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This article appeared in the Summer 2007 edition of Celiac.com's Scott-Free Newsletter. This question, “how early can you diagnose celiac disease?” is a major concern for both parents and paediatricians. This is because, like many diseases, celiac disease comes on slowly. This means that it can take a long time to make the diagnosis. Celiac disease can develop slowly? Yes, celiac disease can develop very slowly. The symptoms can be subtle. It is a progressive disease. When you are first born, you cannot have celiac disease as you have never been exposed to gluten. However, if you have the right genetic make up (that is you have the celiac gene) and the right environmental circumstances (eating gluten and getting gut inflammation), then celiac disease can develop. Finding tissue damage Celiac disease is a condition that is recognised when you get damage to your small bowel tissue. This damage is triggered by gluten. The standard way to detect this tissue damage is by taking a gut biopsy of the small bowel skin (also called the mucosa). This is done by the technique of upper endoscopy whilst under an anaesthetic. Tiny fragments of gut tissue are snipped off with a pair of forceps. This tissue is then sent to a pathology lab. The lab people (histologists) look down their microscopes at this tissue sample. They are looking for the gut damage called villous atrophy which is characteristic of disease. Early antibody changes – IgG-gliadin Importantly, long before the tissue becomes obviously damaged by gluten, your body can begin to react to the gluten in your diet. An early sign of a gluten immune reaction is that your body produces antibodies to the gluten in your diet. This can be seen in a blood test that looks for an antibody called the IgG-gliadin antibody (also known as anti-gliadin-antibody). Also the IgA-gliadin antibody can develop at this time. Even in these early stages of gluten reactions (before the development of any gut damage of celiac disease), you or your child can be feeling unwell. Many of the symptoms of celiac disease can be recognized in these early stages. This is before the tissue damage can be seen by the histologist. The blood test to look for tissue damage is called the tissue transglutaminase antibody (abbreviated as tTG). Early bowel damage cannot be seen The next thing to happen is that the tissue in the small bowel gets slightly injured but not enough to be identified by the histologist. However, such damage can be shown by an electron microscope. This early damage can also be detected by the presence of the tTG antibody. Usually, when the tTG blood test goes up, then this is an indication to do the endoscopy and look for any tissue damage. However, early in the progression of celiac disease, this damage may not show up by conventional methods. This means that the small bowel biopsy and the histology results are good for confirming celiac disease, but they cannot rule it out. To act or to wait? In my experience, I have seen a number of children develop celiac disease whilst I have watched and waited. While we doctors wait and see if the gut will become progressively damaged, these children will continue to experience their gut symptoms and they may not be growing so well. We doctors are waiting to make a certain diagnosis of celiac disease. We want to repeat their blood tests and do another endoscopy. Is this reasonable? Experience has changed my mind. I have come to the conclusion that this is not an appropriate way to deal with these children. Currently, most medical specialists are adamant. They will not make a diagnosis of celiac disease until the histologist can confirm the typical tissue damage. How long can you wait? I have given up the “wait and see” approach. I act. I carefully scrutinize the symptoms and the blood test results - the gluten antibodies (IgG-gliadin) and tissue damage antibody (tTG) levels. I may organise an endoscopy test. If these findings suggest the development of celiac disease, then I make a pre-emptive diagnosis of “early celiac disease”, often before the gut gets badly damaged. I give these children a trial of a gluten-free diet – I see what their clinical response is. Pleasingly, most get completely better! If they get better, then they want to stay gluten-free. The problem is that the diagnosis of celiac disease currently hinges on the abnormal appearance of the small bowel. This damage can take years to develop. The main argument against my approach is that if you do not have a “definite” diagnosis of celiac disease, then you cannot advise a gluten-free diet for life. In my opinion, the decision to go on a gluten-free diet is not a black and white choice. For children, I give them the option of a gluten-free diet early in their disease. Let them feel well. Let them grow properly. Later, as an adult, they can challenge their diagnosis and have a formal gluten challenge when they understand the issues. Conclusion – my approach As you can see, it is difficult to say how early you can diagnose celiac disease. It is my practice to carefully assess children regarding their symptoms, their antibody levels, their genetic status and their endoscopy results (if appropriate). I do not think it is logical to leave children with significant symptoms waiting for the small bowel damage to eventually occur. Indeed, I think that these long delays in treatment are inhumane. Postponement of a gluten-free diet will cause these children to suffer ongoing symptoms. Worse, they can have growth failure, from which they may not recover. My approach is to put these children on a gluten-free diet early. I watch and see if thy have a clinical response: if they get better. The evidence shows that you cannot rely entirely on the small bowel biopsy for your diagnosis of celiac disease. These children can have a gluten challenge later in their lives. The onset of celiac disease is progressive. Why wait until the bitter end before going gluten-free? The onset of celiac disease is progressive. Why wait until the bitter end before going gluten-free? You can find out a lot more from my webpage: www.doctorgluten.com

