Affecting many body systems, celiac disease presents in a multitude of ways – sometimes with no digestive symptoms. Pediatric gastroenterologist Mala Setty, MD, explains the steps to accurate diagnosis, including when biopsy is required. She provides a flowchart for distinguishing celiac from other gluten-related disorders, a timeline for patient improvement on a gluten-free diet, and clarifications on the “gluten-free” product label.
mm. Good afternoon. And um this is my talk on celiac disease and gluten related disorders. I am Malala City, I'm associate professor at UCSF Benioff Children's Hospital, Oakland. Many of you may know me. I I do run the celiac clinic in the East Bay. Uh My disclosures, I receive royalties from up to date. My objectives today is to review the changing clinical presentations of celiac disease to discuss it and examine the current guidelines for screening and diagnosis, discuss gluten and gluten related disorders and review the gluten free diet and monitoring challenges. As many of you know, Celiac disease is now recognized as a common food intolerance and is noted to be a unique autoimmune disease found in 1% of the American population. It is an immune mediated antipathy that has a well recognized environmental trigger of gluten and a well recognized auto antigen tissue translate tammy's. Uh we know that eliminating the trigger leads to complete resolution of the disease and it occurs in genetically susceptible individuals who carry the HLAD- two or DQ- eight molecules. It was first described By Samuel G, who is credited in 1888 uh stating that Celiac disease is a kind of chronic indigestion met in persons of all ages, but especially up to affect Children between one and five years of age signs of the disease are yielded by the feces and the onset of the disease is usually gradual Caxias, a constant symptom and the belly is mostly soft, often distended. Uh It was really in the in this early state that they noted that this was a rare condition and it was highlighted by this malnutrition and cachexia that carried a high mortality rate In the 1920s. It was Sydney Hawes, who another pediatrician who recognized that there was a dietary solution in placebo-controlled trials. They gave eight Children bananas and two were not treated with us. Um, and later died for decades. This became the treatment of choice and prevented many deaths. This diet uh specifically excluded bread crackers, potatoes and all cereals Is really in 1953. Another pediatrician, the setting of World War II, where there was a severe bread shortage in the Netherlands. They saw that there was a beneficial side effect of improving the mortality rate of celiac disease. This strengthen the link to wheat and he's given the term of pioneer of the gluten free diet Worldwide. Worldwide, wheat, rice and maize are the most widely consumed. Food grains introduced over 10,000 years ago, is now the most widely grown crop and is available as processed wheat flour used in the production of baked goods, pastas, noodles and alcoholic beverages. uh, we contains about 75% protein, which is shown to be mostly guidance and glutinous, which can form polymers called gluten. It is in various gluten rich cereals that are capable of eliciting the celiac disease immunogenicity In patients, both gluten ins and Blyden have certain amino acid sequences that act as epitaphs for celiac disease. And these are termed the immunogen IQ peptides or the anti gin peptides, which I will speak of more Later in this diagram, you can see how gluten is a very elastic protein. It is the main structural protein in wheat and contains the toxic protein fractions mentioned previously, glide in and gluten ends. Uh They form a very elastic consistency to do and create stability and softness. In the small bowel, gluten is partially digested to glide in peptides and in this diagram you can see the villa and where gliding is gluten is broken into glide and fragments. These are crossing the epithelial barrier and are acted upon by tissue transfer tameness, which create the denominated Blyden, which is the immunogen IQ portion of the peptides. It is then recognised by H. L. A. To articulate bearing antigen presenting cells that present these to to the city for positive T cells. This then leads to activating The CD eight positive inter epithelial lymphocytes, which caused damage to the epithelium, leading to villus atrophy and villas blunting. This also leads to B cell activation which develops the auto antibody that is a hallmark of the disease called called tissue transfer tammy's uh G. A. It is that this auto immune response that leads to the developing the classical severe gee presentations that were described in early descriptions that are less often seen Now, as we are becoming more aware of this condition in these classical gi symptoms, it is chronic recurrent diarrhea, abdominal distention, poor appetite, malnutrition, abdominal