So now I will introduce our speaker today. Doctor Maliti completed her medical degree at Tree Ramachandra Medical College and Research Institute, followed by her pediatrics residency at University of Illinois Chicago. Her fellowship in pediatric gastroenterology, hepatology and nutrition was completed at University of Chicago Comr Children's Hospital where she then taught for two years following her fellowship. And since then, we've been lucky to have her here at Children's Oakland where she's the medical co-director of the PSG I Department and has taught countless trainees who rotate through Doctor Seti's clinical interests and expertise are in allergic and immunologic diseases of the G I tract, particularly celiac disease, which we'll hear about today and eosinophilic G I disease G I food allergies as well as IBD and other interes. She is director of both the Celiac Disease Clinic and the East Bay Eosinophilic G I Disease Clinic. She has participated in several committees within NAS began. So please welcome Doctor Setti today. I will hand it over to you. Thank you. Good morning to everyone and thank you so much for inviting me here today to present. I'm very excited to share this talk on the uh updates and controversies in celiac disease on this last day of May, which is uh Celiac Awareness Month. So we made it just under the wire. Uh I know you're all coming back from a long weekend as M I but I will try to fly through this uh beginning few slides because there are somewhat background. Uh I have no disclosures to make. And the objectives of this talk is to discuss the role of uh screening tests and celiac disease interpreting their results. Uh and discussing their limitations. There are potential challenges in the diagnosis and management of celiac disease that are important to recognize. And I will also review the current management guidelines uh and discuss potential therapies that are under investigation. I'm gonna start this talk with a case and this was a, a little boy who presented to my G I clinic over the pandemic period. So um this is a two year old toddler who was seen in a G I clinic virtually. He uh was sent for some poor weight gain. So slowing up weight gain but not abnormally low had had persistent recurrent vomiting, some abdominal distension and loose stools but no obvious ideology. We I did some baseline stool studies which were not remarkable and uh there was no known family history of similar symptoms or autoimmune diseases in clinic. We uh examined him. He was a smiling nontoxic appearing boy. Uh he was kind of standing in a lower posture. He had a very distended, soft abdomen. Uh no organ amy was noted. His extremities were extremely thin. He had poor fat stores and uh so a lot of work was done which was essentially normal, uh except for a slightly low alumin of 3.8 and calcium, slightly low at nine and alphos of 108 with a normal CRP of not his uh abnormal findings was his tissue transaminase IG A was less than two, but he had a very low serum ig a low five and his diamond glide in IC G was 100 and 35. Uh still studies were essentially normal uh with a slightly low ph his endoscopy was then the next step, it was a very flat and featureless oneal mucosa that was described and his histology showed active Duits via splinting and increased inter epithelial lymphocytes and they counted it. It's over 65 inter Patel lymphocytes per 100 uh epithelial cells. This graded at A B 2 March type at and Kaza type three. So this confirmed his diagnosis of celiac disease. What is celiac disease? It's a lifelong autoimmune disease. It leads to the destruction of the villa architecture of the small intestine. Uh It is very unique in that it has a known environmental trigger called gluten and gluten is this protein present in wheat rye and barley that actually has no nutritional value. However, is something that uh in celiac patients is uh triggers an immune response. The auto antigen which is tissue transaminase is also known and we know that elimination of gluten from the diet can lead to complete resolution of this disease. Genetics is the strongest risk factor for development. Uh We know monozygotic twins have a 75% accordance rate, sorry guys. But uh this, this then of course, highlights the fact that it's not the only factor uh in the celiac uh gluten induced lesion in the small intestine. Uh This has been really very well studied over the past decade. Primarily, we know that gluten is digested partially to uh glide and fragments. And these are uh incomplete, digested in normal uh individuals. This is actually passed into the stool. But among those that have celiac disease, it trans locates through the epi epithelial barrier. We think it's a paracellular though