This article originally appeared in the Winter 2004 edition of Celiac.com's Scott-Free Newsletter. Transcript of a talk given by Kenneth Fine, M.D. to the Greater Louisville Celiac Sprue Support Group––transcribed by Marge Johannemann; Edited by Kelly Vogt. Celiac.com 03/04/2004 - Gluten sensitivity is the process by which the immune system reacts to gluten contained in wheat, barley, rye, and oats. The reaction begins in the intestine because that is where the inciting antigen, gluten, is present (from food). When this immunologic reaction damages the finger-like surface projections, the villi, in the small intestine (a process called villous atrophy), it is called celiac disease (or sometimes celiac sprue or gluten-sensitive enteropathy). The clinical focus of gluten-induced disease has always been on the intestine because that is the only way the syndrome was recognized before screening tests were developed. The intestinal syndrome consists mainly of diarrhea, gas, bloating, nausea, vomiting, fat in the stool, nutrient malabsorption, and even constipation. Although the small intestine is always the portal of the immune response to dietary gluten, it is not always affected in a way that results in villous atrophy. Even though recent research has shown that celiac disease is much more common than previously suspected, affecting 1 in 100-200 Americans and Europeans, past and emerging evidence indicates that it accounts for only a small portion of the broader gluten sensitive clinical spectrum (often referred to as the “Tip of the Gluten Sensitive Iceberg”). With better understanding of how gluten triggers immune and autoimmune reactions in the body under the control of various genes, and advancing techniques of detecting these reactions, it is becoming apparent that the majority of the gluten sensitive population (the submerged “mass of the iceberg”) do not manifest villous atrophy in its classic, complete form and therefore do not have celiac disease. In these non-celiac, gluten sensitive individuals, the brunt of the immune reaction either affects the function of the intestine, causing symptoms without structural damage, affects other tissues of the body (and virtually all tissues have been affected in different individuals), or both. This is important because the commonly used diagnostic tests of clinically important gluten sensitivity (blood tests for certain antibodies and intestinal biopsies) are only positive when villous atrophy of the small intestine is present. But if only a small minority of gluten sensitive individuals actually develop celiac disease, the majority, who have not yet or may never develop villous atrophy, with or without symptoms, can remain undiagnosed and untreated for years. This can result in significant immune and nutritional consequences, many of which are irreversible even after treatment with a gluten-free diet. Some of these disorders include loss of hormone secretion by glands (hypothyroidism, diabetes, pancreatic insufficiency, etc), osteoporosis, short stature, cognitive impairment, and other inflammatory bowel, liver, and skin diseases, among others. Only with early diagnosis, can these problems be prevented or reversed. I am here to report on a scientific paradigm shift regarding early diagnosis of gluten sensitivity based on about 30 years of medical research by myself and others. My message is that earlier and more inclusive diagnosis of gluten sensitivity than has been allowed by blood tests and intestinal biopsies must be developed to prevent the nutritional and immune consequences of long-standing gluten sensitivity. Imagine going to a cardiologist because your blood pressure is high or you're having chest pain, and the doctor says he is going to do a biopsy of your heart to see what is wrong. If it ‘looks' O.K., you are told you have no problem and no treatment is prescribed because you have not yet had a heart attack showing on the biopsy. You would not think very highly of the doctor utilizing this approach because, after all, isn't it damage to the heart that you would want to prevent? But for the intestine and gluten sensitivity, current practice embraces this fallacious idea that until an intestinal biopsy shows structural damage, no diagnosis or therapeutic intervention is offered. This has to change now because with newly developed diagnostic tests, we can diagnose the problem before the end stage tissue damage has occurred, that is “before the villi are gone,” with the idea of preventing all the nutritional and immune consequences that go with it. There are many misconceptions regarding the clinical presentation of gluten sensitivity or celiac disease: For example, that you cannot be gluten sensitive if you have not lost weight, are obese, have no intestinal symptoms, or are an adult or elderly. However, the most widely held and clinically troublesome misconception is that a negative screening blood test, or one only showing antigliadin antibodies (without the autoimmune antiendomysial or anti-tissue transglutaminase antibody) rules out any problem caused by gluten at that time or permanently. For some reason, the high “specificity” of these blood tests has been tightly embraced. Specificity means if the test is positive, you surely have the disease being tested for with little chance that the positive is a “false positive.” But sadly, a negative test does not mean you do not have the problem. This is the biggest pitfall of all because the only thing a very specific test, like blood testing for celiac disease, can do is “rule in” the disease; it can not “rule it out.” If you've got very far advanced and/or long-standing celiac disease, it is likely that the test will be positive. However, several studies have now revealed that it is only those with significant villous atrophy of the small intestine who regularly show a positive antiendomysial or anti-tissue transglutaminase antibody, the specific tests relied upon most heavily for diagnosis of gluten-induced disease. When there was only partial villous atrophy, only 30% had a positive test. More disturbing perhaps, were the results with respect to screening first degree relatives of celiacs with blood tests. Despite some biopsy-proven early inflammatory changes in the small intestine but without villi damage, all blood tests were negative. For some reason, it's been perfectly acceptable to celiac diagnosticians that a patient must have far advanced intestinal gluten sensitivity, i.e., villous atrophy, to be diagnosed and a candidate for treatment with a gluten-free diet. That means from the specific testing standpoint, there's never (or