DOTT. GIANLUCA IANIRO - 3° Giornata Master ECM in Gastroenterologia 2016 (25/11/2016) - Fondazione Santa Lucia - Sala Congressi - Roma Sito: www.asmad.net Canale Youtube: https://youtu.be/UXpRBihftFo

1. Malattia Celiaca
Gianluca Ianiro, MD
Internal Medicine, Gastroenterology and Liver Unit
Fondazione Policlinico Universitario “Agostino Gemelli”
Catholic University of Sacred Heart - Rome, Italy
Email: gianluca.ianiro@hotmail.it Twitter: @gianluca1aniro
MASTER ECM IN GASTROENTEROLOGIA
Cosa è cambiato e cosa c’è da sapere
Resp. Scientifico: Dott. Gianfranco Tammaro
FONDAZIONE IRCCS S. LUCIA – Roma, 25 novembre 2016

2. Celiac Disease
What’s new?

3. CLASSICA
Segni e sintomi da malassorbimento (diarrea,
steatorrea, calo ponderale, ritardo crescita)
*Prima definita “TIPICA”
NON CLASSICA
Non segni e sintomi da
malassorbimento
*Prima definita “ATIPICA”
Celiac disease: the Oslo definitions

4. ASINTOMATICA
•Non sintomi
•Sierologia positiva
•Istologia positiva
*Prima definita “SILENTE”
POTENZIALE
• Sierologia positiva
•Istologia negativa
*Prima questo concetto era definito
dal termine“LATENTE
** Si intendevano per”celiaci
potenziali” i familiari di 1° grado di
celiaci oppure pazienti con malattie
autoimmuni
REFRATTARIA
Persistenza o ricorrenza di segni
e sintomi da malassorbimento
con atrofia villare nonostante
GFD per >1 aa
SUBCLINICA
Malattia senza segni e
sintomi tali da attivare uno
screening anticorpale
Celiac disease: the Oslo definitions

5. *
Vriezinga – Nat Rev Gastro 2016; Husby et al – JPGN 2012
No more biopsy to diagnose CD in children

6. *
Prescott et al, Pediatr Allergy Immunol 2009
ESPGHAN 2008: gluten introduction suggested between 4°and 6° month of
life
Breastfeeding, gluten introduction,
and risk of celiac disease

7. Apparent protective role for breastfeeding against further risk of CD
Breastfeeding, gluten introduction,
and risk of celiac disease

8. Vriezinga et al – NEJM 2014
Lionetti et al – NEJM 2014
No evidence that breastfeeding either
anticipating/delaying gluten
introduction could influence further
risk of developing celiac disease
Breastfeeding, gluten introduction,
and risk of celiac disease

9. Breastfeeding, gluten introduction,
and risk of celiac disease – ESPGHAN view
Szayewska – JPGN 2016
Breast-feeding and CD
•Recommendations on BF should not be modified because of
considerations regarding prevention of CD
(conditional recommendation; low quality of evidence)
•Introducing gluten while the infant is being breast-fed cannot be
recommended as a means of reducing the risk of developing CD
(conditional recommendation; low quality of evidence)
•BF should, however, be promoted for its other well-established heath
benefits

10. Breastfeeding, gluten introduction,
and risk of celiac disease – ESPGHAN view
Szayewska – JPGN 2016
Timing of gluten introduction
•Gluten can be introduced into the infant’s diet between the ages of 4 and
12 completed months
•The age of gluten introduction ininfants in this age range does not seem
to influence the absolute risk of developing CDA or CD during childhood
(conditional recommendation; depending on the age, quality of evidence varies from
very low to high quality of evidence)
Type of Gluten
•No recommendation can be made regarding the type of gluten to be used at
introduction
(conditional recommendation; very low quality of evidence)

11. Breastfeeding, gluten introduction,
and risk of celiac disease – ESPGHAN view
Szayewska – JPGN 2016
Amount of Gluten
•Neither the optimal amounts of gluten to be introduced at
weaning nor the effects of different wheat preparations on the risks of
developing CD and CDA have been established
•Despite the limited evidence regarding the exact amounts and with no
RCTs to support it, ESPGHAN suggests that consumption of large
amounts of gluten should be discouraged during the first months after
gluten introduction
(conditional recommendation; very low quality of evidence)
Gluten Introduction in Children From Families With
a First-Degree Relative With CD
• No recommendation was made

12. Duodenal microbiota affects gluten
breakdown in celiac disease
• GF mice colonized with bacteria isolated from the small bowel of
patients w/celiac disease or healthy controls
Caminero et al - Gastroenterology 2016
• Bacterial
colonizations
produced distinct
gluten degradation
patterns