trans cellular may also be possible here, tissue transaminase deaminate this glidden uh and makes it more sticky essentially. And this is then recognized by the MH C class two molecule on the antigen presenting cell leading to uh T cell responses. And this then activates a CD four T cell uh uh response with cytokine release and CD eight Iel uh and innate immune cell uh activation. The CD four T cell response also activates B cells which leads to a tissue transglutaminase auto antibody production. So overall this, this leads to normal billa which are then foreshortened and blunted and uh very inflamed as you can see here in this uh picture with lots of lymphocytes and interco cells. So, the genetics are related to the MH C molecule on the edge of your presenting cell. This is reacting to the deaminate glidden peptide. These are HL ad Q two and DQ eight molecules. And these are uh the antigens that are the most frequent in uh celiac disease. We know that DQ two molecules are occurring at about uh 90% of celiac patients. This is uh recognized here below. Uh it can occur in various frequencies. So DQ two can be in uh a homozygous pattern. In which case, you tend to have a higher risk of developing this condition. It's also noted to be a more severe condition in those patients and those that are heterozygous. So, carrying only one um A it does still increase the risk but only to one and 30. Historically speaking, we know that uh celiac disease has been recognized for a very long time. You know, initially, it was thought to be an a very uncommon illness affecting early childhood and individuals. Uh in of European descent, it's uh credited to be uh described by Ariad in the 16th century called it Colac which is east suffering abdomen in 18 88 though Samuel G described it uh and published that. Uh so he gets a lot of credit. He described both the Children between one and five years of age with bulky stools and Caia, these patients were, uh, quite ill, had high morbidity and mortality rates. Many tried various diets but nothing seemed to, uh, be consistent. It was in 1924 that Sydney Haws did, did publish the banana diet, which was, um, a placebo controlled trial where they saw that, uh, uh, 10 such Children were treated, uh, eight of which were treated with the banana diet who survived. So, for many decades, the banana diet was the treatment of choice. So only in that the 19 thirties that uh Will Dyke, a Dutch pediatrician recognized that wheat was the uh potential trigger and he termed uh the uh gluten free diet. So as in our first case, the presentation of celiac disease in the early years are described with that classical picture of malabsorption, iron deficiency anemia, uh diarrhea and weight loss. Though other systemic manifestations are also recognized over the through the years as associated findings. And we often describe celiac disease as this iceberg phenomenon where there's a symptomatic uh classical picture. Uh what we are recognizing over the past uh 20 years is that that's really truly, it's the tip of the iceberg. There's a very large population below this level that is presenting with normal BM I normal growth patterns and no specific D I complaints. So often these are the patients that present with diagnostic delays uh globally. Uh This meta analysis actually looked at various neurologic studies uh among various countries. They found that this was an average of 1.4% of s prevalence. Perhaps this is an overestimation as these are not biopsy proven. Uh in Sweden, it has a uh established a, a routine national testing. And in that country, they have shown a zero prevalence of about 3%. Um but rising gradually, other countries have reported higher rates such as Mexico, Algeria, Saudi Arabia and India. So the global uh prevalence is, is pretty broad. We also know that incidence of celiac disease is increasing over time. In this uh systemic review and meta analysis. They reviewed five decades of s prevalence studies and uh note the overall rise in all of these uh populations. Of note, there's a pooled female to male predominance. Um and overall incidence is increasing by 7.5% per year over the past several decades, which is really not explained by increased testing alone. Uh This pathology database review actually uh looked at 450,000 dual biopsies and uh in in the US. And they saw that the prevalence of Vios atrophy consistent with celiac disease was seen among all age groups uh primarily though among younger uh ages as in the blue bars. Um this may be of course linked to the presence of these risk genes within these populations. Again, an area of interest uh Sweden actually experienced an epidemic of symptomatic celiac disease in the eighties. Uh There was this very