rarely) a false positive. But what about the larger majority of gluten-affected people who do not presently have or may never get this end stage, villous atrophic presentation? They are out of luck as far as blood testing is concerned. So the fact is that we have erroneously relied on specificity (always picks up gluten sensitivity after it has caused villous atrophy, never having a false positive) instead of sensitivity (doesn't miss gluten sensitive people even though they might be picked up early, even before full-blown celiac disease develops). Would a test relying on specificity rather than sensitivity be good enough for you, or your children? Consider the risk of not getting an early diagnosis versus going on a gluten free diet a few months or years prematurely. While I do not recommend anyone to have a biopsy (especially children) for diagnosis because of the shortcomings and invasive nature of this technique, I particularly do not want someone to have a biopsy showing villous atrophy, since by that time, associated bone, brain, growth, and/or gland problems are all but guaranteed. And here is another related problem: You have a positive blood test, but, if a small bowel biopsy comes back normal or nearly normal, you are told that the blood test must have been a “false positive” and that gluten is not your problem. Would you believe that, especially in light of the fact that most such people would have gotten the blood test in the first place because of a specific symptom or problem? Let's hope not. All that means (positive blood test, negative biopsy) is that the gluten sensitivity (evidenced by antibodies to gliadin in the blood) has not yet damaged your intestines severely. Evidence of this comes from a study that I performed. We tested 227 normal volunteers with blood tests for celiac disease. Twenty-five of these people (11%) had either antigliadin IgG or IgA in their blood versus only one (0.4%) that had antiendomysial, anti-tissue transglutaminase, and antigliadin IgA in the blood. So for every one person in a population that has the antibodies that have 100% specificity for celiac disease of the intestine (antiendomysial and anti-tissue transglutaminase), there are 24 that have antibodies to gliadin that may not have celiac disease. So what is going on with the 11% with antigliadin antibodies in blood? Are these false positives (rhetorically)? You're telling me that there is a disease called celiac disease and it is associated with antibodies to gliadin in the blood and sometimes it damages the intestine? But people with antigliadin antibody in their blood but no other antibodies do not have a clinically significant immunologic reaction to gluten? Do you see the problem? How can 11% be false positives? What about the 89% with none of these antibodies? You cannot equate having no antibodies at all (a negative test) with having antigliadin antibodies alone. If you have antibodies to gliadin, something is going on here. Where there's smoke there's fire. The purpose of this study was to test this hypothesis: That an antigliadin antibody alone does indicate the presence of an immune reaction to gluten that may be clinically important. Using tests for intestinal malabsorption and abnormal permeability (i.e., tests of small bowel function, unlike a biopsy which says nothing about function), we found that 45% of people with only an antigliadin IgG or IgA antibody in blood (without either antiendomysial or anti-tissue transglutaminase antibody) already had measurable intestinal dysfunction, compared to only 5% of people with no antibodies to gliadin in their blood. When we did biopsies of these people's intestines, none had villous atrophy with only a few showing some early inflammation. Thus, having an antigliadin antibody in your blood does mean something: That there is nearly a 1 in 2 chance that functional intestinal damage is already present even though it may not be visible structurally at the resolution attained by a light microscope assessment of a biopsy. As mentioned at the outset, not all gluten sensitive individuals develop villous atrophy. Evidence for this has been around for a long time. In 1980, a medical publication titled “Gluten-Sensitive Diarrhea” reported that eight people with chronic diarrhea, sometimes for as long as 20 years, that resolved completely when treated with a gluten-free diet, had mild small bowel inflammation but no villous atrophy. In 1996 in a paper called “Gluten Sensitivity with Mild Enteropathy,” ten patients, who were thought to have celiac disease because of a positive antiendomysial antibody blood test, had small bowel biopsies showing no villous atrophy. But amazingly, these biopsies were shown to react to gluten when put in a Petri dish, proving the tissue immunologically reacted to gluten (which was likely anyway from their positive blood tests). Two other reports from Europe published in 2001 showed gluten sensitivity without villous atrophy (and hence without celiac disease). In one of these studies, 30% of patients with abdominal symptoms suggestive of irritable bowel syndrome having the celiac-like HLA-DQ2 gene but no antibodies to gliadin in their blood, had these antibodies detected in intestinal fluid (obtained by placing a tube down into the small intestine). Thus, in these people with intestinal symptoms, but normal blood tests and biopsies, the antigliadin antibodies were only inside the intestine (where they belong if you consider that the immune stimulating gluten also is inside the intestine), not in the blood. This is the theme we have followed in my research, as we are about to see. More proof that patients in these studies were gluten sensitive came from the fact that they all got better on a gluten-free diet, and developed recurrent symptoms when “challenged” with gluten. Although the gluten-sensitive patients in these studies did not have the villous atrophy that would yield a diagnosis of celiac disease, small bowel biopsies in many of them showed some, albeit minimal, inflammatory abnormalities. Yet, when a symptomatic patient in clinical practice is biopsied and found to have only minimal abnormalities on small bowel biopsy, clinicians do not put any stock in the possibility of their having gluten sensitivity. As much as I would like to take credit for the concept, you can see from these studies that I did not invent the idea that not all gluten