Non-celiac glutensensitivity - Gastrolearning®
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Gastrolearning IV lezione

Gastrolearning IV lezione
Non-celiac glutensensitivity - Prof. G. Corazza (Università di Pavia)
www.gastrolearning.it

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Non-celiac glutensensitivity - Gastrolearning® Non-celiac glutensensitivity - Gastrolearning® Presentation Transcript

  • NON COELIAC GLUTEN SENSITIVITY (NCGS) GR Corazza I Clinica MedicaFondazione IRCCS Policlinico San Matteo Università di Pavia
  • THE DEFINITION OF COELIAC DISEASECD is a chronic inflammatory diseasecharacterised by flattened villi on the smallbowel mucosa and is induced in geneticallysusceptible people by the ingestion ofproline-rich and glutamine-rich proteinscontained in wheat, rye and barley (gluten) Lancet 2009
  • EVOLUTION OF MUCOSAL PATTERN IN COELIAC DISEASE glu mosaic t en -fr ee die tconvolutions ridges & leaves finger villi
  • THE RELEVANCE OF COELIAC DISEASE CLINICAL POINTS RESEARCH AGENDA• ↑↑↑ prevalence (1:100-1:150) • monoetiology• ↑↑↑ clinical heterogeneity • HLA-linked• ↑↑ co-morbidity • predisposing to lymphoma• ↑ mortality (2:1) • reinduction of tolerance
  • MECHANISMS OF MUCOSAL DAMAGE IN COELIAC DISEASE Gluten peptides sIgA Paracellular route CD71Retrotranscytosis D2 NKG Transcytosis ↑ zonulin Lysosome ↑ IL-15 MIC Fas Perforin Granzyme FasL pores Apoptosis CD8+ Apoptosis T-NK IEL Apoptosis cell .... ... ... Enterocyte . mtTG Basement membrane MMPs IFN-γ anti-tTG/anti-gliadin tTG Deamidation Th1 antibodies Deamidated gluten cytokines Fibroblasts, LPMCs Cross-linking plasma Gluten-tTG complex cell Th2 cytokines CD4+ HLA- TCR T cell DQ2/8 B cell Dendritic cell (CD 123+) IFN-α Lancet 2009
  • THE CLINICAL GALAXY OF CD POTENTIAL CD LATENT CD pts with normal mucosa who pts with positive serology but subsequently develop villus with (still) normal mucosa atrophy (retrospective recogniction) SILENT CD MAJOR CD MINOR CD pts complaining of trivial,pts who do not complain pts complaining of frank transient or apparently of any symptom and malabsorbtion symtomps and unrelated symtomps, biopsied because of biopsied because of them biopsied because of active case finding positive serology ? GLUTEN REFRACTORY CD SENSITIVITY ? RCD type I pts complaining of various RCD type II symptoms, with normal Ulcerative enteritis mucosa, negative serology ETCL and not HLA-linked
  • MISDIAGNOSIS AND DIAGNOSTIC DELAY IN CDPts previously Pts with no previousmisdiagnosed misdiagnosis (n=196) (n=223) p 12.9 ± 12.9 8.0 ± 12.5 < 0.005Pts with major Pts with minor presentation presentation (n=129) (n=67) p 14.0 ± 13.8 9.7 ± 9.2 < 0.05 J Clin Gastroenterol 1996
  • IS COELIAC DISEASE MIS/OVERDIAGNOSED? RESULTS OF 605 CONSECUTIVE CASES REFERRED TO UNIVERSITY OF PAVIA (1999/2005) False Predictors605 Clinical diagnosis 187-24 Unconventional tests questioned Poor sample quality 52+27 Marsh 1/2 lesions refused tTG false-positivity In press
  • PATHOLOGIST AGREEMENT WITHIN MARSH CLASSIFICATIONCategories K ValuesM–H type 0 0.46 0.58M–H type 1 0.23 0.03M–H type 2 0.04 0.01M–H type 3a 0.19 0.30M–H type 3b 0.24 0.18M–H type 3c 0.64 0.50 Corazza et al, Clin Gastroenterol Hepatol 2007 Arguelles-Grande et al, J Clin Pathol 2012
