The Spectrum of Gluten –related disorders!: Celiac-sensitivity-allergy. References: 1.Professor David S Sanders Consultant Gastroenterologist Royal Hallamshire Hospital & University of Sheffield 2. Alessio Fasano& Carlo Catassi; NEJM 20 Dec 2012.3.
What will I learn today? (I hope!) Is there an evidence base for Gluten Sensitivity?The intimate relationship between mankind and wheat
The Prevalence of Adult Coeliac Disease in the UK is 1%!• CD in Northern Ireland 1 in 122 (n=1823)Johnston SD et al Lancet 1997;350:1370• CD in Sheffield 1 in 100 (n=1200)Sanders DS et al Eur J Gastroenterol Hepatol 2003;15:407-13• CD in Cambridge 1.2% (n=7550)West J et al Gut 2003;52:960-5• CD in Bristol 1% (n=5470)Bingley P et al BMJ 2004;328:322-3
Why is the prevalence increasing?• Change in endoscopic techniques• Antibody screening• Increased awareness of the spectrum of diversity in the presentation of Coeliac disease• An actual increase in disease incidence!?Lohi S et al Aliment Pharmacol Ther 2007;26(9):1217-25Rubio-Tapia A et al Gastroenterology 2009;137(1):88-93Catassi C et al Ann Med 2010;42(7):530-8
New concepts about coeliac disease!Fassano A & Catassi C Gastroenterology 2001;120:636-51 • The commonest age for presentation is between the 4th to 6th Decade (An adult > a pediatric disease) • For every paediatric case diagnosed there are 9 adult cases • For every adult case diagnosed there are 7 cases still not recognised • People with undiagnosed adult coeliac disease generally have a normal BMI and may even be overweight
Normal & coeliac duodenal mucosa Normal villousNormal numbers of IEL’s No crypt hyperplasia architecture Increased IEL’s Crypt hyperplasia Villous atrophy
Recognising CD in Gastroenterology• Dyspepsia/RefluxBardella MT et al Arch Intern Med 2000;160:1489-91• EndoscopyDickey W et al Am J Gastroenterol 1999;94:2182-6e th• IBS in = VA TG r TSanders DS et al Lancet 2001;358:1504-8 e as A oSanders DS Gastroenterology 2002;123:1408 ise EM• NSAP (non-specific abdominal pain) cal d Surg 2005;242:201-7Sanders DS et Ann o f lia ce c oe en es ive! pr it• Anaemia (Iron, Vitamin B12 and Folate) os• Family history (1st degree relative) ~ 10% risk p
Pitfalls in Serology Antibody negative coeliac disease• Prevalence at endoscopy 3.9%, N=2000 (77/2000) Antibody negative coeliac disease accounted for 9.1% (7/77) of cases within this cohortHopper AD et al BMJ 2007;334(7596):729• The prevalence of seronegative coeliac disease may range 6.4% -9.1% of all diagnosed casesCollin P et al Eur J Gastroenterol Hepatol2005;17:85-91.
The ‘Rise’ of Gluten ‘The main objective of the new Society was to provide ...a common meeting place for workers in various fields of nutrition.’ The very roots of the Society were geared towards necessarily increasing the production of wheat’Copping AM. History of the Nutrition Society. Proc Nutr Soc 1978;37:105-139 .‘By the end of the 20th century, global wheat output had expanded by 5- fold’ International Maize and Wheat Improvement Center. CIMMYT 1998
Why is the prevalence increasing?Lohi S et al Aliment Pharmacol Ther 2007;26(9):1217-25Rubio-Tapia A et al Gastroenterology 2009;137(1):88-93 Wu J et al Gut 2010;59(3):418-9Catassi C et al Ann Med 2010;42(7):530-8
Why is the prevalence increasing? Biagi F & Corazza GR Nat Rev Gastroenterol Hepatol 2010
The epidemiological ‘iceberg model’ of coeliac diseaseHopper AD et al BMJ 2007;335:558-62
What is latent coeliac disease?Latent – case reports• Patients with a normal biopsy while on a regular diet and subsequently have villous atrophy which improves on a GFD• Patients who have villous atrophy but do not adhere to GFD and after 2 years (or more) a repeat biopsy reveals normal mucosaFerguson A et al Gut 1993;34:150-1Troncone R et al Acta Paediatr Suppl 1996;412:10-14