pain, vomiting, irritability and muscle wasting is seen the trending presentations of celiac disease over the years. And especially in research wrist rich countries, we are seeing that the clinical manifestations of celiac disease, maybe more heterogeneous, including the typical uh gi symptoms has seen here with malabsorption, give symptoms of diarrhea, but as well as a myriad of extra intestinal disorders. So, with improved testing recognition and case finding this, uh this particular study noted That 2/3 of their patients had normal body mass index. Okay, more of the newly diagnosed, we're presenting with the nonclassical diagnosed symptoms rather than the classical malabsorption of symptoms and many were actually asymptomatic and found on screening or incidentally and uh in general, these patients were found to have less severe mucosal disease than the classical uh celiac patients and their average age was noted to be higher. This data supports the notion that screening guidelines should not rely on generally malabsorption of symptoms alone. In the public arena, it has been raised that screening may may well be a good question if all Children or most Children should be screened. However, due to cost benefit studies that has not hand out as being useful. It is known that, however, that symptomatic or untreated disease is associated with elevated morbidity and mortality and impressive impaired quality of life in Children who are untreated, it can affect their growth, nutrition and pure Bertel development. So with this, I'm gonna start with our first case scenario, a 14.5 year old girl presented to the uh the endocrinology clinic with um in urea and delay puberty. She is active in cheerleading and gymnastics. She does suffer from joint and musculoskeletal pains, but she denies all gi symptoms. Uh in terms of her growth chart you can see her weight is quite low in her. Hi appears to be uh normal. Uh huh. Laboratory studies were done that noted a normal at CbC CMP, said Ray and CRP a normal data. HCG and thyroid studies. Her FSH was elevated at 98 with an extradite. El less than six. Her T four was normal. Her thyroid peroxide is antibodies and thorough globulin antibodies were negative. Her tissue transport companies I. G. A. Was quite high as well as her total I. G. A. Being normal with a elevated and unusual antibody. Further studies were done uh that revealed a normal carry a type 46 xx. She did have a gi referral by the endocrinologist and endoscopy confirmed the diagnosis of celiac disease, gluten free diet. And hormone replacement therapy was initiated and what you can see is uh with this therapy, her weight and height improved significantly. There is an increased frequency of celiac disease uh noted more than the general population which is one currently. uh where uh the general population has a 40 rate of having H. L. A. D. Two or D. Q. A. And those with genetic syndromes such as Down's turners and Williams, There's a much higher rate or frequency of celiac disease Up to 12 times in down syndrome. uh up to three times more in Turner's and Williams, up to 10 10 among family members. It is seen that uh celiac disease can also increase tenfold Up to 10%. In systemic worldwide review of data published in 2018. This image represents the worldwide celiac disease prevalence rate in the countries that reported data prevalence values were stratified into these four different categories, With the lightest gray being 0-25%ile Uh and all the way up to the 76-100%ile and the lowest and highest percentiles included Countries that had very low uh national prevalence rates of .22.8 up to 8.5% respectively. So the syrup prevalence of celiac disease was observed to be highest in these particular countries. In Asia and Northern africa Up to 8.5% as noted earlier. How the lowest was noted in in sub Saharan africa, where we know that The there is less prevalence of the D. q. two haplotype uh as well as lower wheat consumption. In a national pathology database review of foreign 50,000 duodenal biopsies, they saw that there was villus atrophy uh in in various ethnic groups within this country. Uh In in this analysis, they found that the prevalence Here seen here um undergoing duodenal biopsy was an overall rate of 1.7%. So more than than the 1% previously mentioned. Um The risk was lower in patients identified as South indian east asian uh and hispanic. Whereas compared with other americans such as the North indian uh and jewish middle eastern populations. Uh In terms of the north indian populations, it was seen in mostly the Punjabi. Um subject of the north indian populations with a standard of one in a 40 that was identified. Other risk factors have been looked at with celiac disease. In this a cohort of Type one diabetic studied by the teddy group, the environmental determinants of diabetes, type one diabetes, they saw that several environmental factors were involved in the incidence rates of celiac