Coeliac Disease and gluten sensitivity Coeliac Disease and gluten sensitivityGluten-free dietDiagnosisHistoricalCause Coeliac disease. The top 2 photos show a normal small bowel and the bottom 2 photos show coeliac disease - with loss of villiHow common is coeliac disease? Population screening has shown that 1:85 people have coeliac disease. Many people are unaware of the diagnosis. Symptoms may be severe (such as diarrhoea, bloating, weight loss) but the condition can also be present with no gut symptoms What is gluten sensitivity (where coeliac disease has been excluded or appears unlikely) There is a significant proportion of people who feel better on a gluten-free diet but who do not have coeliac disease (termed non-coeliac gluten sensitivity). The popularity of a gluten-free diet can be partly attributed to "fashion" but there is no doubt that genuine benefits to wellbeing are behind the increased popularity of the diet The challenge to the medical profession is how to understand this benefit and to try to understand the mechanism for this benefit. Coeliac disease is a well understood immune-based condition with a well-defined change in the lining of the small bowel but gluten sensitivity has no agreed definition or tests There may be a genetic basis - people with the susceptibility gene DQ2 may have more gut symptoms and respond to a gluten-free diet. Recent studies have cast doubt on this idea - the benefit of a gluten-free diet for abdominal symptoms may be due to reduction in fermentable carbohydrates and this benefit is the same regardless of DQ2 status. The interpretation of various antibody tests is debated. Tissue transglutaminase (discussed below) suggests coeliac disease. Other less accurate tests probably simply give false positives and are not predictive of a response to a gluten-free diet Hopefully more research will clarify this issue What is the benefit of diagnosing the mild cases of coeliac disease? With better tests and greater awareness amongst doctors and also in the community there are more people who are being diagnosed with coeliac disease. Many of these people could be considered to have mild disease. Most people are pleased with the diagnosis and feel the benefit of the diet. However we also need to consider whether everybody with a positive test found by screening benefits from the diet In a large UK health survey of individuals aged 45-75 years 1.2% had positive endomysial antibodies i.e a diagnosis of coeliac disease. There was no difference between subjects who were antibody positive or antibody negative for a wide range of indicators that were used to measure health and general well-being. The only significant difference was a higher proportion of antibody positive subjects who had anaemia (16% compared with 4%). There was a trend towards lower bone density in those subjects who were antibody positive This study confirms the importance of checking for coeliac disease if there is iron deficiency (+/- anaemia) without any other obvious cause. It is perhaps helpful to use an “iceberg” analogy for coeliac disease with overt severe disease at the top and mild or silent disease forming the majority below sea level. We are diagnosing a lot more people with mild coeliac disease. Also some with "silent" disease. All patients with coeliac disease should attempt to be as gluten-free as possible but it is tempting to be less strict with less severe disease. The reasons to be as careful as possible are discussed below Treatment of coeliac disease The only treatment is a gluten-free diet. There is usually a rapid improvement in symptoms over a few weeks. Continued improvement can occur over the first 6-12 months. If there is not any improvement specialist review is required. Adherence to a gluten-free diet is easier when there is a clear correlation between gluten exposure and abdominal symptoms. This is not always the case. Some people do not observe any direct relationship between inadvertent gluten exposure and symptoms. Adherence to the diet has become easier because of a wide range of commercially available gluten-free foods and the mandatory labelling of foods for gluten content. Helpful advice is available thorough dieticians and through the Coeliac Society of NZ. Dietary supplements are not usually required except during the first 6-12 months if significant nutritional deficiencies are identified. Prompt replacement of vitamin D (if low serum vitamin D) is appropriate. What are the advantages of gluten-free diet when there are no or few abdominal symptoms? There are four main arguments for a gluten-free diet in this situation. You may be surprised by how much better you feel!! That is, there has been an acceptance of a decreased level of well-being and energy levels as part of normality. It is also common to have accepted abdominal bloating and flatulence as normal. Any nutritional deficiency is highly likely to correct on a gluten-free diet without the need for supplements. This includes nutrients that are easily measured (iron, folate, B12, calcium, vitamin D) AND also other nutrients that may be important for well being (but are not easily measured). Osteoporosis is a definite risk with untreated coeliac disease although the fracture risk may not be that large. Bone density does improve significantly on a gluten-free diet. There is an increased risk of some cancers with untreated coeliac disease. This includes two rare cancers - small bowel lymphoma and small bowel adenocarcinoma. This also includes a slightly increased risk for other more common abdominal cancers (stomach / oesophagus / pancreas /bowel). However, the overall cancer risk may not be different (or only marginally elevated). For example some studies show that risk