  • THE CLINICAL GALAXY OF CD POTENTIAL CD LATENT CD pts with normal mucosa who pts with positive serology but subsequently develop villus with (still) normal mucosa atrophy (retrospective recogniction) SILENT CD MAJOR CD MINOR CD pts complaining of trivial,pts who do not complain pts complaining of frank transient or apparently of any symptom and malabsorbtion symtomps and unrelated symtomps, biopsied because of biopsied because of them biopsied because of active case finding positive serology ? GLUTEN REFRACTORY CD SENSITIVITY ? RCD type I pts complaining of various RCD type II symptoms, with normal Ulcerative enteritis mucosa, negative serology ETCL and not HLA-linked
  • NCGS - DEFINITION• symptoms -ranging from abdominal pain to foggy mind- that improve or disappear after gluten withdrawal• lack of intestinal lesion• negativity of anti-transglutaminase and anti-endomysial antibodies• unrelated to a specific HLA status• very high prevalence (6 times >> CD !)• standardized mortality ratio= 2.4 ? (IgG AGA+/IgA EMA-)
  • NCGS - FIRST CASE HISTORIESa F 43yr old presented after 2 yrs of diarrhoea, periumbilical pain,abdominal distension. No improvement with tetracycline or antidiarrhoeals.Intestinal biopsy and other tests: –ve. All symptoms stopped within 4d ofGFD and worsened after 6wks of gluten challenge. Ellis & Linaker, Lancet 1978a F 16mo old referred for diarrhoea, irritability and loss of appetite.Intestinal biopsy and other tests: –ve. Because of family history a GFD wasstarted and within a few days symptoms subsided. Rechallenge →diarrhoea within 24h. Jonas, Lancet 1978a F 24yr old presented with 1mo history of vomiting, abdominal pain, lossof 7kg in weight and 8-10 loose stools/d. Intestinal biopsy → only slightvillous oedema. Prick tests: +ve for gluten and wheat flour. All symptomsdisappeared on a GFD. Dahl, Lancet 1978
  • NCGS - ITS COMPELLING REVIVALCelebrity Endorsement: GwynethPaltrow, Victoria Beckham andOprah Winfrey swear by glutenexclusion from the diet for itshealth benefit and detox effect Everydayhealth.com 2011 L’Espresso 2012
  • NCGS - POPULAR PRESS RISE THE CLAIM… gluten: the new diet villain … Newsweek 2008 … 17 million Americans are estimated to be gluten-sensitive … Washington Post 2011 … 15 to 25% of the general American population want gluten-free foods … USA Today 2008
  • NCGS - GOOGLE / PUBMED CITATIONS NCGS: SENSE OR SENSIBILITY ? 4000 3000ratios 2000 1000 0 Gluten Breast Colon GERD Alzheimer’s Coeliac Lung Parkinson’s Sensitivity Cancer Cancer Disease Disease Cancer Disease Ann Intern Med 2012
  • CLINICAL POINTS IN COELIAC DISEASE (CD) AND NON-COELIAC GLUTEN SENSITIVITY (NCGS) NON-COELIAC COELIAC DISEASE GLUTEN-SENSITIVITY• prevalence (1:100-1:150) • supposed to be higher than CD• ↑↑↑ clinical heterogeneity • ↑↑↑ clinical heterogeneity• ↑↑ co-morbidity • ? co-morbidity• ↑ mortality (2:1) • ? mortality
  • AN IDENTIKIT OF PATIENTS WITH NCGS• many of these patients were formerly on highly restrictive diets• many of these patients withdrawn gluten from their diet• many of these patients were convinced that exclusion of the gluten from the diet had helped their IBS-like symptoms
  • EPIDEMIOLOGY OF GLUTEN SPECTRUM DISORDERS IN USA Gluten spectrum disordersWheat allergy Non-coeliac GS Coeliac disease Occasional consumers∼300,000 people ∼20,000,000 people ∼2,700,000 people ∼37,000,000(0.1% gen popul) (6% gen popul) (1% gen popul) (15% gen popul) Fasano A. FISMAD, March 29th, Naples 2012
  • NCGS. THE SIZE OF THE PROBLEM 5,896 patients referring to the Gastro Unit GS-symptoms 80 347 NCGS pts (6%) EMA/TTG negative 70 Not allergic 60 68Patients (%) 50 40 30 35 34 33 33 20 22 20 10 0 Abdominal Headache Foggy Chronic Diarrhoea Depression Anaemia pain mind fatigue Sapone A. Symposium on Gluten sensitivity, February 9th, Bologna 2012
