Reparto di Alimentazione, Nutrizione e Salute Dipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare

Marco Silano

La celiachia alla luce della Carta di Milano: la sostenibilità della dieta senza glutine

Milano Expo, 10 ottobre 2015

Coordinatore Board del Comitato Scientifico AIC

Criticità e futuro della celiachia, dalla diagnosi

alla terapia

gluten-containing foods. However, these do not lead to overtautoimmune enteropathy, which is characterized by villousatrophy and crypt hyperplasia, which develop in patientswith celiac disease. Although the gastrointestinal (GI)symptoms of patients with NCGS can resemble those asso-ciated with celiac disease, NCGS is not accompanied by thedevelopment of autoantibodies to TG2. Typically, a diag-nosis is made by exclusion; an elimination diet and thenopen challenge (monitored re-introduction of gluten-containing foods) can be used to confirm the diagnosis,based on the rapid reappearance of the intestinal or extra-intestinal symptoms.

Interest in NCGS has increased as studies defined it moreclearly and proposed that its pathogenesis was distinct fromthat of celiac disease, which involves an innate immuneresponse to gluten.6,8 However, an early description of NCGSdates to almost 40 years ago, when Ellis and Linaker9 re-ported a case of a 43-year-old woman in January 1978.According to the investigators, she had the following:

A 4-month history of loose motions, 3 times a day withno blood or mucus. The diarrhea was accompaniedinitially by periumbilical colic, which recurred inter-mittently, and abdominal distension, but she had notlost weight and had retained her appetite. She had beentaking tetracycline for 6 years for acne conglobate.Investigations, which included examination of feces forova, cysts, parasites, and occult blood, radiographs(barium meal, small-bowel meal, barium enema),sigmoidoscopy, and jejunal biopsy, were all normalexcept for a hiatus hernia. She did not improve whentetracycline was withdrawn or when antidiarrhealagents or tranquillizers were tried. Her symptomscontinued for 2 years. However, when a gluten-free dietwas tried the diarrhea stopped within 4 days and thepatient felt very much better. Jejunal biopsy wasrepeated after 6-week gluten challenge (accompaniedby recurrence of diarrhea) but was normal in everyway including normal intraepithelial lymphocytecounts. Resumption of the gluten-free diet was followed

by a rapid disappearance of all her symptoms. Weconsider it very likely that this woman’s symptoms weredue to gluten sensitivity. Her recovery is unlikely to be aplacebo response because other treatments had failed;moreover, relapse during the gluten challenge wasfollowed by remission after the second withdrawal ofgluten from the diet.9

After this publication, NCGS disappeared from the liter-ature with the exception of a few reports.10–12 A study in20106 showed celiac disease and NCGS to be separate en-tities with different mechanisms of pathogenesis. NCGS wasproposed to result from an innate immune response togluten-containing foods, whereas celiac disease was asso-ciated with the adaptive immune response.4,5,8 Since thisreport, there have been several articles published regardingNCGS, attempting to define its clinical presentation, assessits epidemiology, and describe its pathogenesis. Notably,NCGS does not seem to be limited to intestinal symp-toms—it includes extraintestinal pathology. We review ourlimited knowledge about NCGS and the challenges todefining it.

DefinitionSince 2010, the definition of NCGS has been discussed

at 3 consensus conferences, which led to 3 pub-lications.13–15 Given the uncertainties about this clinicalentity and the lack of diagnostic biomarkers, all 3 reportsconcluded that NCGS should be defined by the followingexclusionary criteria: a clinical entity induced by theingestion of gluten leading to intestinal and/or extra-intestinal symptoms that resolve once the gluten-containing foodstuff is eliminated from the diet, andwhen celiac disease and wheat allergy have been ruledout. One of the most controversial and highly debateddiscussions concerns the role of gluten in causing NCGS.Recent reports have indicated that gluten might not be thecause of NCGS, and some investigators still questionwhether NCGS as a real clinical entity.

Figure 1. Classification ofgluten-related disorders.WDEIA, wheat-dependentinduced anaphylaxis.

1196 Fasano et al Gastroenterology Vol. 148, No. 6

NONCELIACGLUTEN

ANDWHEAT

SENSITIVITY

Patologie glutine - dipendenti

GLUTINE

ALBUMINE idrosolubili

GLOBULINE solubili in sol. salina

GLIADINA α β γ ω solubili in etanolo GLUTENINE HMW LMW solubili in acido acetico

GLUTINE

Proteine di riserva

GLUTINE

Alveografo di Chopin

alpha - gliadina

MALATTIA CELIACA

MALATTIA CELIACA

PREDISPOSIZIONE GENETICA

ESPOSIZIONE AL GLUTINE

FATTORE COSTITUTIVO FATTORE AMBIENTALE

?????????????

diffusione agricoltura

World map of celiac disease prevalence (%)

Lionetti et al. Best Practice & Research Clinical Gastroenterology, 2015 29: 365–379