of breast cancer is reduced in coeliac disease (so there are "swings and roundabouts"). The risk is most apparent with more severe disease (ie. significant gastrointestinal symptoms) and with later age of diagnosis (more than 50 years). The important fact is that the risk is virtually eliminated with a gluten-free diet. There is an increased risk of auto-immune diseases (type 1 diabetes, thyroid disease, Sjogrens disease). It is not known if a gluten-free diet protects against getting an auto-immune disease but in theory this is a likely effect if the disease is diagnosed as a young adult. There is a skin disease associated with coeliac disease called dermatitis herpatiformis. There are itchy raised red spots on the back, buttock and thighs - sometimes small blisters. This responds to a gluten-free diet but may take several months or even years to completely respond. A skin biopsy can be useful to accurately diagnose the problem. Bread made from wheat flour needs to be excluded. Gluten-free breads are made from a combination of cornflour, rice flour, soy flour and many other options - e.g tapioca, milletThis is what 10mg of gluten looks like based on bread intake - just a few crumbs!!This slice of "normal" bread contains 1750 mg of glutenThe gluten-free needs to exclude wheat, barley and ryeWhat is a gluten-free diet? It is universally agreed that subjects with coeliac disease have an intolerance to proteins fractions in wheat, rye and barley. The close association of barley and rye to wheat is clear from plant taxonomy. Recent studies of the proteins from each of these grains confirm that these grains are very similar. That is they all contain a critical amino acid sequence that is involved in initiating the immune process. Clearly this means that bread and cereal made from these grains are not allowed. Wheat flour and wheat pasta and noodles need to be excluded. Other foods are wheat crumbed and battered foods. Semolina, couscous and stuffing not allowed Lots of commercial products contain gluten - e.g. confectionery, sausages, sauces, dressings, canned soups, stock, custard powder It is clear that corn and rice are harmless. There remains a debate about oats. There is much scientific data that is reassuring. A large study from Finland showed that pure oats 40-50g per day given for a year had no effect on a group of coeliac who had been established a gluten-free diet. Oats can provide a good source of fibre. There is still some resistance amongst some dietitians and coeliac societies to accept oats. Part of the concern is limited data on the purity of the source of oats. There could be some contamination with wheat. Some longer term follow-up studies on coeliacs given oats over several years are still awaited. Several other grains such as quinoa, millet, sorghum, buckwheat, amaranth, tapioca, arrowroot, sago are now more widely available and form the basis for many gluten-free flours. There is not complete data on all these sources but plant taxonomy would suggest that they are safe (i.e they are very different from wheat, barley and rye). Potatoes and soy are also OK. Natural food sources are likely to be OK (apart from cereals). i.e meat, fish, vegetables, fruit. There is debate with regard to some processed food items. For example, wheat starch, a common component of processed food, distilled alcohol (made from wheat, barley or rye), distilled white vinegar, malt and malt extract. The policy of “if in doubt leave it out” is always going to be safe. However it is possible that unnecessary dietary restrictions are being imposed. Most evidence suggests that amount of gluten in the above products (derived from wheat) is extremely small and not important. Including fibre in a gluten-free diet can be difficult. Constipation is a reported problem with a gluten-free diet. Cornflakes and rice bubbles are good standards for breakfast but provide little fibre. Higher fibre alternatives include rolled rice flakes, brown rice flakes, rice bran, puffed brown rice, puffed buckwheat, puffed millet. A museli can be made from a combination of these ingredients (with added dried fruit and nuts). Rice porridge can be made from rolled rice flakes. For biscuits, try buckwheat crispbreads. For evening meals, brown rice or wild rice gives a different taste. Buckwheat can be used for pancakes or in cake and muffin recipes. There are many excellent gluten-free commercial products that give a good fibre source. Examples are Vogels Cafe Light, Healtheries GF Muesil, puffed wholegrain corn, rice,millet (Abundant Earth) or amaranth (Oragan) OR wholegrain toast (Venerdi Six seeds and Brown Rice, Breadman Buckwheat and Corn, Cassava and Millet), gluten pasta (Organ buckwheat, brown rice, corn) The gluten-free diet may be low in calcium, iron and B vitamins. These nutrients are found in wholegrains Risk of osteoporosis Osteoporosis does improve significantly with a gluten-free diet. Other sensible measures will be a diet high in calcium perhaps with some calcium tablets. Vitamin D levels need to be checked in case there is a problem with absorption of this vitamin and vitamin D supplements may be required Bone mineral density (measured by bone scans) continued to improve for up to 3 years after starting a gluten-free diet. Is there a safe level of gluten exposure? The amount of gluten that can be safely taken in coeliac disease is not known. Many people with coeliac disease have ingested small amounts of gluten over the years with no apparent problems. The reaction of a patient on a strict gluten-free diet to inadvertent small amounts of gluten is highly variable. Most people do not develop immediate symptoms. It is important to realize that there is some debate and variation in advice (varying from country to country). The labelling of foods has changed. Previously food containing < 0.02% gluten was labelled as gluten-free (20mg per 100 g of food) Now to gain this label there has to be “zero gluten”. This change may be an advance for patients who develop gastro-intestinal symptoms with inadvertent exposure to very small amounts of gluten. Testing for gluten detects with reasonable accuracy down to 3 ppm. This has become an accepted standard even the legal definiton is "no detectable gluten" and doesn't specify a particular level However this does increase the cost of producing gluten-free foods and does impose more dietary limitations on the increasing numbers of patients with no gastrointestinal symptoms prior to starting the gluten-free diet. Absence of small bowel villiThere is an iceberg effect with the visible top being overt coeliac but there is probably a larger group with very mild symptoms and another group that are at risk of developing coeliacThe appearance of the duodenum at gastroscopy may be diagnostic (as here) - a nodular appearance - but usually biopsies are requiredNormal small bowel villiHow does the condition present? The disease often presents in adults – presumably it has been silent during childhood (i.e. present but not producing symptoms). Coeliac disease may be like an iceberg There are those with symptoms and a definite diagnosis (the visible iceberg above the water). There are those with definite coeliac disease but have not been diagnosed - perhaps because of mild symptoms. Below this group are latent coeliacs - they have a genetic susceptibilty but no clinical disease. Some trigger may cause them to develop the overt disease The most common gastrointestinal symptoms are Abdominal bloating and/or abdominal discomfort. Diarrhoea(with or without a history of aggravation by wheat/breads). The finding of iron deficiency with or without anaemia (particularly in a younger person with no symptoms and no other obvious cause) is suggestive of coeliac disease. The additional finding of folate deficiency makes the diagnosis highly likely. Low calcium and vitamin D absorption may lead to osteoporosis. The risk of fractures with coeliac disease has probably been over-estimated in some studies but is still an important potential problem. A large population-based study of known patients with coeliac disease showed a 1.3 x risk of fracture (this was only just significant). Blood tests for coeliac disease (antibody tests) A study from nine general practices in Oxford, UK using a targeted approach to blood tests. 1000 blood sample were requested. There were 30 positive results(3 times that expected by population screening). The criteria that yielded the most positive tests was anaemia. Fatigue was a common indication but only 2% were positive. None of the 132 patients with symptoms suggestive of irritable bowel syndrome tested positive. This finding is in contrast to another UK study that showed that 5% of patients attending a gastroenterology outpatients clinic with irritable bowel (IBS) symptoms had coeliac disease. The true figure is likely to be around 2% (perhaps twice that expected of the general population) - see section on irritable bowel. Other possible indications for screening are Early onset or severe osteoporosis. Type 1 diabetes - taking insulin (4% positive). There is no association with type 2 diabetes. There is an association with auto-immune thyroid disease (5%). Screening of infertile couples has been suggested but the data is inconclusive. There have been some exaggerated claims of other associations. For example with ADD, schizophrenia and autism. The association with some other neurological disorders (e.g epilepsy) is also debated. Screening of relatives is an effective means of picking up more people with coeliac disease. 1:10 first degree relatives will be positive (1:35 second degree relatives). Currently, up to 25% of people with coeliac disease are identified by this method. Less than 50% of people diagnosed with coeliac disease today have abdominal symptoms. In a typical NZ general practice (with 2000 patients) there should be 20 people with coeliac disease (according to the Christchurch population survey). Using the clinical criteria of diarrhoea and weight loss only 2-3 patients will be identified. Testing people who present with anaemia (or with a past history of unexplained anaemia) will identify another 5. Testing of 1st degree relatives will identify another 2-3. Some will be hard to find! Making the diagnosis The initial test will usually be a blood test - endomysial antibody or tissue transglutaminase antibody. Some people are diagnosed initially by duodenal biopsy directly because of a high index of suspicion at the time of the procedure (gastroscopy). The endomysial antibody was the first accurate antibody test to be developed. The endomysial antibody is absent with IgA deficiency (found in 2% of coeliacs). Most labaoratories will routinely check the IgA level. The test may be falsely negative if low Ig A levels The transglutaminase antibody (tTGA) is also an IgA test. This is a simple test that is automated and quantitative (i.e will give a number for the level of antibody). The two tests give highly similar but not identical results. Currently most laboratories are able to offer both tests. Probably this is preferable as up to 20% of people with coeliac disease will have only one test positive. Testing of family members using HLA DQ2 and DQ8 has been proposed as a screening test. If these two genetic markers are not present then the condition does not occur. This test has limited availability in NZ at present. It is useful if the blood tests or biopsy are equivocal If the antibody test is positive