disease, including geography, seasonality, the amount of gluten intake, uh infectious episodes, their genetics, a female gender and first degree relatives. Further evaluation of these of this particular study group showed uh the D. R. three. Or did you too homo Vegas having the highest risk factor? Um Did you ate first degree relatives in this? This was primarily being Swedish. Um Female, the amount of gluten that was being intake and those born in spring. And then you start seeing some negative risk factors as well. Um Yeah so our next case scenario and we will have our Poll question after this. Uh in this case this is a 15 year old girl. She presented with fatigue, rapid waking, poor school performance for the past 1.5 years uh and with occasional abdominal pain, constipation bloating. She also complains of some cold intolerance and muscle aches uh and some sleep issues. Great. So in this uh uh full panel was sent uh and agreeably, this is not the classic symptoms that you would see with celiac disease. However, in this case uh celiac panel was sent and was found to have a tissue translator Tamminen idea of greater than 100 as well as uh autoantibodies for uh thyroid peroxide dis. And an elevated TSH referrals were made to um mhm Gastroenterology and endocrinology. She had an upper endoscopy that confirmed the diagnosis of celiac disease. She was started on thyroid hormone replacement and a gluten free diet. So we see an increased prevalence of celiac disease, an autoimmune conditions. In fact up to 15 to 25% In some studies of celiac disease have uh autoimmune thyroid itis And 40% will have anti thyroid antibodies. Other conditions that are seeing are type one diabetes up to 10%,, as mentioned, thyroid itis, our immune hepatitis Up to eight Addison's disease uh as well as arthritis, um other autoimmune liver diseases. Uh Shogren syndrome can be up to 15%. Uh idiopathic dilated cardiomyopathy as well as I. G. A. N. A. For apathy. A common denominator tends to be that they all have H. L. A. D. Two or D. Q. Eight. Mhm. Our next case scenario, yeah is an 11 year old girl who had a several year history of recurrent abdominal pains, known lactose intolerance and increased gas. And she's been seeing her pediatrician for several years for these conditions. She has normal growth parameters. And finally lab work was done showing a tissue shantou terminus idea of 25 An entire museum antibody idea that was negative and a total idea of 81. She has a family history of thyroid disease, no family history of celiac disease. Um And a referral was placed to see the gastroenterologist. Uh endoscopy was done and she had uh visual findings of furrowing and oedema in the esophagus and histology that showed over 200 years. NFL's per high power field in the distal Esophagus and 50 s. sniffles per high power field in the middle and proximal esophagus. Knowing that normally there is zero. Yes NFLs. Um This is what we call eosinophilic esophagitis. Her duodenal biopsies were completely normal. So establishing the diagnosis, the north american guidelines which is from the A. G. A. And Nasa began uh require a positive celiac serology while on a gluten containing diet which includes tissue translate, tammy's. I. G. A. And a total I. G. A. Uh The denominated glide in I. G. Is uh important in less than two year olds and the tissue trans contaminates. I. G. Is important to add to I. G. A. Deficient. Um Children, The endoscopy with biopsy should be done while on a gluten containing diet Where 4-6 biopsies are obtained from the distal duodenum and separate biopsies are obtained from the bulb of the, which is the first part of the small intestine characteristic has to pathology. A partial or complete villus, atrophy crypt hyperplasia and increased intra epithelial lymphocytes should be identified on these biopsies mm. So again initial testing is a total aiga. With the tissue trans contaminate saiga, which is more accurate than other test combinations. Children who have The tissue transfer terminates below 10 times the upper limit of normal should undergo biopsies. To decrease the risk of false positives. Uh The european society put out guidelines several years ago recommending that those who had elevated T. T. G. I. G. Over 10 times the upper limit of normal could be considered to go without biopsy. Uh So we here in North America have not embraced those guidelines, mainly because the increased um incidents in europe allows them to have a bit more flexibility in this. Whereas here we do see frequently false positives. And so do need to still consider doing a biopsy. So who can we diagnose without biopsy? A symptomatic child who has a high serum I. G. A. Level which it with a tissue trans contaminates I. G. A greater than 10 times the upper limit of normal. Uh A and unusual antibody I. G. A. That's positive uh along with another tissue transferred to me I. G. A. On a second serum sample. But I think the most