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Dipartimento di Scienze Mediche e Chirurgiche

(DIMEC)
Impiego Razionale della Terapia Farmacologica in Medicina Interna
19 Giugno 2017

Le Malattie Glutine-Correlate

Umberto Volta
Dipartimento di Scienze Mediche e Chirurgiche
Universit degli Studi di Bologna
Board Societ Europea per lo studio della Celiachia (ESsCD)
Board Scientifico Associazione Italiana Celiachia (AIC)
Vice-Presidente Comitato Etico Policllinico S.Orsola-Malpighi.
Gi Direttore del Centro per la Diagnosi e Follow-up della
Celiachia, Policlinico S.Orsola-Malpighi
Cosa il glutine?
Il glutine rappresenta la frazione proteica principale del frumento e di altri cereali
(orzo, segale, farro, kamut). Non esiste come composto naturale ma si forma
quando la farina viene impastata con acqua: alcune proteine (gliadina e
glutenine) si organizzano in un reticolo proteico tridimensionale che conferisce
elasticit e resistenza allestensione dellimpasto

GLIADINE (45%)
GLUTENINE (55%)
Gluten
Related
Consensus Conferences on Disorders
Gluten Related Disorders:
1st London, 2011
2nd Munich, December, 2012
3rd Salerno, 2014
4 th Merano, December 2016
Pathogenesis

Immune-
mediated
(innate
Autoimmune Allergic
/adaptive
immunity?)

Non Celiac
Dermatitis
Celiac Gluten
Gluten Ataxia herpeti- Wheat allergy
Disease Sensitivity
formis

Respiratory Contact
Symptomatic Silent Potential Food Allegy WDEIA
Allergy Urticaria
COELIAC DISEASE TODAY
autoimmune disorder
very frequent in the general population
onset at any age (even in the elderly)
polymorphic clinical presentation
diagnostic gold standard: both serology and histology
Coeliac disease pathogenesis
Gliadin
extrinsic trigger
Precipitating factors:
stress, pregnancy,
viral infections (rotavirus, Microbiota changes
Reovirus, etc..)

HLA-DQ2 or DQ8
close genetic linkage

Nat. Med 1997;3:797-801

Tissue transglutaminase (TG2)


How intestinal microbiota contributes to celiac disease
Caminero A et al., Gastroenterology 2016; 151:670-683
A che et va fatto lo svezzamento con glutine?

October 2014 October 2014

Lepoca di introduzione del glutine non


influenza lo sviluppo della celiachia
Mancato effetto protettivo dellallattamento al seno
La genetica il fattore pi rilevante per lo sviluppo della celiachia
(i figli di celiaci con DQ2 in omozigosi sviluppano celiachia dal 25% al 40%)
Prevalence of coeliac disease (CD) among
1st degree CD relatives
30

25

Mean value 10%


20
(range 5%-17%)
15

10

0
Fasano 2003 Hogberg 2003 Esteve 2006 Biagi 2008

205/4508 10/120 16/221 28/158


0.5%
0.6%
1%
0.8% ? ?
0.8%
5% Case findings
0.6% 0.8% diagnoses in
0.2% ? China and Japan

0.8%
0.5%

Expected Prevalence of Coeliac Disease (CD) in the World: 1%


La Celiachia in Italia nel 2017
90
80

Trend diagnostico in aumento 70


60
50 diagnosi
40 raddoppiate negli
ultimi 7 anni
30
20
10
0
1980 1990 1995 2004 2014

>190.000 diagnosi
Ma ancora liceberg delle 10%
anno
diagnosi sommerso perch si
pensa poco a questa patologia
su oltre 600.000 attese
40
35

Scarsa conoscenza di una 30 > 20% dopo i 50 anni


25
M+F
patologia che pu insorgere 20
15
F
M F/M 1.5-2

ad ogni et 10
5
0
1-14aa 15-40aa 41-50aa 51-60aa 61-70aa >70aa
Le varie forme cliniche di celiachia
Classica: segni e sintomi di malassorbimento (diarrea e calo
ponderale) con o senza sintomi extraintestinali
Non classica: sintomi gastrointestinali atipici (stipsi, alvo
alterno e meteorismo) e/o sintomi extraintestinali
Subclinica: senza sintomi o con sintomi cos sfumati da essere
al di sotto della soglia di rilevamento
Potenziale: soggetti con lesioni duodenali minime o mucosa
normale, ma con sierologia positiva (EmA e/o tTGA)
Refrattaria: persistenza di sintomi di malassorbimento e di
atrofia dei villi nonostante una dieta aglutinata stretta seguita
per pi di 12 mesi