abrupt increase uh in the incident of uh celiac disease. And uh it turns out that 3% of all patients uh in the 12 year old range had celiac disease. By the end of this epidemic, some of the things that they saw and thought was uh impactful was the delay of gluten exposure from 4 to 6 months earlier. Uh that decade. The other changes that occurred where there are larger uh amounts of gluten containing flour in infant foods uh as well as a stoppage of breastfeeding. At six months of age, many of the uh Swedish moms were going back to work and these were all thought to be potential uh environmental uh causes or modifiers, increasing the risk when they changed the some of these uh these very market, uh they found that that there was a decrease again from, from the um epidemic. This, of course, uh this experience, of course, of the Swedish story suggested the role that there were environmental modifiers to the development of celiac disease. And ongoing research is underway regarding these modifications. Um Some of the studies that are currently undergoing is the Daisy study, which is a uh birth cohort study. This is a prospect of um birth cohort of uh infants that have risk alleles, the DQ two and DQ. Uh And they are, they are noting that there was a higher association of celiac disease auto antibodies in those that were introduced to gluten earlier before three months of age or beyond six months. Further studies are ongoing. We know celiac disease is a multisystem disease. It can affect many different systems including neuro neurologic symp symptoms, uh mental health cardiovascular risk factors, malignancies and reproductive health, as well as bone health celiac hepatitis is a notable condition. 30 to 40% of those with celiac disease have elevated liver enzymes. Uh So should always be looked, looked at in those that present to you. Uh in 9% of adults with elevated A LTNESG, they may have silent celiac disease. Uh So adults also may present in this way uh liver biopsies in these patients. So show very nonspecific uh reactive hepatitis and these enzymes typically normalize on a gluten free diet. Uh skin manifestations, there is granular IG A or TIS TG three IG A deposits in the skin which are very itchy uh popular vesicular rashes. They are uh it is known that the epidermal tg three is a target or transaminase three. Many of them also have a tissue transaminase uh at two, which is our usual study that we normally run for celiac and uh they all improve on a gluten free diet. There is an increased risk of B cell lymphoma in these patients. Uh neurologic manifestations are also um of import. We're seeing a um very high rate of neurologic conditions in our celiac patients. Uh Celiac disease is associated with several neurologic and psychiatric manifestations like ataxia, peripheral neuropathy epilepsy, headache, cognitive impairment and depression. That one meta analysis uh noted that neuropathy had a fivefold increased risk. Uh among those with celiac disease. Um and gluten ataxia is a very uh rare but, but severe condition that leads to uh cerebellar changes as seen in this MRI uh with limb and ataxia that is associated with tissue trans A six auto antibodies. Uh It does improve with a gluten free diet. Pulmonary manifestations can also present uh This is a rare condition in this child. Presented with uh severe anemia. Uh had a had no G I symptoms but was um iron deficient and responsive to iron. Uh and had uh these pulmonary findings of uh infiltrates in the uh right lung as well as glass obesity. His tt gig was positive and his biopsies confirmed the diagnosis. He improved on a gluten free diet. So, in popular culture, the awareness of the gluten free diet and celiac disease has spread over the past decade. Um In this uh headline from the New York Times, it raised that question. Should you screen your child for celiac disease? Uh since about 60% of Children and 40% of adults have no symptoms. Uh They also remarked on the diagnostic delay that it can take up to four years on average for these, these diagnoses. So how do you test anti tissue transaminase IG A and the total IG A is the initial recommended screening tests. Uh These remain the same uh antibody testing is only the first step. We use a tissue transaminase IG A because of its uh broad sensitivity and specificity. Uh limitations of this testing is um unfortunate but true selective IG A deficiency occurs in about 2% of patients with celiac disease. It's uh where there is absent but detectable IG A and in a patient with normal IgG and IgM, so always check an IG A level at least once. And if low then run the anti Tt Gigg and the D MD did glide in IgG. Many patients are already on a gluten free diet, uh or gluten reduced