important part is the third which is those who are prepared to commit to the treatment. Um And uh and often this is a day like this is a discussion that we have in our clinic in terms of long term uh need for confirmation have this chronic condition. So controversies still exist. The endoscopy is important in terms of clarifying the degree of inflammation but also ruling out other conditions that seem to be found in in co occurrence with celiac disease such as a Crohn's disease and eastern filic gi conditions. The endoscopy with biopsy shows duodenal scalloping as seen here, as well as a mosaic pattern. You will see occasionally flattened folds. Um We do get 46 biopsies from the distal duodenum and the characteristic history pathology of partial villus, atrophy crypt hyperplasia. And uh the the excess pinkish color which is the increased inter epithelial lymphocytes should be seen under micro micro sippy in order to confirm this diagnosis. When should we do the genetic test? The genetic test is done to allow celiac disease to be ruled out. So it's important to do in screening our first degree relatives. So if a child is diagnosed, then all siblings and parents are recommended to also undergo testing, including the TTG IGA. And the genetic test will help to rule out the potential for long term need for screening in doubtful cases. We use this. If the biopsies don't correlate well with the with the serology tests and we can do it to see if there is a need for further testing when the patient presents to us already on a gluten free diet, uh, endoscopy can sometimes be reveal a very patchy sort of disease and may be missed. The genetic test will allow us to determine if a patient should be put back on gluten in order to proceed with an endoscopy, uh knowing the genetic and sometimes helped provide risk estimates based on the ideals that are present. So we know that Hamas Agosti Q two appears to have a 30 time increased risk as compared to uh the you know non Hamas agus uh the hetero zeitgeist used to has an eight time increased risk of this estimated prevalence. So it can give you guidance in terms of a long term follow up uh and how, you know, how likely is a parent or a family member to develop celiac disease. The negative test has a very strong negative predictive value and I can help you rule out the potential for developing celiac disease. So challenges to establishing the diagnosis. Uh I. G. A deficient Children Who actually have an increased risk of developing celiac disease to 2%. Uh The diameter glide and peptide I. G. And the T. T. G. I. G. Can be used. These are not as good as the T. G. I. G. A. But can provide some help in terms of ruling in this condition and those who are already on a gluten free diet, it can be challenging as ah often it is required several weeks to months in order to um show Sira lodge neurology positive on blood work. So gluten challenge is recommended up to four, 4-6 weeks prior to endoscopy is an ideal time point. More is always better. And in terms of Blood work alone, if you want to challenge somebody, it should be at least 12 weeks prior to doing blood work to see if they develop antibodies. Potential celiac disease is seen really in the G. I. Um clinic. They are a serology positive but have normal biopsies. Uh and in in this uh subset we often screen regularly. As it has been shown up to 40 can progress to active disease. Celiac disease is a multi systemic disease. It affects many different systems. Uh skin growth, dentition, bone uh can affect blood, liver neurologic issues, joint issues, psychiatric disorders as well as um kidneys. Anemia most commonly as a result of iron deficiency has been reported in 12-60% of newly diagnosed patients. It is the most common systemic manifestation in adult studies. Uh huh. 5-8% of adults and up to 12% of Children have uh have iron deficiency anemia. And we think it's because of reduced absorption of iron, vitamin B 12 and folate G. I. Blood loss, Hamal Asus and other conditions such as production deficiency and Lane Hamilton syndrome, which is a a lung condition uh with lung hemorrhages, um very rare. Uh and in in these Children who do have iron deficiency anemia, it's more prevalent than those with severe atrophy in their biopsies versus mild interest Apathy. Oral manifestations is quite common. Dental enamel defects are seen in up to 50% of cases with celiac disease, especially during the onset. Uh If the onset is prior to eruption of of the secondary permanent teeth. Uh so below seven years of age. So most of this is occurring on permanent teeth. It may be the only manifestation in some of these Children Recurrent at this dermatitis zero Estonia uh delayed eruption of primary and secondary teeth is also noted. Kill itis or a. E. Traffic loss. Itis is also seen Up to 60% of newly diagnosed celiac disease have elevated trans am illnesses. Um 9% of adults with elevated L. T. And S. T. Have been shown to