sensitive patients have villous atrophy. It has been around for at least 23 years, and reported from different parts of the world. For many years there has also been proof that the intestine is not the only tissue targeted by the immune reaction to gluten. The prime example of this a disease called dermatitis herpetiformis where the gluten sensitivity manifests primarily in skin, with only mild or no intestinal involvement. Now from more recent research it seems that the almost endless number of autoimmune diseases of various tissues of the body also may have the immune response to dietary gluten and its consequent autoimmune reaction to tissue transglutaminase as the main immunologic cause. A study from Italy showed that the longer gluten sensitive people eat gluten, the more likely they are to develop autoimmune diseases. They found that in childhood celiacs, the prevalence of autoimmune disease rose from a baseline of 5% at age two to almost 35% by age 20. This is a big deal if you think of how much more complicated one's life is when one is both gluten sensitive AND has an additional autoimmune disease. So preventing autoimmune disease is one very important reason why early diagnosis and treatment of gluten sensitivity is important. Early diagnosis before celiac disease develops also holds the potential of preventing other clinical problems such as malnutrition, osteoporosis, infertility, neurologic and psychiatric disorders, neurotube defects (like spina bifida) in your children, and various forms of gastrointestinal cancer. Another reason for early diagnosis and treatment is very straightforward and that is because many gluten sensitive individuals, even if they have not yet developed celiac disease (villous atrophy), have symptoms that abate when gluten is removed from their diet. Furthermore, from a study done in Finland, a gluten sensitive individual who reports no symptoms at the time of diagnosis can improve both psychological and physical well-being after treatment for one year with a gluten-free diet. Despite the common sense and research evidence that early diagnosis of gluten sensitivity offers many health advantages over a diagnostic scheme that can only detect the minority and end-stage patients, until now, the limitation was still in the tests being employed. As mentioned above, the main tests used for primary (before symptoms develop) and secondary (after symptoms develop) screening for celiac disease, blood tests for antigliadin and antiendomysial/anti-tissue transglutaminase antibodies, are only routinely positive after extensive damage to intestinal villi. As shown in a 1990 publication, this is because unless you have full blown, untreated celiac disease, the IgA antibodies to gliadin are only INSIDE the intestine not in the blood. Measuring antigliadin antibody in blood and intestinal fluid (obtained by the laborious technique of having research subjects swallow a long tube that migrates into the upper small intestine), researchers found that in untreated celiacs, antigliadin antibody was present in the blood and inside the intestine, whereas after villous atrophy healed following a year on a gluten-free diet, the antigliadin antibody was no longer in the blood but was still measurable inside the intestine in those with ongoing mild inflammation. An important conclusion can be drawn from these results, as these researchers and myself have done: Gluten sensitive individuals who do not have villous atrophy (the mass of the iceberg), will only have evidence of their immunologic reaction to gluten by a test that assesses for antigliadin IgA antibodies where that foodstuff is located, inside the intestinal tract, not the blood. This makes sense anyway, because the immune system of the intestine, when fighting an antigen or infection inside the intestine, wages the fight right in that location in an attempt to neutralize the invading antigen, thereby preventing its penetration into the body. It does this with T cells on the surface of the epithelium, the intraepithelial lymphocytes, and with secretory IgA made with a special component called secretory piece that allows its secretion into the intestine. The excellent English researchers that made the discovery that they could detect the immunologic reaction to gluten inside the intestine before it was evident on blood tests or biopsies knew it was a breakthrough, testing it many times over in different ways, and further extending the clinical spectrum of gluten-induced disease to include a phase before the villi are damaged, so-called “latent celiac sprue”. Furthermore, they developed this technique of assessing the intestinal contents for antigliadin antibodies into what they viewed as a “noninvasive screening test for early or latent celiac sprue” (what others and I would simply call “gluten sensitivity”). However, this was not exactly noninvasive, nor was it simple. It still required the patient to swallow a tube, followed by a complete lavage of all their gastrointestinal contents with many gallons of nonabsorbable fluid that had to be passed by rectum and collected into a large vat to be analyzed for the presence of antigliadin antibodies. While this was indeed a conceptual breakthrough, it practically went unnoticed by the medical community because the cumbersome procedure of washing out the intestine just could not be done in a normal clinical setting. To this day, I am not sure how many people even know that it was not me, but rather this well known celiac research group, led by the late Dr. Anne Ferguson, who pioneered the assessment of the intestinal contents as a viable and more sensitive source of testing material for the early reactions of the immune system to gluten. What we did in my research was to refine and simplify the method of collecting and measuring these intestinal IgA antigliadin antibodies before they can be detected in blood. That is, instead of washing out the antibodies from the intestine, we allow them to be excreted naturally in the stool (feces). And so with that idea, and our ability to measure these antibodies in stool, as others before us had done for fecal IgE antibodies directed to food antigens, our new gluten (and other food) sensitivity stool testing method was born. It was actually my research of microscopic colitis that led me to discover that stool analysis was the best way of assessing for gluten sensitivity