diet. This does result in a down regulation of the inflammatory immune response and reduces the autoantibody production. So you can have a false negative result. Often the the guidelines is to uh advise patients to start a gluten diet before doing the blood work. At least six weeks of two slices of bread a day is the recommended gluten challenge. Case finding is uh now the important part now that we recognize that there is non G I symptoms associated with celiac disease in patients that have a normal BM I and uh no G I symptoms. We should still consider this diagnosis uh especially in those with abnormal liver enzymes, uh skin manifestations, uh neuropathy or headaches, uh growth failure and teeth discoloration. Other conditions that should also be considered to cast a wider net are first degree relatives which A which has a, a rate of 5% prevalence in type one diabetics up to 10%. Uh and in autoimmune hepatitis arthritis, Shogren syndrome and Down Syndrome and other conditions. Unfortunately, mass screening of asymptomatic individuals is not supported at this time because it does not fulfill the who criteria, but it remains a, a point of discussion. One study looking at improving case finding is the prospect of birth cohort study. Uh The environmental determinants of diabetes in the young, which is a multi center study uh of uh infants who were found to be uh DQ two or DQ eight. In this uh study, they, they found a 1000 339 patients. Excuse me. Yeah. And uh 66 of them developed celiac disease. This was a cumulative incidence rate estimating to 3% of the denver population in this particular study. They also showed that HL a genotypes uh were significantly related to their uh and the allele frequencies. So higher rates of HL A uh noted increased risk of developing celiac disease. Another high risk population are um Children with Down Syndrome with reported rates of up to 12%. Uh guidelines currently are not aligned unfortunately. And um in this uh report, they looked at various guidelines among um various Down Syndrome groups and there are testing screening recommendations that are very variable in our own population. We uh recently presented at DDW that up to 16% of our uh Children with Down Syndrome were zero positive. So to recap uh screening and training tests are primarily TT gig A and a total IG A level. Uh following this algorithm, if you see a positive Tt Gig A, the recommendation is to confirm by uh a dual biopsy prior to starting a gluten free diet. In in those cases, if there is a positive biopsy, we can confirm the diagnosis of celiac disease in cases where there is disagreement. However, we do recommend proceeding with further testing and potentially genetic testing as well as other workout. Genetics can help those uh who are at risk, primarily those uh who are family members. Um It can be useful genetics can also uh tell you how, how at risk you are uh depending on which alleles are found. They are not diagnostic but does narrow down those with potential risk who may need ongoing screening. My second case is uh a 12 year old girl who has a very strong family history of celiac disease. Uh she was screened and found to have low ig a level but a normal tt gig A she had no G I symptoms and normal growth parameters. A repeat comprehensive panel was drawn and it showed a serum ig a less than five att gig a of less than two diami glide and ig of two diam gliding IgG of 85 and a tissue transaminase IgG of over 100 but a negative E MA. So the next step in management, we proceeded with a an upper endoscopy and uh villus there, the villa look very healthy, the folds look also very healthy. But the biopsy showed a mild to market villus blunting with focal fool metaplasia. It was described as patchy in in these biopsies and um but there was intra lymphocytosis. So the findings in the duodenum support the clinical impression of celiac disease. So in establishing the diagnosis, the North American guidelines continue to uh request that we screen with Tt gig A and a total ig A while on a gluten containing diet. Uh and uh it's positive to proceed with an endoscopy with biopsy. But can you diagnose a celiac disease without a dual biopsy? Uh Pediatric guidelines from the European Society of Pediatric G I in 2012 actually brought that up. Um in 2020 they modified this uh to a symptomatic child who has att gig a more than 10 times the upper limit of normal on two separate blood draws. Uh It should show the presence of Endomysial ig eight antibodies. Families should understand that issue of bypassing the diagnostic uh gold standard. And uh also understand the need for con consistent follow up this particular uh re provision, removed the requirement of celiac genetics. This uh limitations