Prevalenza della celiachia in Italia (%)

Relazione al parlamento sulla celiachia 2013

164.492

•  effetto del fondatore

•  vantaggio selettivo

Lionetti et al, Dig Liv Dis 2014; S1590-8658

Patogenesi della MC

Sollid et al., Mucosal Immunology, 2009

Accumulo intralisosomiale dei peptidi della gliadina (minuti)

Immunità innata (3 ore) Immunità adattiva (24 ore)

normale

celiaca

Patogenesi della MC

SINTOMATOLOGIA Forma classica o tipica

•  Diarrea cronica

•  Scarso accrescimento

•  Distensione addominale

Guandalini, JAMA Pediatr. 2014;168(3):272-278

diagnosi età pediatrica

— 151 —

GA

ZZ

ET

TA U

FFICIA

LE D

EL

LA R

EPU

BB

LIC

A ITA

LIA

NA

Serie generale - n. 19119-8-2015

diagnosi adulti

— 150 —

GA

ZZ

ET

TA U

FFICIA

LE D

EL

LA R

EPU

BB

LIC

A ITA

LIA

NA

Serie generale - n. 19119-8-2015

Terapia

Una permanente e rigorosa DSG è l’unico trattamento disponibile per la celiachia

La malattia celiaca è in aumento?

NO

I grani ancestrali sono tollerati dai

celiaci ?

NO

U.S. per capita wheat flour use

Kasarda et al. J. Agric. Food Chem. 2013, 61, 1155-1159.

L’aumento della prevalenza di “intolleranze al glutine” è legata ad un

aumentato consumo di glutine ?

GLUTEN

SENSITIVITY

RESEARCH ARTICLE Open Access

An Italian prospective multicenter survey onpatients suspected of having non-celiac glutensensitivityUmberto Volta1*, Maria Teresa Bardella2, Antonino Calabrò3, Riccardo Troncone4, Gino Roberto Corazza5

and The Study Group for Non-Celiac Gluten Sensitivity

Abstract

Background: Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issuesdespite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers forthe diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and toestablish roughly its prevalence compared with celiac disease.

Methods: From November 2012 to October 2013, 38 Italian centers (27 adult gastroenterology, 5 internal medicine,4 pediatrics, and 2 allergy) participated in this prospective survey. A questionnaire was used in order to allowuniform and accurate collection of clinical, biochemical, and instrumental data.

Results: In total, 486 patients with suspected NCGS were identified in this 1-year period. The female/male ratiowas 5.4 to 1, and the mean age was 38 years (range 3–81). The clinical picture was characterized by combinedgastrointestinal (abdominal pain, bloating, diarrhea and/or constipation, nausea, epigastric pain, gastroesophagealreflux, aphthous stomatitis) and systemic manifestations (tiredness, headache, fibromyalgia-like joint/muscle pain,leg or arm numbness, 'foggy mind,' dermatitis or skin rash, depression, anxiety, and anemia). In the large majority ofpatients, the time lapse between gluten ingestion and the appearance of symptoms varied from a few hours to1 day. The most frequent associated disorders were irritable bowel syndrome (47%), food intolerance (35%) andIgE-mediated allergy (22%). An associated autoimmune disease was detected in 14% of cases. Regarding familyhistory, 18% of our patients had a relative with celiac disease, but no correlation was found between NCGS andpositivity for HLA-DQ2/-DQ8. IgG anti-gliadin antibodies were detected in 25% of the patients tested. Only aproportion of patients underwent duodenal biopsy; for those that did, the biopsies showed normal intestinalmucosa (69%) or mild increase in intraepithelial lymphocytes (31%). The ratio between suspected NCGS and newCD diagnoses, assessed in 28 of the participating centers, was 1.15 to 1.

Conclusions: This prospective survey shows that NCGS has a strong correlation with female gender and adult age.Based on our results, the prevalence of NCGS seems to be only slightly higher than that of celiac disease.

Please see related article http://www.biomedcentral.com/1741-7015/12/86.

Keywords: Non-celiac gluten sensitivity, Celiac disease, Prospective survey, Clinical picture, Duodenal biopsy,Anti-gliadin antibodies

* Correspondence: umberto.volta@aosp.bo.it1Department of Medical and Surgical Sciences, University of Bologna,Bologna, ItalyFull list of author information is available at the end of the article

© 2014 Volta et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

Volta et al. BMC Medicine 2014, 12:85http://www.biomedcentral.com/1741-7015/12/85

EFFETTO PLACEBO/NOCEBO !!

Di Sabatino et al, Clin Gastroenterol Hepatol. 2015 Sep;13(9):1604-1612

Gluten sensitivity vs CD •  agente ambientale (gluten, wheat, ATIs) ?????

•  predisposizione genetica NO

•  marker serologico noto NO

•  lesioni mucosali intestinali NO

•  terapia ????

•  permanente NO

•  sintomi SI

GRAZIE PER L’ATTENZIONE