before celiac disease develops. Microscopic colitis is a very common chronic diarrheal syndrome, accounting for 10% of all causes of chronic diarrhea in all patients, and is the most common cause of ongoing chronic diarrhea in a treated celiac, affecting 4% of all celiac patients. However, from my published research, despite the presence of the celiac HLA-DQ2 gene in 64% of patients with microscopic colitis, very few get positive blood tests or biopsies consistent with celiac disease. Yet, small bowel biopsies revealed some degree of inflammation sometimes with mild villous blunting in 70% of cases. According to the facts and previously discussed shortcomings of celiac blood tests, antibodies to gliadin are unlikely to be detected in the blood in these patients because they lack villous atrophy. So negative blood tests for antigliadin antibodies per se did not, in my mind, rule out the possibility that these patients with microscopic colitis, a disease that under the microscope looks like celiac disease (but of the colon), and that affects many celiac patients, were not gluten sensitive themselves. But as Dr. Ferguson's research revealed, these antibodies might be detectable inside the intestine. And since we surely were not going to perform that cumbersome intestinal lavage test in my patients, we decided to see if we could find these antibodies in the stool as a reflection of what is coming through the intestine. Here's the first set of data that we found showing the superior sensitivity of stool testing versus blood tests for antigliadin IgA antibodies. In untreated celiac disease patients, we found a 100% positivity in the stool versus only 76% in blood. In hundreds of microscopic colitis patients since tested, only 9% have antigliadin antibody in blood but 76% have it in stool. And the same is true of 79% of family members of patients with celiac disease; 77% of patients with any autoimmune disease; 57% of people with irritable bowel syndrome-like abdominal symptoms; and 50% of people with chronic diarrhea of unknown origin, all of whom have only about a 10-12% positivity rate for blood tests (like normal volunteers). Thus, when you go to the source of production of these antibodies for testing, the intestine, the percentage of any population at a higher than normal genetic and/or clinical risk of gluten sensitivity showing a positive antigliadin stool test is 5 to 7.5 times higher than would be detected using blood tests. In normal people without specific symptoms or syndromes, the stool test is just under 3 times more likely to be positive than blood (29% vs. 11%, respectively). That's a lot more people reacting to gluten than 1 in 150 who have celiac disease. 29% of the normal population of this country, almost all of whom eat gluten, showing an intestinal immunologic reaction to the most immune-stimulating of dietary proteins really is not so high or far fetched a percentage, especially in light of the fact that 11% of them display this reaction in blood, and 42% carry the HLA-DQ2 or DQ8 celiac genes. Why is this so important? Because some people with microscopic colitis never get better when they're treated, and most autoimmune syndromes only progress with time, requiring harsh and sometimes dangerous immunosuppressive drugs just for disease control. If the immune reaction to gluten is in any way at the cause of these diseases as research suggests, and if we had at our disposal a sensitive test that can diagnose this gluten sensitivity without having to wait for the intestinal villi to be damaged, then treatment with a gluten free diet might allow the affected tissues to return to normal or at least prevent progression. We now have that test in fecal antigliadin antibody. Just a few weeks ago we completed the first follow-up phase of our study: What happens when a gluten sensitive person without villous atrophy goes on a gluten-free diet for one or two years. While I am still gathering and analyzing the data, most of the subjects reported a much improved clinical status (utilizing an objective measure of symptoms and well being). Not everybody gets well, because sadly not everyone stays on a gluten-free diet (as they sometimes admit on the surveys). Some people have the misconception that if they don't have celiac disease, but “I just have gluten sensitivity” then maybe they do not have to be strict with their gluten elimination diet. I do not think that is the case. Although a gluten free diet is like anything: Less gluten is not as damaging as more gluten, but certainly no gluten is optimal if a gluten sensitive person desires optimal health. Of the first 25 people with refractory or relapsing microscopic colitis treated with a gluten-free diet, 19 resolved diarrhea completely, and another five were notably improved. Thus, a gluten-free diet helped these patients with a chronic immune disease of a tissue other than small bowel (in this case the colon), who have been shown to be gluten sensitive by a positive stool test in my lab. The same may be true of patients with chronic autoimmune diseases of any other tissue, but who do not have full-blown celiac disease. Gluten-free dietary treatment, sometimes combined with dairy-free diet as well, has been shown to help diabetes, psoriasis, inflammatory bowel disease, eczema, autism, and others. Thus, my approach (and I believe the most sensitive and most complete approach) for screening for early diagnosis and preventive diagnosis for clinically important gluten sensitivity is a stool test for antigliadin and anti-tissue transglutaminase IgA antibodies (IgG is not detectable in the intestine) and a malabsorption test. The malabsorption test we developed is special, because you no longer have to collect your stool for three days; we can find the same information with just one stool specimen. Stool testing in combination with HLA gene testing, which we do with a cotton-tipped swab rubbed inside the mouth, is the best diagnostic approach available for gluten sensitivity. Who should be screened for gluten sensitivity? Certainly family members of celiacs or gluten sensitive people being at the highest genetic risk. For the most part, all of the following patient groups have been shown to be at higher risk than normal for gluten sensitivity: Chronic diarrhea; microscopic colitis; dermatitis herpetiformis; diabetes mellitus; any autoimmune syndrome (of which there is an