What is potential coeliac disease?Potential e =• The presence of EMA (and perhaps as now high levels of TTG?)• High Intraepithelial Lymphocyte (IEL) d ise iac ! counts• el ty In uncomplicated coeliac disease co ivi IEL’s express CD3+ & CD8+ (T ial sit suppressor/cytotoxic phenotype) and nt en ote n s there is an increase in γδ T-cells• P te A positive rectal gluten challenge! guFergusonlA et al Gut 1993;34:150-1Troncone R et al Acta Paediatr Suppl1996;412:10-14
Okay everything makes sense or does it?!• N=1320 children with CD associated HLA• Serological testing at 1 year intervals for 3 years• 3.7% were TTG positive BUT ~ 50% spontaneously lost the antibody without starting a GFD• Is this a regulatory immune response or immune tolerance?Simell S et al Am J Gastroenterol 2007;102:1-10
What diagnostic criteria should we be using in 2012? = Should we reclassify mild enteropathy as coeliac disease ? Marsh 1 with +ve EMA• Raised IELs with +ve EMA were all HLA +ve in this studyKaukinen et al. Diagnosing mild enteropathy Coeliac disease: A randomised, controlledclinical study. Gastroenterology 2009;136: 816-823
What is the role of immunohistochemical markers – (small bowel mucosa TG-2 specific IgA deposits) in patients with normal villous architecture?Koskinen O et al J Paediatr Gastroenterol Hepatol Nutr 2008;47:436-42
What is the role of small bowel mucosa TG-2 specific IgA deposits in patients with normal villous architecture?• TG-2 targeted intestinal autoantibody deposits – they are produced in the small bowel mucosa and can deposit on extra- cellular TG-2 in the intestinal mucosaKorponay-Szabo IR et al Gut 2004;53:641-8• TG-2 deposits may allow us to differentiate which patients with raised gamma/delta IEL’s may be sensitive to glutenKaukinen K et al Scand J Gastroenterol 2005;40:5640-72• Have been valuable in antibody negative coeliac diseaseKaukinen K et al Gut 2006;55:1746-53In diagnosing mild enteropathy coeliac disease the sensitivity and specificity was 93%!Salmi TT et al Aliment Pharmacol Therap 2006;24:541-62
Neurological manifestations of coeliac disease and gluten sensitivity Dietary treatment of Gluten ataxia gluten neuropathy Lancet Muscle and Nerve 1998 Dietary treatment 2006 of gluten ataxia 1996 2003 2006 2010 Lancet JNNP Neurology Lancet NeurologyDoes cryptic gluten Autoantibody target of Gluten sensitivity: sensitivity brain and intestinal from gut to brain play a part in transglutaminaseneurological illness? in gluten ataxia
Isolated gliadin antibodies are prevalent in the general population but more prevalent in IBSSanders DS EJGH 2003 & Lancet 2001
CD CD + IBS IBS ? GS + IBS CD Coeliac Disease GS IBS Irritable Bowel Syndrome GS Gluten Sensitive GS (extraintestinal)A Model for the relationship between coeliac disease, IBS and gluten sensitivity? Ball A and Sanders DS Am J Gastroenterol 2010;105:222-3
What do IEL’s have to do with IBS?Causes of Raised Duodenal IELs NumberNo cause found but majority with IBS symptoms 34NSAIDs 21Coeliac disease 16Helicobacter pylori 14Gastrointestinal infection 5Immune dysregulation 5Inflammatory bowel disease 4IgA Deficiency 1Total 100Aziz I et al Aliment Pharmacol Therap 2010;32(11-12):1392-7.
Gluten Sensitivity & Irritable Bowel Type Symptoms• N=102 (35% CD HLA type)• HLA type predicted response to GFDWahanschaffe U et al Gastroenterology 2001;121:1329-38Wahanschaffe U et al Clin Gastroenterol Hepatol 2007;5:844-50
Non-celiac gluten intolerance may existBiesiekierski JR et al Am J Gastroenterol 2011;106:508-14
This research field is taking off! Sapone A et al In press BMC 2012
The U.S. market for gluten-free food and beverage products grew at a compound annual growth rate of 28 percent from 2004 to 2008, to finish with almost $1.6 billion in retail sales• Gluten Free diet • Low Carb diet• Low Fat diet The UK retail market is worth £125 million*- when you consider the healthcare market is only worth around £37 million** and that there are only around 120,000 diagnosed coeliac patients in the UK then this may suggest other individuals opting for a gluten-free diet* Kantar Worldpanel, April 2011**IMS data
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