Coeliac Disease, Non-Coeliac Gluten/Wheat Sensitivity, Irritable Bowel Syndrome What is it all about?
Marianne Williams, Specialist Gastroenterology Community Dietitian
As a Specialist Gastroenterology Community Dietitian who regularly sees patients in clinic with irritable bowel syndrome (IBS), I predominantly use the Low FODMAP Diet which improves symptoms in many patients. However, I am increasingly seeing a number of patients with what appears to be 'non-coeliac gluten sensitivity'. Hence, I was particularly interested in this webinar, hosted by the Dr Schär institute, in which Professor David Sanders, a leading researcher in the gluten-related disorders field, discussed the latest research findings in this clinical area. The following article is a summary of the points from his fascinating presentation.
Globally, gluten-free diets are on the increase, but why? Over the last 10 years they have been rising in popularity with many companies providing gluten-free products and improving patient choice. But is this health or hype? There is potential overlap between these clinical conditions as all three can have almost identical gastrointestinal symptoms. However, with coeliac disease we have the opportunity to obtain a cast iron diagnosis through blood tests and duodenal biopsy and it is vital to rule this out before moving on to suspect either IBS or non coeliac gluten/wheat sensitivity (NCGS).
However, in coeliac disease there are many ‘grey cases’ where a diagnosis may be unclear – see Figure 1. At what point is it not coeliac disease? In patients with the potential to develop coeliac disease the intraepithelial lymphocyte (IEL) is the initial ‘attack cell’. In those with positive HLA DQ genetic typing and a possible positive EMA blood result, the IELs enter the small bowel and initiate the inflammatory response. Dr Mike Marsh, who established the March criteria, noted that IELs could be raised in the bowel of relatives of coeliac patients and he referred to this cohort as ‘Potential Coeliac Patients’. Could this be modern day ‘gluten sensitivity’?
Coeliac disease
Figure 1: The Reality of the Coeliac Iceberg 2015
Introduction
It affects 1% of the population and, historically, it was seen in children with classic malabsorption symptoms, but now there are far more adult cases than paediatric cases and we are still only recognising about 20% of cases in the UK. They could have a normal BMI, or even be overweight, and it is important that we change the way we look at coeliac disease. The prevalence of coeliac disease appears to be changing with a Finnish study showing a population increase of 1% to 2% over the last 20 years. Their data also showed that Type 1 diabetes was following a similar trajectory.1 Are all autoimmune diseases on the increase? Is it a sign of a bored Western World immune system? At the same time, in developing countries that are adopting western-style diets, coeliac disease is also rising – e.g. China.2
HLA status DQ2: DQ8 (>95% coeliac disease; 25% general population)
In a Finnish study looking at patients with mild enteropathy, i.e. Marsh 1, with positive EMA and no villous atrophy, it showed that those who continued to eat a gluten containing diet exhibited a deteriorating histology, while those who used a gluten-free diet showed an improved histology similar to clinically diagnosed coeliac patients. Those eating the gluten containing diet then swapped on to a gluten-free diet and their histology also improved.3 The important message from this study is that those who have a positive EMA, normal biopsy with low marsh level are in the ‘waiting room’ for coeliac disease. In Professor David Sanders clinical experience they will re-present if they decide not to follow the gluten-free diet.