almost end-less number like rheumatoid arthritis, multiple sclerosis, lupus, dermatomyositis, psoriasis, thyroiditis, alopecia areata, hepatitis, etc.); Hepatitis C; asthma; chronic liver disease; osteoporosis; iron deficiency anemia; short stature in children; Down's syndrome; female infertility; peripheral neuropathy, seizures, and other neurologic syndromes; depression and other psychiatric syndromes; irritable bowel syndrome; Crohn's Disease; and people with severe gastroesophageal reflux (GERD). Autism and possibly the attention deficit disorders are emerging as syndromes that may improve with a gluten- free (and additionally casein-free) diet. A diagnosed celiac might be interested in our testing to know (after some treatment period no shorter than a year) that there is no on-going damage from malabsorption, for which we have a test. If a celiac is having ongoing symptoms or other problems, a follow-up test should be done just to be sure there's no hidden gluten in the diet, or something else that could be present, like pancreatic enzyme deficiency which often accompanies celiac disease, especially in its early stages of treatment. Historically, with respect to diagnostic methods for celiac disease, from 100 A.D., when celiac disease was first described as an emaciating, incapacitating, intestinal symptom-causing syndrome, to 1950, we had just one diagnostic test: Clinical observation for development of the end stage of the disease. Then in 1940 to 1960, when the discovery of gluten as the cause of celiac disease occurred, the best diagnostic test was removing gluten from the diet and watching for clinical improvement. It was during this period that the 72-hour fecal fat and D-xylose absorption tests were developed as measures of gluten-induced intestinal dysfunction/damage. In the mid- to late1950's, various intestinal biopsy methods were pioneered and utilized, showing total villous atrophy as the diagnostic hallmark of celiac disease. You've heard the intestinal biopsy called the “gold standard”; well as you can see, it is a 50 year-old test, and thus, the “old” standard. It was not until the 1970's and 80's (and improved upon in the 1990's) that blood tests for antigliadin and antiendomysial/anti-tissue transglutaminase were developed, but again these tests like all methods before, can reliably reveal only the “heart attack” equivalent of the intestinal celiac syndrome: Significant villous atrophy or bad celiac disease. We are in a new century, a new millennium, and I have built upon what my research predecessors have started; mostly on the work of researchers who laboriously put down tubes and sucked out intestinal fluid for testing for antigliadin antibody when it was not present in blood. We now know that a stool test for antigliadin antibody is just as good and much simpler. The wide-reaching ramifications of knowing that so many more people and patients are gluten sensitive than have ever been previously known has led me to assume a professional life of medical public service. To do so, I started a 501©3 not-for-profit institute called the Intestinal Health Institute, have brought these new diagnostic tests to the public on the internet (at http://www.enterolab.com), and volunteer my time helping people with health problems by email and by lecturing. With greater awareness and education of both the public and medical community that early diagnosis of gluten sensitivity can be achieved before the villi are gone, more of the gluten sensitive iceberg will be diagnosed and treated early, leading to far fewer gluten-related symptoms and diseases than has ever been experienced before. Dr. Fine has been an intestinal researcher and an academic and clinical gastroenterologist for 15 years. He is the Director of The Intestinal Health Institute and The www.EnteroLab.com Clinical Laboratory in Dallas Texas.

Celiac.com 10/05/2015 - Studies on early life infections and risk of later celiac disease (celiac disease) are inconsistent but have mostly been limited to retrospective designs, inpatient data, or insufficient statistical power. A team of researchers recently set out to determine whether early life infections are associated with increased risk of later celiac disease using prospective population-based data. The research team included K. Mårild, C.R. Kahrs, G. Tapia, L.C. Stene, and K. Størdal. T Division of Epidemiology at the Norwegian Institute of Public Health in Oslo, Norway, the Department of Medical Epidemiology & Biostatistics at the Karolinska Institutet in Stockholm, Sweden, and with the Department of Pediatrics at Østfold Hospital Trust in Fredrikstad, Norway. This study is based on the Norwegian Mother and Child Cohort Study, and includes prospective, repeated assessments of parent-reported infectious disease data up to 18 months of age for 72,921 children born between 2000 and 2009. The team identified celiac disease patients through parental questionnaires and the Norwegian Patient Registry. Logistic regression was used to estimate odds ratios adjusted for child's age and sex (aOR). Their data showed that, over an average follow-up period (ranging from 4.5-14.5 years, and averaging 8.5 years, 581 children (0.8%) were diagnosed with celiac disease. Children with ten or more infections up to age 18 months had a significantly higher risk of later celiac disease, as compared with children with four or less infections (aOR=1.32; 95% confidence interval (CI)=1.06-1.65; per increase in infectious episodes, aOR=1.03; 95% CI=1.02-1.05). The aORs per increase in specific types of infections were as follows: upper respiratory tract infections: 1.03 (95% CI=1.02-1.05); lower respiratory tract infections: 1.12 (95% CI=1.01-1.23); and gastroenteritis: 1.05 (95% CI=0.99-1.11). The results were largely unchanged even after making additional adjustments for maternal celiac disease, education level, smoking, birth weight, prematurity, infant feeding practices, birth season, and antibiotic treatment. This is the first large-scale population-based cohort study of this association. These results are in line with earlier studies that suggest that early life infections may have a role in celiac disease development. However, further study is needed to fully eliminate surveillance bias and reverse causation as non-causal explanations for this association. Source: Am J Gastroenterol. 2015 Sep 8. doi: 10.1038/ajg.2015.287.

