non-celiac glutensensitivity - gastrolearning®
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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
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