of this testing is with IG A deficiency, type one diabetics and other autoimmune conditions. Those who have no symptoms really can't uh fit this particular um guideline. Um and then those who might have other conditions as well. So in our next case, this is at a 19 month old male who had a history of eczema suspected malp protein intolerance and infancy had a very low weight for height and an elevated D GP IgG and IgE levels. His diami glide in IgG was 100 and 65.6 with also an elevation of the diam glide in ig A. His TT G uh antibodies were negative as was his E ma endoscopy was done. Uh And this was notable for edema and furrowing and the esophagus and uh a nodular Duno bulb but was otherwise normal. Histology showed in or dual mucosa but there was moderate to severe phia in all three levels of the esophagus consistent with eosinophilic esophagitis. So, in biopsy, serology, disagreements, um workout for other causes of those atrophy should be uh considered other causes of elevated TT G or D GP antibodies. Uh include inflammatory bowel disease, lic G I disease and food allergy. As in our last patient, uh viral infections can cause transient rises into in the auto antibodies as do um patients with other autoimmune conditions like thyroiditis, type one diabetes and Down syndrome potential celiac disease is where there is positive serology but normal dual biopsies. Um this patient population con continues to uh cause some head scratching. There is some fluctuating levels seen in these patients. Uh The predicaments that we often find ourselves. Is there. Is this false positive serology? Is this early celiac disease? Was there patchy disease that was missed? Uh So no guidelines are really available on. Follow up some uh follow a wait and see pattern or some families will start a gluten-free diet in 1 12 year follow up study of potential celiac patients. Uh They saw that the cumulative incidence was 43% who developed celiac disease. Some of the correlations to progression were high risk groups like first degree relatives type one, diabetes and autoimmune thyroid disease as well as those who had higher uh risk type, eh, las like homozygous DQ. Two, the gold standard remains the uh endoscopy and biopsy. And the cut off for Marsh criteria is over 25 in inter lymphocytes per 100 intestinal epithelial cells. And this ranges between uh infiltrative hyperplastic and etro mucosa. There are imitators to some of these findings. Those that have increased iel alone may consider that they have NSAID injury, inflammatory bowel disease. CBO or H pylori mimickers of both iel and atrophy include certain medications, common, variable immunodeficiency, uh Gr un iun an the collagenous brew and uh T cell lymphoma management for uh celiac disease. The only treatment that is available is a strict gluten-free diet which is avoiding any uh wheat rye and barley. This requires close dietician and nutritional. Uh follow up and counseling as well as routine. Follow up annually. The treatment goals uh with the guidance of a celiac dietician. The goals of therapy is really a healthy gluten free transition. We would uh recommend increasing consumption of naturally gluten free cereals, increasing dietary fiber, limiting high sugar intake and increasing micro nutrient intake as well as uh limiting the consumption of ultra processed foods. How much gluten is safe? Uh In a fairly old study, they did do trials to see how much gluten would induce the inflammation. Uh This range from 10 mg to 50 mg. Uh and what is 10 mg of gluten? This was a graphical representation of 10 mg of gluten which is uh representative of exposure over the course of the day. So, the diet is quite challenging. Um Some of the challenges include the persistent economic burden of the gluten free diet. This report looked at uh the overall cost of gluten free products and compared it to their gluten based counterparts. Seeing that cost of gluten free products was uh almost twice and maybe three times as much. Uh an overall average of 100 and 83% more access to options are limited. Uh There is cross contamination risks and maladaptive food behaviors. In one study, they saw that approximately half of all adolescents with celiac disease who uh expressed maladaptive eating behaviors in managing their gluten-free diet. This was characterized by rigidity, avoidance controlling behaviors, preoccupation, which are all known risk factors of the development of a diagnosable eating disorder. So, what do we do? Uh this recent position statement on the management and follow up of celiac disease uh recommended uh three monthly to six monthly uh visits in the initial years of after diagnosis. Followed by annual follow ups. We cover uh persistent symptoms, monitor