Celiac.com 04/08/2015 - The goal of growth-monitoring programs in children is the early detection of any disorders that affect growth. Celiac disease is under-diagnosed in kids whose symptoms include faltering linear growth, short stature, or poor weight gain. A team of researchers recently set out to develop new evidence-based parameters for screening for growth disorders and to evaluate the performance of these cutoffs among children with celiac disease measured regularly in a nationwide growth screening program. The research team included Antti Saari, MD; Samuli Harju, BM; Outi Mäkitie, MD, PhD; Marja-Terttu Saha, MD, PhD; Leo Dunkel, MD, PhD; and Ulla Sankilampi, MD, PhD. They are variously affiliated with the Department of Pediatrics, School of Medicine, University of Eastern Finland, Kuopio, the Children’s Hospital at the University of Helsinki and Helsinki University Hospital in Helsinki, Finland, the Folkhälsan Research Centre in Helsinki, Finland, the Department of Molecular Medicine and Surgery at the Karolinska Institute in Stockholm, Sweden, the Department of Pediatrics at Tampere University Hospital in Tampere, Finland, the Centre for Endocrinology at the William Harvey Research Institute of Barts and the London School of Medicine and Dentistry at Queen Mary University of London in London, England and the Department of Pediatrics at Kuopio University Hospital, Kuopio, Finland. Their longitudinal retrospective study included growth data of healthy children from primary health care providers, and children with celiac disease from primary health care, and three university hospital outpatient clinics in Finland, Kuopio University Hospital, Tampere University Hospital, and Helsinki University Hospital, from January 1, 1994, to April 9, 2009. Children of the reference population were under 20 years of age, while children in the celiac disease group were between 1 and 16 years of age. In the reference population of 51,332 healthy children, the team screened according to five age- and sex-specific growth parameters: height standard deviation score and body mass index standard deviation score, distance from the population mean, distance from target height, change in height standard deviation score, and change in body mass index standard deviation score. They evaluated these parameters and their combination in 177 children with celiac disease by analyzing longitudinal growth data from birth until diagnosis of celiac disease. They measured the screening accuracy for detecting abnormal growth in children with celiac disease by using receiver operating characteristics analysis expressed as the area under the curve. When the team screened using the combination of all 5 growth-screening parameters, they detected celiac disease with good accuracy ([95% CI] = 0.88 [0.84–0.93] for girls and 0.84 [0.77–0.91] for boys). When they set the screening specificity at 90%, they saw abnormal growth in 57% of the girls with celiac disease, and in 48% of the boys with celiac disease for two years prior to diagnosis. This study shows that most kids with celiac disease experience faltering growth prior to diagnosis. An effective growth-monitoring program could have detected celiac disease in these kids several years earlier. By using several growth-monitoring parameters in combination, preferably using computerized screening algorithms that are integrated into an electronic health record system, researchers can improve sreening accuracy. Source: JAMA Pediatr. 2015;169(3):e1525. doi:10.1001/jamapediatrics.2015.25.

10/05/2009 - Pregnant women with celiac disease suffer early pregnancy loss more often than women without celiac disease. A team of Italian researchers recently set out to look at a possible role of genetic pro-thrombotic variants in early pregnancy loss in women with celiac disease. The research team was made up of C. Ciacci, R. Tortora, O. Scudiero, R. Di Fiore, F. Salvatore, and G. Castaldo. The team looked at 39 women with celiac disease, who had experienced at least two early pregnancy losses within the first 3 months of pregnancy, a control group of 72 celiac women with a history of one or more normal pregnancies with no pregnancy loss. Each of the women were enrolled in the study immediately upon diagnosis for celiac disease, whereupon, the researchers obtained a clinical history obtained from each woman. The researchers then screened leukocyte DNA for factor V Leiden (mutation G1691A), factor V R2 (H1299R), factor II (G20210A), methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), beta-fibrinogen (−455 G>A), PAI-1 alleles 4G/5G, factor XIII (V34L), and HPA-1 (L33P). Women with pregnancy losses were notably older (p = 0.002) among the celiacs than in controls. Of the gene variants examined, the allelic frequency of 4G variant of PAI-1, and the frequency of mutant genotypes were significantly more frequent in the group of celiac women with early pregnancy loss (p = 0.00003 and 0.028, respectively). Interestingly, the beta-fibrinogen −455 G>A genotype distribution differs substantially between the two groups, though frequency of the variant allele remains the same. The control group showed more frequent variant genotypes (p = 0.009). Based on these data, the research team believes the 4G variant of the PAI-I gene may predispose some celiac women who carry the gene to early pregnancy loss, though they note that their data should be confirmed on larger populations. Digestive and Liver DiseaseVolume 41, Issue 10, October 2009, Pages 717-720

Celiac.com 01/14/2013 - Sweden has seen a sharp rise in cases of celiac disease in children under two years of age. A research team recently studied the possible connection between early infections and celiac disease, along with their possible role in the explosion of celiac cases in Swedish children. The research team included Anna Myléus, Olle Hernell, Leif Gothefors, Marie-Louise Hammarström, Lars-Åke Persson, Hans Stenlund and Anneli Ivarsson. They are affiliated with the Epidemiology and Global Health, Department of Public Health and Clinical Medicine at Umeå University, Pediatrics unit of the Department of Clinical Sciences at Umeå University, the Immunology unit of the Department of Clinical Microbiology at Umeå University in Umeå, Sweden, and with the International Maternal and Child Health, Department of Women's and Children's Health in Uppsala University in Uppsala, Sweden. The team used a questionnaire to carry out a population-based incident case-referent study. The questionnaire went out to 475 cases and 950 referents, and included questions on family characteristics, infant feeding, and the child's general health. All cases of celiac disease cases were diagnosed before two years of age, and fulfilled the