GR CorazzaGR Corazza

I Clinica MedicaFondazione IRCCS Policlinico San Matteo

Università di Pavia

NON COELIAC GLUTEN SENSITIVITY (NCGS)

THE DEFINITION OF COELIAC DISEASE

CD is a chronic inflammatory disease characterised by flattened villi on the small bowel mucosa and is induced in genetically susceptible people by the ingestion of proline-rich and glutamine-rich proteins contained in wheat, rye and barley (gluten)

Lancet 2009

mosaicmosaic

convolutionsconvolutions

finger villifinger villi

ridges & leavesridges & leaves

gluten-free diet

EVOLUTION OF MUCOSALEVOLUTION OF MUCOSALPATTERN IN COELIAC DISEASEPATTERN IN COELIAC DISEASE

THE RELEVANCE OF COELIAC DISEASETHE RELEVANCE OF COELIAC DISEASE

prevalence (1:100-1:150)

co-morbidity

mortality (2:1)

monoetiology

HLA-linked

predisposing to lymphoma

reinduction of tolerance

CLINICAL POINTS RESEARCH AGENDA

clinical heterogeneity

tTG

Gluten peptides

CD4+

T cell

FasL Fas

CD8+

IELApoptosis

Deamidation

Deamidated glutenFibroblasts, LPMCs

HLA-DQ2/8

TCR

MMPs... ...... ...

Apoptosis

Th2cytokines

B cell

Cross-linking

Gluten-tTG complex

Perforinpores

Granzyme

MICNKGD2

T-NKcell

plasmacell

anti-tTG/anti-gliadinantibodies

EnterocyteApoptosis

Basement membrane

IL-15

IFN-

mtTG

IFN-

zo

nu

lin

Tra

nsc

yto

sis

Paracellular routeCD71

sIgA

LysosomeR

etro

tran

scyt

osi

s

Dendritic cell (CD 123+)

Th1cytokines

MECHANISMS OF MUCOSAL DAMAGEMECHANISMS OF MUCOSAL DAMAGEIN COELIAC DISEASEIN COELIAC DISEASE

Lancet 2009

THE CLINICAL GALAXY OF CDTHE CLINICAL GALAXY OF CD

MAJOR CD

pts complaining of frank malabsorbtion symtomps and

biopsied because of them

POTENTIAL CD

pts with positive serology but with (still) normal mucosa

LATENT CDpts with normal mucosa who subsequently develop villus

atrophy (retrospective recogniction)

MINOR CDpts complaining of trivial,

transient or apparently unrelated symtomps, biopsied because of

positive serology

SILENT CD

pts who do not complain of any symptom and biopsied because of active case finding

REFRACTORY CD

RCD type IRCD type II

Ulcerative enteritisETCL

? GLUTEN SENSITIVITY ?

pts complaining of various symptoms, with normal

mucosa, negative serology and not HLA-linked

MISDIAGNOSIS AND DIAGNOSTIC DELAY IN CDMISDIAGNOSIS AND DIAGNOSTIC DELAY IN CD

Pts previouslymisdiagnosed

(n=196)

J Clin Gastroenterol 1996

Pts with no previousmisdiagnosis

(n=223) p

12.9 12.9 8.0 12.5 < 0.005

Pts with major presentation

(n=129)

Pts with minor presentation

(n=67) p

14.0 13.8 9.7 9.2 < 0.05

IS COELIAC DISEASE MIS/OVERDIAGNOSED?IS COELIAC DISEASE MIS/OVERDIAGNOSED?RESULTS OF 605 CONSECUTIVE CASES REFERREDRESULTS OF 605 CONSECUTIVE CASES REFERRED

TO UNIVERSITY OF PAVIA (1999/2005)TO UNIVERSITY OF PAVIA (1999/2005)