anthropometry, uh assess the dietary adherence. Uh follow up lab work, management of deficiencies and persisting s positivity, Rebi re biopsying if necessary quality of life monitoring is an important part of this uh clinic. And we discuss transition issues. Uh Other things that we cover during our clinic visit include uh unclear diagnoses, potential coeliac follow ups. And uh many who have self diagnosed uh need a gluten challenge. Follow up of celiac disease is a very time sensitive uh issue. In one multi center retrospective. They saw that up to 50% of uh those who were diagnosed were lost to follow up after the first year. Consequences are really unclear. However, we do know that some long term risks uh exist and we will discuss that later in this talk. The important thing of monitoring and uh follow up is that we, the goal is to settle this gluten driven immune response. We like to improve quality of life, resolve the symptoms that they are often persisting, achieve intestinal um mucosal healing and limit the comp complications. We also uh find ourselves addressing uh limitations in uh family understanding and uh educational barriers. How do we follow up? Serology is often tested. However, antibody tests in celiac disease did did not reliably detect persistent Vios atrophy in the study. Uh up to 40% of those with uh villous atrophy had normal uh auto antibodies. So, are there other methods of follow up? There's many that are still in research. Uh One recent uh biomarker is the gluten immunogenic peptide. These are peptides that are detected in the human urine and stool. Uh and it positively correlates with intake of gluten as well as the amount of intake of gluten. So as little as 25 mg of gluten can be measured in both urine and stool. So this particular study confirmed the poor correlation between uh patient reporting of gluten free diet and actual presence of uh the gluten in their urine, uh particularly among the 13 year olds, males and, and um less so among the 4 to 12 year olds and much less. So in the uh toddler age groups repeat biopsies, the questions uh for repeat biopsy which isn't often used in the adult population. Um in pediatrics, this is not part of our guidelines. But when we do look at uh the intestine, again, 15% of pediatric patients uh have been shown to have persisting anthro at two years after diagnosis. Yeah, cross contamination risks are everywhere. Uh This particular study looked at classroom risks and saw that uh basic classroom uh activities can lead to gluten uh ingestion. What do we do with persistent symptoms after starting the gluten-free diet. Uh often we have to ask the question is celiac disease, the current the correct diagnosis, uh checking the serology, histology uh and ruling out other potential causes of enteropathy. Uh We also run the genotyping if necessary. And uh if, if uh no other issues are noted, can consider a gluten challenge to reassess. Uh specialist dietician review can reveal any ongoing gluten intake. And this is important uh as well as the G IP testing, which is um fairly accessible testing. These days, we do consider barriers to ave uh and uh discuss as other uh adjunctive treatment for ongoing symptoms. Complications that are recognized include um a potential increased risk of auto other autoimmune diseases or associated autoimmune diseases. Deception has been noted to be a presenting uh feature due to intestinal inflammation in some younger kids. Uh osteopenia, osteoporosis is seen in up to 40% of adults with uh newly diagnosed celiac disease and is part of their guidelines. After diagnosis is to get a DEA refractory celiac disease is seen in 1% of adults with uh celiac disease where they are uh no longer responsive to a gluten free diet and have ongoing inflammation requiring immunosuppression. There is an increased risk of hematologic cancers and lympho proliferative cancers uh primarily in the uh adult age groups and a notable elec elevated mortality rate. Uh There is a small but significantly increased mortality rate, primarily due to cardiovascular cancer and respiratory conditions. Uh Bone health and celiac disease is noted to be impacted. There's a 95% bone accrual rate by age 18. Um with a peak bone mass at 30 years of age and there's uh then a rapid loss uh in the uh 40 above. So this is uh normal and in uh celiac disease, this curve can be greatly blunted, uh particularly if uh bone health is impacted during the growing years. Exercise can improve uh the strength of bone and uh is a modifiable risk factor and can persist throughout uh late adulthood. In our population, we saw that 34% of our patients had low bone mineral density and correlated with lower BM IC scores and age. So many different