13. Flattened villi: not only celiac disease
Sprue-like, olmesartan-induced enteropathy
• Syst Rev + case series of olmesartan-related
spruelike enteropathy
• 11 publications - 54 patients
• Almost all patients: diarrhoea and weight loss
• Frequent normocytic normochromic anaemia and
hypoalbuminaemia
• Antibody testing for coeliac disease was always
negative
• Duodenal villous atrophy was present in 98% of
patients
• Increased IEL in only 65% of cases
• After discontinuation of olmesartan, all reported
patients achieved resolution of signs and symptoms
Ianiro et al – AP&T 2014

14. Curbing our enthusiasm for therapeutic
gluten-degrading enzymes
• Double blind RCT - 494 patients with celiac disease - latiglutenase
• orally administered combination of two proteases that have been
engineered to digest gluten into non-immunotoxic fragments
• No differences between latiglutenase and placebo groups in change
from baseline in:
o Villous height:crypt depth ratio
o Numbers of IELs
o Serologic markers of celiac disease
Murray et al - Gastroenterology 2016

15. Hope from modified barleys?
Tanner – Plant Biotechnol J 2016
• Traditional breeding strategies were
applied to combine three recessive
alleles, which act independently of each
other to lower the hordein content in the
parental varieties
• Breeding and characterization of a novel ultra-low gluten barley variety in
which the gluten content was reduced to below 5 ppm

16. Non-celiac Gluten Sensitivity
What’s new?

17. Non-celiac Gluten Sensitivity
NCGS is a syndrome characterized by intestinal and extra-intestinal symptoms
related to the ingestion of gluten-containing food, in subjects that are not
affected by either celiac disease or wheat allergy
Catassi et al – Nutrients 2015
Pinto-Sanchez et al – Gut 2016
• Evidence supports the role exerted by both innate and adaptive immunity

18. Non-celiac Gluten Sensitivity
Catassi et al – Nutrients 2015
Symptoms associated
to NCGS

19. Non-celiac Gluten Sensitivity
Catassi et al – Nutrients 2015
Diagnosis: the Salerno Criteria
Switch from an exclusion diagnosis to a diagnosis based on positive Criteria:
•The evaluation of symptom variation after gluten / wheat withdrawal by using a
modified version of the GSRS integrated with extra-intestinal manifestations
•The identification of biomarkers
•The use of DBPCC as confirmatory diagnostic test (At least a variation of 30%
between the gluten and the placebo challenge should be detected to
discriminate a positive from a negative result)

20. Innate and adaptive immunity in self-
reported NCGS
• Ex vivo-cultured duodenal biopsies from 14 self-reported NCGS
patients, 9 untreated and 10 treated CD patients, and 12 controls
Di Sabatino et al – Dig Liver Dis 2016
• Innate cytokines
IL-15, TNF-a, IL-1b, IL-6,
IL-12p70, IL-23, IL-
27,
IL-32a, TSLP, IFN-a
• Adaptive cytokines
IFN-g, IL-17A, IL-4, IL-5,
IL-10, IL-13
• Chemokines
IL-8, CCL1, CCL2,
CCL3, CCL4, CCL5,
CXCL1, CXCL10, G-
CSF, GM-CSF
• No alteration of innate and adaptative immunity
in patients with NCGS

21. Positive gluten challenge in only a
minority of patients w/NCGS
• 35 non-CD subjects that were on GFD were randomised to receive
either gluten-containing flour or gluten-free flour for 10 days, followed by
a 2-week washout period and were then crossed over
Zanini et al – AP&T 2016
• 49% erroneously
considered the GF
flour to contain gluten
and 17% were unable
to distinguish between
the flours
• 34% of pts identified gluten-containing flour
(then they were classified as having
NCGS)

22. The gluten hype
• CD prevalence remained
stable over time
o 0.70% in 2009-2010
o 0.77% in 2011-2012
o 0.58% in 2013-2014
• Adherence to GFD w/out CD
has increased significantly
over time
o 0.52% in 2009-2010
o 0.99% in 2011-2012
o 1.69% in 2013-2014
Kim et al – AP&T 2016
• US National Health & Nutrition Examination Surveys 2009-2014

23. De Palma– Br J Nutr 2009
30 days of gluten-free diet in healthy people
Bifidobacterium
C. lituseburense
F. prausnitzii
Bifidobacterium
Lactobacillus
Enterobacteriaceae
E.coli
FISH
qPCR
Microbiota & GFD in healthy people

24. • A better diagnosis of CD is still needed
• Time for sparing-biopsy diagnosis of CD?
• NCGS? Need for thorough assessment
• Avoid unjustified GFD!
Take-home messages