605605

187-24187-24

52+2752+27

False Predictors

Clinical diagnosis

Unconventional tests

Poor sample quality

Marsh 1/2 lesions

tTG false-positivity

questionedquestioned

refusedrefused

In press

PATHOLOGIST AGREEMENT WITHIN MARSH CLASSIFICATION

Categories K Values

M–H type 0M–H type 1M–H type 2M–H type 3aM–H type 3bM–H type 3c

0.460.230.040.190.240.64

Arguelles-Grande et al, J Clin Pathol 2012

0.580.030.010.300.180.50

Corazza et al, Clin Gastroenterol Hepatol 2007

THE CLINICAL GALAXY OF CDTHE CLINICAL GALAXY OF CD

MAJOR CD

pts complaining of frank malabsorbtion symtomps and

biopsied because of them

POTENTIAL CD

pts with positive serology but with (still) normal mucosa

LATENT CDpts with normal mucosa who subsequently develop villus

atrophy (retrospective recogniction)

MINOR CDpts complaining of trivial,

transient or apparently unrelated symtomps, biopsied because of

positive serology

SILENT CD

pts who do not complain of any symptom and biopsied because of active case finding

REFRACTORY CD

RCD type IRCD type II

Ulcerative enteritisETCL

? GLUTEN SENSITIVITY ?

pts complaining of various symptoms, with normal

mucosa, negative serology 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

standardized mortality ratio= 2.4 ? (IgG AGA+/IgA EMA-)

very high prevalence (6 times >> CD !)

NCGS - FIRST CASE HISTORIES

a 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 of

GFD and worsened after 6wks of gluten challenge.Ellis & Linaker, Lancet 1978

a F 16mo old referred for diarrhoea, irritability and loss of appetite.

Intestinal biopsy and other tests: –ve. Because of family history a GFD was

started and within a few days symptoms subsided. Rechallenge →→

diarrhoea within 24h. Jonas, Lancet 1978

a F 24yr old presented with 1mo history of vomiting, abdominal pain, loss

of 7kg in weight and 8-10 loose stools/d. Intestinal biopsy →→ only slight

villous oedema. Prick tests: +ve for gluten and wheat flour. All symptoms

disappeared on a GFD.

Dahl, Lancet 1978

NCGS - ITS COMPELLING REVIVAL

Celebrity Endorsement: Gwyneth Paltrow, Victoria Beckham and Oprah Winfrey swear by gluten exclusion from the diet for its health benefit and detox effect

Everydayhealth.com 2011

L’Espresso 2012

… gluten: the new diet villain …Newsweek 2008

… 15 to 25% of the general American population want gluten-free foods …

USA Today 2008

… 17 million Americans are estimated to be gluten-sensitive …

Washington Post 2011

NCGS - POPULAR PRESS RISE THE CLAIM

NCGS - GOOGLE / PUBMED CITATIONSNCGS - GOOGLE / PUBMED CITATIONS

4000

3000

2000

1000

0

rati

os

Breast Cancer

Gluten Sensitivity

ColonCancer

GERD Alzheimer’s Disease

CoeliacDisease

Lung Cancer

Parkinson’s Disease

NCGS: SENSE OR SENSIBILITY ?NCGS: SENSE OR SENSIBILITY ?

Ann Intern Med 2012

prevalence (1:100-1:150)

co-morbidity

mortality (2:1)

supposed to be higher than CD

clinical heterogeneity

? co-morbidity

? mortality

COELIAC DISEASECOELIAC DISEASENON-COELIACNON-COELIAC

GLUTEN-SENSITIVITYGLUTEN-SENSITIVITY

clinical heterogeneity

CLINICAL POINTS IN COELIAC DISEASE (CD) AND NON-COELIAC GLUTEN SENSITIVITY (NCGS)

AN IDENTIKIT OF PATIENTS WITH NCGS

many of these patients were formerly on highly restrictive dietsmany of these patients were formerly on highly restrictive diets

many of these patients withdrawn gluten from their dietmany of these patients withdrawn gluten from their diet

many of these patients were convinced that exclusion of the gluten many of these patients were convinced that exclusion of the gluten

from the diet had helped their IBS-like symptomsfrom the diet had helped their IBS-like symptoms

EPIDEMIOLOGY OF GLUTEN SPECTRUM DISORDERS IN USA

Fasano A. FISMAD, March 29th, Naples 2012

Gluten spectrum disorders

Wheat allergy Non-coeliac GS Coeliac disease Occasional consumers

300,000 people(0.1% gen popul)

20,000,000 people(6% gen popul)