gluten uh targets are under a study currently, um these are drug, drug uh studies that are impacting different parts of the um mechanism of this disease. Uh Some are looking at gluten, impacting gluten breakdown, uh epithelial strengthening tt G uh blockage, um tolerance induction where gluten specific T cells are uh no longer reacting uh cytokine targets like il 15. So blocking those can help protect the epithelial barrier uh as well as other immune targets. It's a very exciting time. Uh In the most recent DDW, there was uh reports of several phase one and phase two studies. Uh many are still in these early stages. And as you know, uh phase one studies are really just a proof of concept. Phase two can look at safety. It is really when they get into phase three, that it will be more available there. The most recent one was lati gluten that was able to reach to phase three but was discontinued due to a difficulty in uh recruitment and would require very large population studies. So take home points. Uh so screening, take home points is to screen all symptomatic Children. But also consider case finding strategies like first degree family members down syndrome type one diabetics, Hashimotos, turners, elevated liver enzymes and that whole host of uh symptoms previously mentioned testing strategies should be with att gig A and a total IG A level and in Children below two years of age, um we should consider a diam glide in IgG and att Gigg a positive screen test result. It is important to refer to G I for confirmation and follow up before starting a gluten-free diet. Uh to avoid uh the complications of uh uh under diagnosis. Comprehensive clinical referral is also important for those already on a gluten free diet for long term follow up adherence, monitoring, symptom management, and uh growth monitoring as well. So there are many open questions in celiac disease, uh how to select our patients, how frequent to do the screening tests, identifying who will benefit most from either a biopsy, uh confirmation versus just a cer confirmation. Uh There's no adequate symptom scoring tool or a patient reported outcome tool, uh biomarkers are still under investigation. So current biomarkers are less than 100% reliable, follow up testing protocols uh continue to be developed. And uh long term morbidity and mortality concerns need to be addressed as we are picking up more silent celiac patients, uh equity and care and access as well as um uh appropriate access to follow up and management uh as well as treatment outcomes. Um However, the future remains very bright. Thank you. Thank you for that comprehensive review. We do have several questions. Um I guess there's two questions going back to early in life, gluten exposure. Is there a recommendation for when, how to counsel parents about when to introduce gluten? Is it, you know, 4 to 6 months or is there any sort of recommendation there? Yes. Uh The current uh studies which I didn't get into too many details. The Daisy study did show that there was um a prote protective or delay in onset of celiac uh autoantibody formation and the higher risk uh genetic infants. So, if you were to introduce uh between the 4 to 6 month window, um in small quantities only, it seemed to be slightly protective, I guess similar to like peanut exposure early in life, correct? While breastfeeding is the ideal way? Ok. And what role if any does genetically modified wheat play these days such as more gluten in today's grains? Yeah. So uh this is definitely uh uh an interesting point. We do know that gluten is uh the the wheat products are are modified to increase gluten intake. Gluten is the um protein that causes a elastomeric uh change in the in wheat. And so it's what makes wheat rise. Um and this has been very attractive. So you think the wonder bread effect? Um and so there is increased amounts but they haven't been able to correlate that with the direct cause of this rise in incidence alone. Thank you. And we have a, a comment from Doctor Becker. Thank you, Doctor Setti for this great overview. And could you describe why it is that VIIS atrophy is the gold standard for a diagnosis when um a disease can manifest in multiple symptoms. Could there not be patients with this that do not have bio atrophy? Yeah. So uh autoimmunity to gluten, you can have um like dermatitis or peformance without the enteropathy. There is actual auto antibody production though that you can measure uh you know, related to trans contaminate three as well as in biopsies of the skin. Uh in neurologic manifestations, they can measure TT G six and which has been shown in some patients who have neurologic issues. Um So, anthropopathy is not the only uh autoimmune uh target in these cases. And um