this results should be checked by a gastroscopy and duodenal biopsy to confirm the diagnosis by showing loss of small bowel villi (often called villous atrophy). Although false positive antibody tests are uncommon the diagnosis needs to be confirmed beyond doubt. Duodenal biopsy is a straightforward procedure performed at the time of a gastroscopy. There is a justification for diagnosis without duodenal biopsy (gastroscopy) when the tTGA is strongly positive (>250) particulatly in children where requested a gastroscopy is more difficult. In general for adults gastroscopy is recommended Follow-up testing It is not adequate to use the response to a gluten-free diet as evidence of coeliac disease. patients with irritable bowel syndrome often improve with exclusion of bread from the diet. This may be related to a decrease in wind from the fermentation of wheat. There is no need for another biopsy after gluten re-exposure if there was a good clinical response to a gluten-free diet. The transglutaminase antibody can be used to monitor progress. It is to some extent a surrogate marker of villous atrophy although villous atrophy may be present with a negative antibody test. The antibody levels should gradually fall into the normal range within 12-18 months. If there are continuing symptoms then a repeat gastroscopy at 1-2 years is sensible. If there is still villous atrophy on biospsy then it is likely there is still enough gluten exposure to continue the immune-mediated damage Evaluationat this stage needs specialist input as the course of symptoms needs to be carefully evaluated. Sometimes the symptoms prior to diagnosis were mainly due to irritable bowel and these symptoms may continue on a gluten-free diet. Careful dietary advice is required to add in most aspects of a low FODMAP diet. Constipation on a gluten-free diet is common and can cause new symptoms Occasionally there is an associated condition called microscopic colitis - an inflammtion of the colitis that does not respond to the gluten-free diet and needs specific treatment. Historical perspective Coeliac disease is a condition where there is an abnormal lining of the small bowel that improves after excluding wheat from the diet. Possible described by a physician in Cappadochia, Turkey in the 2nd century There was a case report by Dr Samuel Gee in 1888 The link with wheat was only recognised after the end of WWII when children who had been deprived of wheat during the war years started eating wheat again. This was described by Dutch paediatrician Willem Dicke In the past the diagnosis was only made when there was significant weight loss and multiple problems with absorption of nutrients (vitamins). The diagnosis was confirmed by a small bowel biopsy - this was a difficult and cumbersome test. The simple realisation that a duodenal biopsy - obtained at the time of a gastroscopy - was as accurate led to more frequent diagnosis of the condition. Blood tests - gliadin antibody tests - have been available for many years - but there were problems with false positive and false negative tests. In the last 10 years more accurate antibody tests have become available. Community surveys showed that this condition was much more common than initially shown. Previously thought to be 1:2000, now shown to be 1:100 Dq2 is the name for a binding site on specific cells in our body that present antigens (in this case gliadin) to the immune cells that start the inflammationThere is a strong genetic component to the disease. About 1:10 1st degree relatives will have coeliac disease (positive antibodies and abnormal duodenal biopsies). There is now a genetic test that look for two susceptibility foci on HLA genes. HLA genes are involved in the recognition of self - they are important in immune processes and also part of testing for compatibility prior to organ transplants They are called HLA DQ2 (90%) or DQ8 (10%). If you have the gene, then coeliac disease is more likely. If you do not have the gene, then coeliac disease is excluded (only 1% do not have DQ2 or DQ8). 25-30% of the general population will have one of the 2 susceptibility genes - therefore the test is most useful to exclude coeliac disease. The risk of having coeliac disease varies around the world. It is common in people with Northern European ancestry. Populations with low prevalence of HLA DQ2 are Japanese and Chinese. They do not develop coeliac disease. The coeliac disease is not just a European disease. It is just as as common in northern Indian populations, Turkey and most North African countries. DQ2 appears to be more common in countries with a long history of wheat consumption. This is difficult to explain on an evolutionary basis - what is the potential advantage of being DQ2 positive? How does the damage to the small bowel occur? Immune cells, called antigen-presenting cells (APC) combine with HLA receptors (on the surface of cells), then become activated by the gliadin protein that is found in wheat. The resulting tissue damage leads to the release of the enzyme - tissue transglutaminase. This enzyme alters an important section of the gliadin protein. This changes a critical portion in the gliadin molecule that then activates lymphocytes. Tissue damage in the duodenum and further down the small bowel in the jejunum is caused by activated lymphocytes (immune cells). There are antibodies against the enzyme transglutaminase in the blood. However, these antibodies are not doing the damage. They are a by-product of the inflammation and damage caused by activated immune cells. The bowel tries very hard to replace the damaged villi (frond-like projections in the liming of the bowel) but cannot keep up with the tissue damage from the activated immune cells.