  • PEOPLE FREQUENTLY MISATTRIBUTE ABDOMINAL SYMPTOMS TO FOOD INTOLERANCE• although many patients are certain that they can link the ingestion of various foods to subsequent abdominal symptoms, it is extremely difficult to pinpoint accurately which, if any, constituents of the diet cause abdominal distress• there is a tendency to attribute symptoms to a food that others have declared to be a problem -for example lactose or gluten-, and this conclusion is reinforced by an apparent improvement in symptoms when the food is avoided• given the enormous placebo effect of food, to document a food intolerance reliably it must be demonstrated that ingestion of the putative offender results in symptoms that do not occur when a placebo, that appears and tastes identical, is ingested Levitt, NEJM 1995
  • NCGS - THE BIRMINGHAM STUDY Symptoms after gluten 30 g F.U. GFD F.U. F.U. GFD at beforePatient Normal gluten Abd. Abd. double-blind No diet (yr) challenge (mo) pain distension Diarrhea Malaise (mo) 1 7 9 + + - + 50 2 0.5 5 + + + + 46 3 1 24 + + + + 60 4 4.25 No challenge 44 5 0.5 12 + + - + 50 6 2 4 + + + + 42 7 4.25 7 + + - + 42 8 3.25 9 + + + + 40 9 0.75 5 + + + + 38 Cooper et al, Gastroenterology 1980
  • GLUTEN CAUSES GI SYMPTOMS IN SUBJECTS WITHOUT CD: A DOUBLE-BLIND RANDOMIZED PLACEBO-CONTROLLED TRIAL IN IBS PTS Overall symptoms Screened Gluten (n=103) Placebo No exclusion of CD No consent to partecipate Pain Bloating Symptomatic on GFD Randomised Satisfaction with Tiredness stool consistency (n=39)(1) (4)Gluten Placebo Wind Nausea(n=19) (n=15) Biesiekierski et al. Am J Gastroenterol 2011
  • RETROSPECTIVE EVALUATION OF 43 CASES WITH SUSPECTED NCGS 812 patients referring to the Gastro Unit in the last 10 months GS-symptoms 80 43 NCGS pts (5.3%) EMA/TTG negative 70 74 Not allergic 60Patients (%) 50 48 40 30 32 30 20 27 10 18 0 Abdominal Bloating Diarrhoea Headache Chronic Anaemia pain fatigue Di Sabatino et al. FISMAD, March 28-31, Naples 2012
  • COMPARISON OF DIFFERENT CASISTICS OF PATIENTS WITH SUSPECTED NCGS Pavia Naples 80 Bologna 70 74 77 72 60 68Patients (%) 50 40 48 51 40 36 30 33 32 35 32 33 30 27 20 20 18 10 15 0 Abdominal Bloating Diarrhoea Anaemia Headache Chronic pain fatigue
  • NCGS - PUTATIVE MECHANISMSSapone et al, Int Arch Allergy Immunol 2010 Sapone et al, BMC Medicine 2011
  • BREATH HYDROGEN CONCENTRATION DURING A 10-HOUR FAST ANDAFTER INGESTION OF 100 G OF CARBOHYDRATES IN HEALTHY SUBJECTS Fasting Sucrose Hydrogen concentration (ppm) White wheat bread Pasta Low-gluten wheat bread Low-gluten wheat bread + Gluten Rice bread Hours Anderson et al. NEJM 1981
  • NCGS - POSSIBLE HETEROGENEITY OF THE ETIOLOGICAL SPECTRUM of gluten Opioid-like activity St rbo bso as al ca ala ar h rp se i n es m ch yd tio di test ce ain ra n du xtr IgE d te ed -in E wh -med uc n eat iat nd /ye ed te n-i matio ast Glu nflam en al l e ei ut r gy ad gl - gr lowInnate immune Placebo/nocebo effect ofreaction to gluten gluten withdrawal/challenge Ann Intern Med 2012
  • NCGS – PROVISIONAL CONCLUSIONS• there is an absolute need of in-depth clinical research to prevent the convinction that gluten is a toxin for most of the population and that a possible health problem would translate into a social-health problem• self prescription of gluten withdrawal would lead to the consequent preclusion of a correct diagnosis of CD and to a high and unjustified economic burden• at present a reliable marker of gluten sensitivity is not readily available and double-blind placebo-controlled food challenge tests are mandatory to confirm this diagnosis Ann Intern Med 2012
  • NCGS – CHARACTERISTICS AND INDICATIONS OF ORAL GLUTEN CHALLENGE TESTSChallenge Test Characteristics Indications Ann Intern Med 2012