have silent celiac disease. The liver enzymes usually normalized on the gluten free diet after about six months. I thought to be due to increase intestinal permeability and inflammation as well as bacterial despite aosis in the intestine. It too is associated with severe villus atrophy and malnutrition. It is also seen In 4-6% of autoimmune hepatitis. So this too should be evaluated for celiac disease affects bone structure. This manifest with low bone mineral density and early onset of osteoporosis and osteopenia asia even in those who don't have intestinal complaints. So uh malabsorption, nutritional deficiencies, secondary hyper parathyroid is um um and autoimmune diseases affecting the BmD Are thought to be the primary drivers. Over 60% of adults have low bone mineral density with 20% in the osteoporotic range. Uh The gluten free diet in kids have shown to be very effective in reversing low bone mineral density um In addition to physical activity and proper nutrition dermatitis. Her better for. Mr. Is actually a skin presentation of celiac disease. There are granular I. G. A. Deposits uh in the skin. It's more common in adults and older teenagers. Uh And it's characterized by these symmetric predict blisters followed by erosions, excoriation, sometimes hyperpigmentation, it's usually seen on the elbows, knees, shoulders, buttock, a sacral region and face. The diagnosis depends on demonstrating the typical aiga deposits on skin biopsies And it is the epidermal T. G. three that is the target or trans contaminates three. Um You will also find they have tissue translate tammy's I. G. A. Positive in their blood. Uh And they do have uh villus atrophy on biopsy uh and like celiac disease, they have a risk of the solid from us. Gluten ataxia is rare, it may have a slight male predominance uh and onset is typically in middle age. And though there are rare case reports of younger ages, there are cerebral are changes uh, in in these, leading to a toxic symptoms in either upper lower limb gait, ataxia and dis are three to in this condition, there is an auto immune response leading to antibody deposition in brain tissue. You can see a legal clonal bands in the CSF and sara Bell are inflammation. Uh anti perkin g cell antibodies and anti tissue translate chamness six antibodies are seen in blood. There is some improvement with a gluten free diet. However, residual damage may be present even after this. Um, so early diagnosis and recognition is important. So management of celiac disease, a strict gluten free diet is really the uh only treatment for this condition currently avoiding wheat, right and barley is very important. Dietitian and nutrition counseling has shown to be a important part of maintaining good adherence to this therapy. Routine follow up is recommended at least annually. Um as noted in uh johN ciders paper published in pediatrics monitoring growth development and bone health micronutrient levels, uh serology testing, psychological assessments uh and symptom evaluation as well as uh testing for other autoimmune conditions is clinical remission possible. So, this is an important question that we uh consider as an open question. There is no validated tools for measurement of adherence in clinical practice. Serology is the only common assessment but is really validated for diagnosis and not for follow up. So, in a recent middle analysis, uh they showed that 38% of patients had persisting and neuropathy at two years after gluten free diet in this population that had a repeat endoscopy. In this, um, the tissue transmit harmonies was elevated and only 43 Of that 38. So the tissue transfer to venice and the Indonesia antibody did not correlate very well with dietary compliance reports and raise the questions um, for his clinical remission possible. So these serological markers unfortunately do not reflect complete healing of the mucosa. Other tests that are now in studies and also in practice is the gluten immunogen IQ peptide assessment, which is a stool test. That is more of a point of care test to assess presence and concentration of gluten peptides in the stool. It's only a single time point assessment. So that is its main limitation, but it can give you a sense of whether gluten has been ingested. Um There is no other non invasive measure of adherence available Currently. Recent large scale STIs systemic review of 49 pediatric studies cited that adherence rates were between 23 and 98 over time. There's been no increase in rate of endurance over time, despite the improvement in accessibility. Some of the barriers that have been noted are taste and lack of availability of foods, higher expenses for gluten free alternatives, parental knowledge seemed to play a role in the adherence membership to groups or societies and close physician follow up barriers that seem to be noted were misunderstandings about the disease, difficulty in educating others. Um And adolescence complications