Diagnosed
Classical coeliac disease (0.2%) Villous Atrophy Sub-Clinical coeliac disease (0.8%)
Potential coeliac disease
Healthy individuals
Equivocal
Normal Mucosa
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Dr Sch채r Webinar Report | Coeliac Disease
Non coeliac gluten/wheat sensitivity (NCGS) What is the prevalence of NCGS? It is still unclear and although several contemporary studies have tried to assess prevalence, they have been based on patient self-reporting so may not be accurate. The Maryland Centre looked at those presenting in secondary care and suggested that 6% of their patients were categorised with NCGS.4 A second study in Italy, again in secondary care, looked at clinical outcomes in NCGS patients and showed a higher prevalence of HLA DQ status in this cohort, possibly suggesting that they could be potential coeliac patients.5 A UK-based study in Sheffield took over 1000 healthy volunteers from the general population and asked them about their dietary habits, gastrointestinal symptoms and whether they used a gluten-free diet. Thirteen per cent reported symptoms when they ate gluten and 2.7% were already on a gluten-free diet even though they had no diagnosis of coeliac disease.6 This gives you an idea of what is happening in the general population. The study allowed us to look more closely at the differences in symptoms and phenotype of NCGS patients: they were more likely to be female, more likely to have IBS type symptoms, may have other food intolerances and had a higher HAD (Hospital Anxiety & Depression Status) score. In Sheffield they also looked at 200 further patients who presented to their centre reporting symptoms when they ate gluten: this cohort had similar demographics to the general population study and they found a high representation of HLA DQ2 and DQ8 status. What are the differences when we compare the NCGS patients with those with diagnosed coeliac disease? The NCGS patients do not appear to suffer with the classical coeliac symptoms of vitamin B12, iron, folate deficiency and other malabsorptive features. This allows us to differentiate these patients. However, even in the NCGS patients we will suggest a gluten challenge in order to exclude coeliac disease and about 10% of these patients will be found to have coeliac disease. If negative for coeliac disease then international research still remains unclear as to how strictly they need to adhere to the gluten-free diet or for how long. Is there any evidence to support the pathophysiology of NCGS? Looking at innate markers of inflammation, NCGS patients have high levels of these immune cells, while those with coeliac disease do
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not show the same expression. Conversely, if we look at adaptive markers, e.g. interleukin 6, then they are high in coeliac patients but not raised in NCGS patients. It would appear that NCGS is being driven by a different immune mechanism, e.g. the innate immune system.7 Research also shows high levels of alpha-amylase/trypsin inhibitors (ATI) in NCGS patients and these are potent stimulators of the innate immune system, which adds further weight to the theory of NCGS being driven by a different innate immune mechanism.8 In Professor Sanders paper from 2003, he took 1200 healthy volunteers and found that 1% of those tested had undiagnosed coeliac disease. However, 12% also had antibodies to gliadin but a normal duodenal biopsy.9 A second study looked at those patients presenting to secondary care with IBS-type symptoms and showed a 5%
undiagnosed
coeliac
prevalence.
Antibodies to gliadin were 17% in this population. 10 Work done by an Italian group may also support these findings, as they found that NCGS patients had a high prevalence of IgG antigliadin antibodies but not a higher level of TTG.5 What does this tell us? a. In those individuals eating gluten who do not have coeliac disease, the gluten is crossing their small bowel mucosa and generating an immune response resulting in the production of gliadin antibodies b. If you have gastrointestinal symptoms then you are more likely to have a positive antibody than if you are in the general population.
Is this a pathophysiological mechanism for non coeliac gluten sensitivity? A model for this situation can be seen in Figure 2. This diagram shows that some coeliac patients on a strict gluten-free diet may still present with IBS-type symptoms, while some patients with non coeliac gluten sensitivity on a strict gluten-free diet may also continue to suffer with IBS type symptoms. Hence, there is some form of cross over and we are still learning.
Irritable bowel syndrome and the Low FODMAP Diet This is a very important area and the Low FODMAP Diet is now being regularly used in our clinical practice. Is there any pathophysiology behind the Low FODMAP Diet? MRI scans show the increased bowel water and gas content which can occur following the consumption of FODMAPs, although this paper did not show a change in associated symptoms and more research is needed.11 Many other papers have shown a relationship between the improvements in IBS symptoms with the use of this diet.12-17 However, there seems to be some controversy surrounding the use of a gluten/wheat-free diet and/ or the low FODMAP diet: some studies suggest that a gluten or wheat-free diet is most effective, while others suggest that it is simply the effect of removing the wheat-based FODMAPs which is resulting in the improvement in symptoms. The nocebo affect in these dietary studies must be considered and the jury is still out as to which diet is most effective for those with
Figure 2: A Model for the relationship between coeliac disease, IBS and gluten sensitivity?
CD ?