diagnostic criteria of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. The team randomly selected referents, matched by criteria, from the national population register. The final analysis included 373 (79%) cases of confirmed celiac disease and 581 (61%) referents, for a total of 954 children. For each case of celiac disease, the team matched complete information on main variables of interest with one or two referents. The results showed that children who suffered three or more parental-reported infectious episodes, regardless of type of infection, during the first six months of life faced a significantly higher risk for later celiac disease.. This risk remained after the team adjusted for infant feeding and socioeconomic status (odds ratio [OR] 1.5; 95% confidence interval [CI], 1.1-2.0; P=0.014). Infants who had several infectious episodes, and whose parents introduced dietary gluten in large amounts, compared to small or medium amounts, after breastfeeding was discontinued faced an even greater risk (OR 5.6; 95% CI, 3.1-10; P<0.001). This study suggests that children who suffer repeated infections before age two face an increased risk for developing celiac disease later on. The risk was even greater in children who suffered repeated infections and whose parents introduced gluten in large quantities after weening. The team concludes that early infections probably made a minor contribution to the rise in celiac disease cases in Swedish children relative to the amounts of gluten introduced into the children's diets after weening. Source: BMC Pediatrics 2012, 12:194 doi:10.1186/1471-2431-12-194

AUTHORS: Cuoco L; Certo M; Jorizzo RA; De Vitis I; Tursi A; Papa A; De Marinis L; Fedeli P; Fedeli G; Gasbarrini G AUTHOR AFFILIATION: Department of Internal Medicine, Catholic University S.C., Rome, Italy. SOURCE: Ital J Gastroenterol Hepatol 1999 May;31(4):283-7 [MEDLINE record in process] CITATION IDS: PMID: 10425571 UI: 99354303 ABSTRACT: BACKGROUND AND AIMS - Celiac disease is associated with several autoimmune disorders such as insulin-dependent diabetes, Sjogrens syndrome, Addisons disease and thyroid diseases. The aim of our study was to evaluate the prevalence of celiac disease in patients affected by autoimmune thyroid diseases by means of anti-gliadin and anti-endomysial antibodies. PATIENTS: We studied 92 patients affected by autoimmune thyroid diseases (47 chronic autoimmune thyroiditis, 22 Hashimotos thyroiditis and 23 Graves disease). Ninety patients with non autoimmune thyroid disorders (51 multifollicular goitre, 28 solitary nodule and 11 papillary carcinoma) and 236 blood donors also took part in the study as control groups. METHODS: Total serum IgA were measured in all subjects to exclude selective IgA deficiency; then we measured anti-gliadin antibodies and anti-endomysial antibodies. In patients with anti-gliadin/anti-endomysial antibody positivity and/or with haematinic and laboratory signs of malabsorption we carried out gastrointestinal endoscopy with duodenal histological examination. RESULTS: Among the 92 patients with autoimmune thyroid disease, 4 (4.3%) showed anti-gliadin and anti-endomysial positivity and had celiac disease; among the 90 patients with non autoimmune thyroid diseases, 1 (1.1%) had celiac disease; finally, among the blood donors, 1 subject (0.4%) was anti-gliadin-anti-endomysium antibody positive and had celiac disease. Those subjects presenting with only anti-gliadin antibody positivity did not have celiac disease. CONCLUSIONS: These results show that the prevalence of celiac disease in patients with autoimmune thyroid diseases is significantly increased when compared with the general population (p = 0.009) but not with patients affected by non autoimmune thyroid disorders (p = 0.18). We suggest a serological screening for celiac disease in all patients with autoimmune thyroid disease measuring anti-endomysial antibodies, considering that early detection and treatment of celiac disease are effective in preventing its complications.

Celiac.com 06/25/2003 - The following is an abstract of a recent study published in the June edition of the Journal of Association of Physicians of India by Dr. Y.A. Gokhale and colleagues from the Lokmanya Tilak Medical College and General Hospital, Mumbai (Bombay). The researchers conclude that symptomatic osteoporotic patients, especially those with associated anemia, who are younger than 55 years of age should be screened for celiac disease. Here is the abstract: Celiac Disease in Osteoporotic Indians YA Gokhale, PD Sawant, CM Chodankar, ND Desai, MV Patil, S Maroli, MN Patil, NK Hase J Assoc Physicians India June 2003;51:579-584 Abstract: Objective: The aim of the study was to identify the atypical celiac disease (celiac disease) in a cohort of symptomatic osteoporotic patients, younger than 55 years of age and 2) To study associated clinical and laboratory features and outcome with gluten-free diet. Material and Methods: We studied 33 patients (F:M =28:5),mean age 29 years (range 15-52 years) with osteoporosis (WHO diagnostic criteria, T-score less than -2.5 on DEXA scan) from January 2000-June 2002. Serological screening for celiac disease was done by detecting circulating IgA antibodies to tissue transglutaminase by ELISA. Patients with presence of antibodies to transglutaminase were subjected to biopsy from the 2nd part of the duodenum by upper GI endoscopy. The biopsies were reported independently by two pathologists who were blinded for the serology report. Measurement of mucosal thickness, crypts and villi were done with an ocular micrometer. Other parameters like complete hemogram, serum iron, total iron binding capacity (TIBC),calcium profile,25-OH-D, parathyroid hormone (PTH) were evaluated. Assessment of clinical and laboratory parameters was performed within 4-12 weeks of starting gluten-free diet (GFD). Results: Thirteen patients had circulating IgA antibodies to transglutaminase. Intestinal biopsies were performed on 11 patients and were consistent with the diagnosis of celiac disease (total villous atrophy -two, subtotal villous atrophy with crypt hyperplasia -nine). Patients with celiac disease had significant anemia when compared with non-celiac disease osteoporotic patients. Other important observations in these 11 patients were low serum calcium and phosphorus, low 25-OH-D, high PTH. Significant improvement in clinical and laboratory parameters was noted in all patients within 6-12 weeks of starting GFD. Conclusion: Symptomatic osteoporotic patients (younger than 55 years of age) especially with associated anemia should be investigated for celiac disease. Simple measures like omission of wheat from diet (GFD) lead to significant improvement in symptoms within weeks.