37,000,000(15% gen popul)

2,700,000 people(1% gen popul)

NCGS. THE SIZE OF THE PROBLEM

Sapone A. Symposium on Gluten sensitivity, February 9th, Bologna 2012

5,896 patients referring to the Gastro Unit

0

10

20

30

40

50

60

70

80

Pat

ien

ts (

%)

Abdominalpain

Headache Foggymind

Chronicfatigue

Diarrhoea Depression Anaemia

68

35 34 33 33

22 20

347 NCGS pts (6%)

GS-symptoms

EMA/TTG negative

Not allergic

PEOPLE FREQUENTLY MISATTRIBUTE ABDOMINAL SYMPTOMS TO FOOD INTOLERANCE

Levitt, NEJM 1995

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

NCGS - THE BIRMINGHAM STUDY

Cooper et al, Gastroenterology 1980

Patient No

F.U. Normal diet (yr)

F.U. GFD at gluten

challenge (mo)Abd. pain

Abd. distension Diarrhea Malaise

F.U. GFD before

double-blind (mo)

1 7 9 + + - + 50

2 0.5 5 + + + + 46

3 1 24 + + + + 60

4 4.25 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

Symptoms after gluten 30 g

No challenge

Biesiekierski et al. Am J Gastroenterol 2011

GLUTEN CAUSES GI SYMPTOMS IN SUBJECTS WITHOUT CD: A DOUBLE-BLIND RANDOMIZED

PLACEBO-CONTROLLED TRIAL IN IBS PTS

Overall symptoms

Pain Bloating

Satisfaction withstool consistency Tiredness

Wind Nausea

Gluten

Placebo

Screened(n=103)

Randomised(n=39)

No exclusion of CD

No consent to partecipate

Symptomatic on GFD

Gluten(n=19)

Placebo(n=15)

(1) (4)

RETROSPECTIVE EVALUATION OF 43 CASESWITH SUSPECTED NCGS

Di Sabatino et al. FISMAD, March 28-31, Naples 2012

812 patients referring to the Gastro Unit in the last 10 months

0

10

20

30

40

50

60

70

80

Pat

ien

ts (

%)

Abdominalpain

Diarrhoea Anaemia

74

2718

43 NCGS pts (5.3%)

GS-symptoms

EMA/TTG negative

Not allergic

Bloating

48

Headache Chronicfatigue

3230

COMPARISON OF DIFFERENT CASISTICS OF PATIENTS WITH SUSPECTED NCGS

0

10

20

30

40

50

60

70

80

Pat

ien

ts (

%)

Abdominalpain

Diarrhoea AnaemiaBloating

Pavia

Naples

Bologna

74

68

77

27

3340

1820

15

48

72

51

Headache Chronicfatigue

32 35 3230

3336

NCGS - PUTATIVE MECHANISMS

Sapone et al, Int Arch Allergy Immunol 2010

Sapone et al, BMC Medicine 2011

BREATH HYDROGEN CONCENTRATION DURING A 10-HOUR FAST AND

AFTER INGESTION OF 100 G OF CARBOHYDRATES IN HEALTHY SUBJECTS

Anderson et al. NEJM 1981Hours

Hyd

rog

en co

ncen

tration

(pp

m)

Fasting

Sucrose

White wheatbread

Pasta

Low-glutenwheat bread

Low-glutenwheat bread

+ Gluten

Rice bread

Innate immunereaction to gluten

Starch

carbohydrate

malabsorption

Op

ioid

-like activityo

f glu

ten

Extra

inte

stin

al

glut

en-in

duce

d di

seas

es

Placebo/nocebo effect ofgluten withdrawal/challenge

Gluten-induced

low-grade inflammation

IgE-mediated

wheat/yeast allergy

Ann Intern Med 2012

NCGS - POSSIBLE HETEROGENEITY OF THE ETIOLOGICAL SPECTRUM

NCGS – PROVISIONAL CONCLUSIONS

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

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

Ann Intern Med 2012

NCGS – CHARACTERISTICS AND INDICATIONS OF ORAL GLUTEN

CHALLENGE TESTS

Ann Intern Med 2012

Challenge Test Characteristics Indications