CD + IBS
IBS
GS + IBS
GS
Coeliac Disease Irritable Bowel Syndrome
GS (extraintestinal)
Gluten Sensitive
Coeliac Disease | Dr Schär Webinar Report
IBS or perceived ‘gluten sensitivity’.15, 18-21 The gluten-free diet is simply the cousin of the low FODMAP diet and it is important to consider which dietary approach is right and best for each patient. In Sheffield, they took a straight forward approach and took patients from clinic presenting with diarrhoea dominant IBS with excluded coeliac disease and recorded their symptom scores using a validated method. It was then suggested that they try a gluten-free diet for six weeks and they were sent to see the specialist dietitian. If they had improved symptoms by 50 points then this showed a significant therapeutic benefit of the dietary intervention. On analysis of the
data 60% of patients showed a positive response and most wished to continue with gluten-free diet in the long-term.22
Finally
and there is an improvement in symptoms with the use of a gluten-free diet.
In summary 1. It is essential to exclude coeliac disease
Are you confused? Here is some clarification: 1. Coeliac disease has a cast iron diagnosis with positive blood tests and biopsy and positive HLA DQ typing 2. Potential coeliac disease or non coeliac gluten sensitivity where the HLA DQ typing is positive but where there may only be raised IELs and possible positive antibodies 3. Non coeliac gluten sensitivity with negative HLA DQ typing and limited coeliac-like features where an innate immune mechanism may be responsible
2. This is not a battle between FODMAP and gluten-free researchers and we can ask our expert dietitians to differentiate which diet is best for each patient 3. The
general
population
are
using
gluten-free diets and we, in the medical profession, need to catch up with their needs.
In conclusion Nutrition therapies are back on the menu for functional gastrointestinal disease.
The full webinar is now available to view in the Continuing Professional Development section of the Dr Schär Institute website: www.drschaer-institute.com References: 1. Lohi S, et al (2007). Increasing prevalence of coeliac disease over time. Alimentary Pharmacology & Therapeutics; 26(9): 1217-25. 2. Kang JY, et al (2013). Systematic review: worldwide variation in the frequency of coeliac disease and changes over time. Alimentary Pharmacology & Therapeutics; 38(3): 226-45. 3. Kurppa K, et al (2009). Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology; 136(3): 816-23. 4. Sapone A, Bai JC, Ciacci C (2012). Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine; 10(13). 5. Volta U, et al (2012). Serological tests in gluten sensitivity (nonceliac gluten intolerance). Journal Clinical Gastroenterology; 46(8): 680-5. 6. Aziz I, et al (2014). A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. European Journal of Gastroenterology & Hepatology; 26(1): 33-9. 7. Sapone A, et al (2011). Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Medicine; 9(23). 8. Junker Y, et al (2012). Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. The Journal of experimental medicine; 209(13): 2395408. 9. Sanders DS, et al (2003). A primary care cross-sectional study of undiagnosed adult coeliac disease. European Journal of Gastroenterology & Hepatology; 15(4): 407-13. 10. Sanders DS, et al (2001). Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. The Lancet; 358(9292): 1504-8. 11. Murray K, et al (2014). Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am J Gastroenterol.; 109(1):110-9. 12. Staudacher HM, et al (2012). Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome. The Journal of Nutrition; 142(8): 1510-8. 13. Staudacher HM, et al (2011). Comparison of symptom response following advice for a diet low in fermentable carbohydrates (FODMAPs) versus standard dietary advice in patients with irritable bowel syndrome. J Hum Nutr Diet.; 24(5): 487-95. 14. Halmos EP, et al (2014). A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology; 146(1): 67-75 e5. 15. Vazquez-Roque MI, et al (2013). A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology; 144(5): 903-11 e3. 16. Ong DK MS, et al (2010). Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome. Journal of Gastroenterology and Hepatology; 25(8): 1366-73. 17. Biesiekierski JR, Muir JG, Gibson PR (2013). Is gluten a cause of gastrointestinal symptoms in people without celiac disease? Current Allergy and Asthma Reports; 13(6): 631-8. 18. Biesiekierski JR, et al (2011). Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol.; 106(3): 508-14; quiz 15. 19. Biesiekierski JR, et al (2013). No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology; 145(2): 3208 e1-3. 20. Carroccio A, et al (2012). Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol.; 107(12): 1898-906; quiz 907. 21. Wahnschaffe U, et al (2007) . Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol.; 5(7): 844-50; quiz 769. 22. Aziz I NJ, et al (2015). A single-blinded study evaluating the effects of a gluten-free diet in diarrhoea-predominant irritable bowel syndrome. Gut; 64(1): A584.
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