there's a question just to further describe how when patients present with G I symptoms, how do families describe the stool? Are they thinking it looks normal? Most of the time or is it more often watery, frequent stinky, intermittent, does it always result in weight loss? It seems like, you know, it's very big spectrum here, right. So there is a fairly wide spectrum. Uh you can have um loss of like diarrhea and um loss of nutrients through uh that um many, many have patchy uh inflammation. So that does not result in diarrhea, some have even constipation. Um And so it can vary, got it. And there's more, also um more within that is are these kids often picky eaters and or hard to potty train, they can be very hard to potty train, I think related more so to uh the constipation issues that they are dealing with. Uh I wouldn't say that necessarily uh all Children with um constipation have celiac but it is one of the reasons we will recommend screening and what are the hypotheses about this connection to hematologic cancers? Is it, does it have to do with generalized inflammation or nutritional deficiencies or the genetic association or all of the above? Yeah. So there is uh because this is a T cell mediated inflammation, it leads to um increased or activated B cell uh production. And so you'll have a significant number of B cell uh or plasma cells in the lamb appropriate these uh patients, it can uh then lead to um kind of an autoreactive B cell um inflammation uh as well as a CD A T cell. And so these are then decoupled from the gluten response in those like with re refractory celiac disease. Um meaning that they no longer require gluten and can uh become autoreactive and potentially have been for uh lymphomas. Got it. Thank you. Um There is a question from the community in terms of a gluten free diet, there is a struggle to, to find a nutritionist or a dietician that works specifically with that. Is this the service accessible through Joe? Yeah. So we have a, a Celia clinic that we run um on a weekly basis and it is with a dietician, a social worker. Um Often we are spending significant time in teaching and education for families. Uh We recommend all family members be present. Um are all caregivers who are helping uh care for this child be present so that uh all can learn about the gluten free diet. Thank you. Um Do you recommend universal screening blood work on kids with Down Syndrome? Yes. So uh yes. Uh personally, I recommend uh that screening is important uh as in some of these guidelines, they recommend that uh symptoms should prompt screening in the Down Syndrome guidelines. Uh However, uh many of the Children with Down Syndrome have no uh obvious symptoms like growth failure. They'll be um within their uh growth parameters. Um constipation, there could be many reasons for it. Uh abdominal pain, it can sometimes be challenging. So, in, in general, I think uh screening alone is is enough since it is about 12 to 16% in our population that were zero positive. Yeah, that makes them. Um So what happens when the endoscopy shows the village village atrophy that um does not meet the criteria for the lic infiltration or the lymphocyte infiltration. Is it still meet criteria for Celia disease? Yeah. So if there's uh there is blunting but no increased inter epithelial lymphocytes, I think that's what that question is asking. I, I think you cannot call it um Celiac disease. It requires that, that uh increased number of inter lymphocytes. I see. OK. And I had a question um that's not listed here. It's just, I was struck by the um the slide that you had on the neurologic manifestations because I guess I hadn't thought of it that way before. Um When, by the time you're seeing these neurologic manifestations, are you definitely going to see like other physical manifestations or might that be the only thing? Because I feel like I would miss that if I just saw ataxia, I wouldn't be looking for celiac disease necessarily, right? And, and uh it's not always associated with a uh growth failure or diarrhea or abdominal pain um or even uh weight loss. So it can be challenging. These are Children that are, you know, um uh with headaches alone and uh no obvious G I manifestations and a normal BM I, so it can be challenging. I think the uh question is good. Uh At which point do you just run a panel? Um I think it's important to uh know that that is a potential differential to consider. Thank you. Well, if there are no more questions for the morning that brings us basically to 9 a.m. So I just wanted to thank you for your presentation again. Um Hopefully we can welcome you back sometime in the future at our grand rounds and I encourage everyone to tune in next week. Awesome. Thank you so much.