of untreated celiac disease include persistent gi symptoms, risk of developing other autoimmune diseases. In some rare cases, intussusception has been seeing, do do the intestinal inflammation, osteopenia and osteoporosis. Uh Refractory celiac disease is where the inflammation too trigger no longer requires gluten presence for celiac inflammation to persist. And this is seen often in the middle aged population that have not been a adherent to their diet. Uh and then cancer risks of course exist, such as the inter apathy associated T cell lymphoma. Um and other cancers like non Hodgkin's on them. And this shows an increased overall odds ratio for the inter apathy associated to cell lymphoma. There's also an elevated mortality rate that has been shown in diagnosed patients who chose not to follow the diet. There was this X fold increase in the systemic mortality rate and undiagnosed patients. Subjects who had elevated anti TTG had a significantly increased mortality rate Up to three times. Um Mostly due to intestinal cancers. Follow up mortality. Studies indicate no change, unfortunately, into the systemic mortality rate in recent years, which of the following statements about the gluten free lifestyle is false. Patient compliance is a concern. Sources of gluten are always easily detected. Individuals with celiac disease require ongoing education and support individuals with celiac disease, and their families should be encouraged to participate in support or advocacy groups. Yes, very true. So you guys did. Great sources of gluten are always uh easily detected. Is absolutely false. Yeah. Uh So what is gluten free? The F. D. A. Labelling standards were determined in 2004 with the Food Allergen labelling and Consumer Protection Act. It permitted the voluntary use of gluten free on packaged goods. So it's really only for packaged goods uh and voluntary meaning they can, if they want to uh get the their food product, test it, It has to be an official test. A sandwich Eliza test has a cut off of uh sensitivity of 20 parts per million of gluten. Um And so uh those that have the particular label which there are currently in a transition phase of this certified gluten free to this certified gluten free label um have been tested through the FDA protocol. The gluten free diet is costly, complex and can be challenging uh and requires strict avoidance of these sources of wheat. Right and barley, as well as cross contamination. The gluten free diet has many benefits for celiac patients that are seen in early medium and long term uh stages. In the early stages. Some of the G. I. Symptoms are noted to be reduced. Um There are increased food costs that are often brought up well being, is often improved but may also be impaired. Um And there's food related anxiety that seems to occur and so requires a lot of uh kind of counseling through that. In the medium term, what we see is a lot of the deficiencies are corrected uh And we start seeing some symptom response in some of the non G. I. Sort of symptoms such as headaches or joint pains or fatigue or kicker sores. Many often at that point start regaining their weight. Um In the long term we do note some improvement in bone health. Uh So we do try to monitor that. Um There is a decreased fracture risk associated with that. Um And of course the uh more remote kind of long term issues, there's decreased risk that has been shown in long term studies for cancer lymphoma, increased survival rates. The unfortunate side effects are the weight gain that sometimes seen um and needs to be also counseled with uh trying not to replace every gluten product with a gluten free product as these are often double and calories and social restrictions and isolation. Um is often a discussion point with with our adolescence. A common discussion point with patients include how much gluten is safe. So in uh controlled studies it was seen that 10 mg of gluten was sufficient to cause endoscopy diagnosed intestinal inflammation. Uh and so this remains a standard 10 mg. Uh And this is a in this website, which I think is on the on the last page as well, which I'll share with you uh shows a visual approximation of what 10 mg of gluten can look like compared to quarter the role of the dietician is crucial in monitoring and reinforcing the diet as this is really the only current treatment for this chronic condition. The dietician address is um the psycho social status and helps with counseling. Um And we also have a social worker that follows up with patients and does some screening uh as well as assist with financial constraints and family support. I'll be routinely monitor a nutritional status and review common sources of cross contact, which is quite detailed. It can be even in uh fields where brains are grown in adjacent fields, uh factories where processed foods can sometimes cross contaminate uh and at home shared toasters, cutting boards, etcetera. As well as restaurants