we made sure to also connect with the AAP and put it through all of their committees. And I think that those types of efforts, so both the local efforts and the national efforts need to continue. And I think finally, research is a big part of that. If you look historically, I can remember very clearly some of the papers that we published that I think led to many more pediatric gastroenterologists paying attention and becoming involved. And then you get an amplification where more people working in the field doing broader studies further expands the level of interest. So I think on each box, local with pediatricians, national society efforts, as well as continuing the research efforts. The next question is for Dr. Sundaram, is about the long-term safety of vitamin E. Any comment on that? That's a great question. And Jeff, you can jump in here because obviously you were a part of that big study. Most of the data that is out there in pediatrics, unfortunately doesn't speak to the long-term effects of vitamin E yet. There have been concerns raised certainly in the adult population about the long-term morbidity, mortality associated with vitamin E and the potential risk of prostate cancer. And so I think these are things that we have to keep an eye on. As far as I know, there isn't a pediatric study looking at the long-term side effects of vitamin E or long-term toxicity. I think it will be important. And we may over time have the data because many people are using this clinically. I certainly use vitamin E in patients who have 5C proven NASH and speak to families, frankly and honestly about what the risks might be in adults and the fact that we really don't have this data in pediatrics. Yeah, and there is a really interesting question in the chat box is about the end point of treatment. And those are mainly patient clinical trial, whether NASH resolution should apply to pediatric patients because those criteria were adopted from other clinical trial. And what's your take on that? I think Dr. Sundaram, you can start since you had it in your slides, but also we will welcome input from Dr. Schumer also. That is a very, very interesting and very, very valid question, right? In terms of preventive end points. I think one of the things that we sometimes get stuck on a little bit in terms of prevention, and I think Jeff hit on this a little bit in his talk is how do we know when the disease starts? How do we know when it progresses? And therefore, how do we define prevention? And I think until we can continue to hash some of that out, it may be a little bit tricky, but I think prevention is absolutely the key to what we are doing. I'm not certain that drug therapies or pharmacotherapies are gonna be the answer for prevention. I think it's going to be lifestyle changes and obesity treatments that are gonna lead to prevention. I think earlier and earlier, and I think that is where partnering with pediatricians, family practitioners, first-line medical providers, may help us shift that target. I think the question about current FDA-defined end points that are really based on adults, great question. There is much discussion and much debate about this in the pediatric hepatology community, and especially those of us who do NASH research. It comes up during research talks. There's a lot of people in the symposium that have tackled this. I think even there've been discussions with the FDA, and I think even as all that has happened, we haven't really moved the needle because it doesn't seem that we can propose, at least right now, a better end point. And Jeff may have a different perspective on that. I think that one of the key pieces of this is the different types of pathology in children. And so younger children tend to have more disease that is portal zone one-based or predominant. Older adolescents tend to have disease that is more zone three, central lobular-based or predominant, as is more typical in adults. And the SINCH trial, I think, was a very good example that if that had been a younger child, you know, 13 and under trial only, it would have been a positive study. You know, what we saw was that the people that were most responsive to that particular drug were the ones who had the pediatric zone one NASH pattern. And so I think as we look at studies, we really need to think about, should we be doing separate trials in younger children or older children or basing studies on particular sub-types of disease? In terms of outcomes beyond that, for long-term, certainly the thing as hepatologists that we all know that we're trying to prevent is the progression of fibrosis. The challenge is what timeframe is required to know that and how to best assess it. It's definitely an area of further research and work. So there is some interesting questions about the risk of HCC in the pediatric population with NASH. As we know, there are data that HCC can develop without a background of cirrhosis. And what's your take on that in adolescents? Should we be more vigilant screening them? So I think this is kind of open question for both of you. I think I would like your take, Dr. Sundaram, on that. It's a great question. And my answer has nothing to do with data, but really just my personal experience. And