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

1. NON COELIAC GLUTEN
SENSITIVITY (NCGS)
GR Corazza
I Clinica Medica
Fondazione IRCCS Policlinico San Matteo
Università di Pavia

2. 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

3. EVOLUTION OF MUCOSAL
PATTERN IN COELIAC DISEASE
glu
mosaic t en
-fr
ee
die
t
convolutions
ridges & leaves
finger villi

4. 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

5. MECHANISMS OF MUCOSAL DAMAGE
IN COELIAC DISEASE
Gluten peptides
sIgA Paracellular route
CD71
Retrotranscytosis 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

6. 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

7. MISDIAGNOSIS AND DIAGNOSTIC DELAY IN CD
Pts previously Pts with no previous
misdiagnosed misdiagnosis
(n=196) (n=223) p
12.9 ± 12.9 8.0 ± 12.5 < 0.005
Pts 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

8. IS COELIAC DISEASE MIS/OVERDIAGNOSED?
RESULTS OF 605 CONSECUTIVE CASES REFERRED
TO UNIVERSITY OF PAVIA (1999/2005)
False Predictors
605
Clinical diagnosis
187-24 Unconventional tests
questioned
Poor sample quality
52+27 Marsh 1/2 lesions
refused tTG false-positivity
In press

9. PATHOLOGIST AGREEMENT
WITHIN MARSH CLASSIFICATION
Categories K Values
M–H type 0 0.46 0.58
M–H type 1 0.23 0.03
M–H type 2 0.04 0.01
M–H type 3a 0.19 0.30
M–H type 3b 0.24 0.18
M–H type 3c 0.64 0.50
Corazza et al, Clin Gastroenterol Hepatol 2007
Arguelles-Grande et al, J Clin Pathol 2012

10. 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

11. 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-)

12. 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

13. 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

14. 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

15. NCGS - GOOGLE / PUBMED CITATIONS
NCGS: SENSE OR SENSIBILITY ?
4000
3000
ratios
2000
1000
0
Gluten Breast Colon GERD Alzheimer’s Coeliac Lung Parkinson’s
Sensitivity Cancer Cancer Disease Disease Cancer Disease
Ann Intern Med 2012

16. 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

17. 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

18. EPIDEMIOLOGY OF GLUTEN SPECTRUM
DISORDERS IN USA
Gluten spectrum disorders
Wheat 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

19. 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
68
Patients (%)
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

20. 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

21. NCGS - THE BIRMINGHAM STUDY
Symptoms after gluten 30 g F.U. GFD
F.U. F.U. GFD at before
Patient 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

22. 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

23. 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
60
Patients (%)
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

24. COMPARISON OF DIFFERENT CASISTICS
OF PATIENTS WITH SUSPECTED NCGS
Pavia
Naples
80 Bologna
70 74 77
72
60
68
Patients (%)
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

25. NCGS - PUTATIVE MECHANISMS
Sapone et al, Int Arch Allergy Immunol 2010
Sapone et al, BMC Medicine 2011

26. BREATH HYDROGEN CONCENTRATION DURING A 10-HOUR FAST AND
AFTER 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

27. 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
low
Innate immune
Placebo/nocebo effect of
reaction to gluten
gluten withdrawal/challenge
Ann Intern Med 2012

28. 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

29. NCGS – CHARACTERISTICS
AND INDICATIONS OF ORAL GLUTEN
CHALLENGE TESTS
Challenge Test Characteristics Indications
Ann Intern Med 2012