where serving utensils and food handling can be a common source of cross contamination. Gluten-related disorders has been the overarching um kind of classification system described in 2012 by uh anna's a pony. Um They they attempted to describe the autoimmune portion, which is what we've discussed already uh from allergy and then the non autoimmune or non allergic groups. Um So I will talk a little bit about this as well as us. We allergy is an aiga mediated process. It's primarily directed towards the wheat proteins and the Emily strips and inhibitors that are in wheat. And these are not necessarily in other grains like rye or barley. Although there can be cross reactivity. Uh in wheat allergy, you have to teach to sell response that leads to L. Four, L five and L. 13. They will have local manifestations as well as severe uh with the potential for severe systemic symptoms as well. So vomiting abdominal pain but also to carry a NGO diem a handful axis. Uh This is uh worked up typically by the allergist. Um and some patients carry a EpiPen. It's quite rare in comparison to celiac disease, bakers. Asthma is a type of wheat allergy where inhaled we leads to uh asthma symptoms and uh we dependent exercise induced anaphylaxis is uh uh also fairly rare condition, but it is sometimes identified if there's index of suspicion where there's ingestion of wheat and uh followed by mild exercise that leads to an anaphylactic reaction. Uh So the dose of the protein androgen does play a role. The tests uh that are done are to look for specific I. G. Against wheat and specific wheat allergens, as well as a in office placebo controlled. We exercise challenge done by the allergists. Non celiac gluten sensitivity has uh I. B. S. Like symptoms that occur after ingestion of gluten or wheat hovering. This condition, they have negative allergy test to eat negative celiac serology. Uh normal histology, though occasionally have anti glide, an antibody positive. There are clinical symptoms that overlap with celiac disease and wheat allergy. Uh In this condition there is resolution with a gluten free diet and uh confirmatory diagnosis is with a double blind placebo controlled diet. There is some suspect suspicion that it is a fod map sort of response to week through towns which are uh as wheat has a tremendous amount of carbohydrate fraction in it. Um and so may trigger a gas production through that. The gluten free search trend is very popular as you can see, it's very sustained uh and this is a google search term and it can tell you that overall gluten free has been searched several times more than celiac disease, which is the orange line. And so the general population is very interested. The gluten free diet uh is thought to be healthy and without a downside. Is that fact or fiction? We say it's false. And the reason is only 5% of gluten free breads were fortified with all four mandatory fortification nutrients such as calcium, iron, nice and and diamond. 9% of gluten free bread products were fortified with three of those these micronutrients And 28% were fortified with two. Uh the other belief as gluten is toxic, that too is false. It is a important protein in our diet and provides essential nutrients and immuno assets. A gluten free diet is appropriate for first degree family members and for infants at risk for developing celiac disease. Also false as it can sometimes mask the development of celiac disease. So take home points at whom to screen screen all first degree family members. Uh Screen down syndrome type one diabetics, Hashimoto's turner syndrome, iron deficiency anemia and those with persistently elevated liver enzymes. How do you screen the T. T. G. I. G. A. And total I. G. A. The Children less than two would also need the G. P. I. G. For I. J. Deficient. The TTG is recommended. And if you do have a positive screen test result, please refer to gI before having them start a gluten free diet to confirm diagnosis. Long term follow up is a A challenge where up to 50% have been shown to be lost. To follow up. We recommend annual or twice yearly routine monitoring as this has shown to be good for adherence to the diet and for long term morbidity and mortality risks. Dieticians and psychologists led celiac clinics have shown to be the most helpful and reinforcing endurance. There is no single validated tool to measure this. Uh and we know poor adherence leads to poor growth outcomes. So are open questions which I've mentioned previously, uh how to best follow up celiac disease patients. This remains open how many have persistent villus atrophy. Uh and what is the morbidity risk related to this? Um The rules of medical therapy, there's many drugs um and therapeutics in trials um in the adult population and potential in the pipeline as well as well as other alternative complementary strategies uh such as probiotics etcetera. This is um U C. S F pediatric gi Yeah. Team. And how to refer. Mm. Mm. Yeah