I don't think there is any data. So I do not screen patients with NASH or even NASH-associated severe fibrosis or cirrhosis for HCC. And I make that statement based on extrapolations from other pediatric liver diseases, including things like biliary atresia and allergy syndrome or PSC, for example. And we know that those patients are potentially at increased risk and they often have cirrhosis in their background. And even in those patients, there isn't good data that's screening them for HCC, whether you do that by alpha beta protein or whether you do that by ultrasound or other imaging, it's helpful and changes that marker, with the exception, of course, of progressive femoral intrahepatic cholestasis. So when I think about diseases that we know have an increased risk and have cirrhosis and can be quickly progressive and then extrapolate that thought process to NASH, it's hard to make that justification in cost. Yeah, that sounds reasonable. And there is a question about post-transplant patients with fatty liver disease. It seems that we're seeing more of those patients developing significant steatosis post-transplant and the risk of recurrence of NASH even in the pediatric age group. So what's your advice on that? Great, it's a great question. And we are absolutely seeing it. It is very much a shift, I think, for those of us who practice in transplant medicine, where we typically think of the average transplant patient as being skinny and malnourished. And then sometimes post-transplant, because they're feeling well, because of familial factors, because of steroids and medications, they do develop obesity. And certainly we can all probably share experiences of patients who have developed fatty liver disease in their transplanted graft, including with increased liver tests, which make it very, very tricky to manage their immunosuppression and sometimes figure out, are elevated LFTs related to NASH? Are they related to low-grade rejection or something else? Or is it really a combination of those two things? And so there's some diagnostic dilemmas that come up. But in terms of treating and or preventing disease, I think for those patients, prevention is really key. We have the opportunity. We're following those patients very, very closely to be paying careful attention to nutrition, paying careful attention to weight gain, bringing nutritionists in at the ground level so that they don't all of a sudden come back to clinic and now their BMI is two, three, four standard deviations above where it needs to be. And again, not based on data, but my personal and clinical experience has been that for many of those patients and families, they have a difficult time shifting from pre-transplant, where we tell them, feed your kids as much as they can possibly eat and as many high calorie foods as you can get in them all the time to let's go back to a good, healthy, balanced diet after transplant. I think to expand that beyond transplant, really to hepatology more broadly, we've increasingly seen children who will have dual diagnoses, who will have another condition and have NAFLD. Say, the challenge of you have somebody who has autoimmune hepatitis and NAFLD and the therapies for autoimmune hepatitis may worsen your NAFLD, et cetera. And so I think that increasingly our messaging is that quality nutrition is an important part of liver health across the spectrum. And so the sooner that becomes part of the messaging and conversation, it then is not coming out of the blue if you have to bring it up after several years of a new problem emerging. Yeah. There was an interesting question. This is for you, Dr. Schwimmer. Do you do like stratification based on genetic risk regarding the management of the patient? Are we there yet? Do we do like, you know, a panel for a gene that increases your risk of developing rapidly progressive disease in NASH? Is this just research-based at this stage? What's your take on that? The genetics of NASH and NAFLD are quite interesting and I'll throw the microbiome to that as well. I think there's promise in both of those arenas to play a role in perhaps prognostic indicators, but currently that is still all in the research arena. There's no proven value in the clinic as of yet for those tools. This has been an amazing discussion and I hate to be the person that puts a cap on it, but unfortunately we are running short on time and it's going to be the top of the hour. So I'd like to take the privilege of thanking Drs. Sundaram and Schwimmer for their valuable insights and presentations and also thank Dr. Ibrahim for cohorting the questions so beautifully. As you can see, the chat is still full, the Q&A is still pouring in. That tells all the trainees that are online probably a big hint that NASH has tremendous amounts of outstanding areas of research yet to be looked into and careers to be made. So thanks to the ASLD for supporting this morning's session if you're on the East Coast or elsewhere in the world. Thank you.

ASLD webinar

Natural History of Pediatric Nash

pediatric non-alcoholic fatty liver disease

pediatric non-alcoholic steatohepatitis

Dr. Jeffrey Schwimmer

Dr. Shikha Sundaram

disease monitoring

lifestyle modifications

pharmacotherapy