Ludvigsson J et al., Gut 2013, 62:43-52


Clinical features of coeliac disease
Gastrointestinal symptoms
diarrhoea, abdominal pain, bloating,
Female/Male > 2:1 dyspepsia, alternating bowel habits,
constipation, subocclusion, vomiting

Extra-intestinal symptoms
Onset age:
anemia (iron, folate, vit B12 def.),
from infancy to elderly aphthous stomatitis, short stature,
anxiety, depression, osteoporosis,
with the highest cryptogenic hypertransaminasaemia,
frequency after weaning neurological signs (headache, loss of
concentration, numbness), dental
and between the age of enamel defects, haemoragyc syndrome
twenties and thirties (vit. K malabsorption), fibromyalgia,
reproductive abnormalities

Volta U Villanacci V. Cell Mol Immunol 2011, 8:96-102


Hematologic manifestations of celiac disease

Anemia: iron deficiency, folate deficiency, vit. B12 and other


nutritional deficiencies
Autoimmune thrombocytopenia, Microcytic /macrocytic red cells
autoimmune haemolitic anemia
Leukopenia/ neutropenia
Coagulopathy (vit. K deficiency)
Splenic hypofunction

Howel Jolly bodies


as sign of splenic
hypofunction

Halfdanarson TR, et al Blood 2007, 109:412-21


Osteopenia/Osteoporosis and Celiac Disease (CD)

Unexplained osteopenia in women in fertile age or in young


men can be a sign of CD

Symptomatic and non-symptomatic CD: osteopenia/or


osteoporosis present in >50%

Partial regression after gluten-free diet

Risk of fractures in non-treated CD: low (RR 1.3)

Risk of fractures higher in symptomatic forms and peripheral


skeleton

West J et al. Gastroenterology 2003, 125:429-36


Cryptogenic hypertransaminasaemia can hide
asymptomatic coeliac disease (CD)

About 10% of patients with unexplained


raised transaminases (ALT>AST) are
affected by symptom-free CD

Liver damage, characterised by mild


periportal inflammation and fatty
infiltration, is gluten-dependent, as
confirmed by its disappearance and and
ALT normalisation after GFD

Antibody screening for CD is highly


recommended in patients with
hypertransaminasaemia of unknown
origin
Volta U et al., Lancet 1998, 352:26-9
Aphthous stomatitis: a frequent sign of celiac disease

Recurrent aphthous stomatitis


are a frequent sign observed at
celiac disease onset, being
present in the 15-20% of
untreated celiacs

Aphthous stomatitis disappear


after a few months of strict GFD,
but they tend to recur also after
minimal ingestion of gluten
Cheng J et al., J Clin Gastroenterol 2010, 44:191-4
Dental enamel hypoplasia

Found in 26% of patients


with coeliac disease
compared to 9% of controls
(p >0.0001)

Campisi G et al., APT 2007, 26:1529-36


Fertile life abnormalities
in undiagnosed celiac women

Late menarche
(13.6 vs 12.7 aa*)

4-5 fertile life years

Riduced fertility
Early menopause Birth number
(47.6 vs 50.1 yrs*) 1.9 vs 2.5*

controlli, * P < 0.01


Sher KS et al., Digestion 1994, 55:243-6
Coeliac disease: a systemic disorder
in and outside the gut

Pandoras Box

Absent or mild
(Potential Coeliac
Disease)

Modified from Maki M,


Nat Rev Gastroenterol Hepatol 2012, 9:305-6
DERMATITIS HERPETIFORMIS
Defined as coeliac disease of the skin
Granular skin IgA deposits detected by direct IFL are
mandatory for confirming its diagnosis
A gluten-related intestinal damage is always present, but it
is generally milder than in coeliac disease
Same genetic and serology of coeliac disease (HLA-
DQ2/DQ8 and ,besides TG2, serum TG3 antibodies)
Papulovescicular lesions usually located symmetrically on
the elbows, knees, buttocks, sacrum, face, scalp, neck and
trunk

Volta U et al., J Clin Gastroenterol 1992, 14:298-301


Skin and coeliac disease (CD)
A close association between
psoriasis and CD has been
recently reported
De Bastiani R et al., Dermatology 2015, 230:156-60

A slight increased finding of CD


has been found in pts with
alopecia areata
Volta U et al., Br J Dermatol 1997, 136:801-2
Before GFD After GFD
A possibile association between
vitiligo and CD has been
hypothesized
Shahmoradi Z et al., Int J Prev Med 2013, 4:200-3
Close association between coeliac
disease and Hashimoto thyroiditis
Antibody screening for CD in AT in CD
autoimmune thyroiditis (AT)

6 CD/152 AT (4%)
Test: EmA
Sategna-Guidetti C et al., EJGH 1998,10:927-31
20-25% of CD patients are positive for
thyroid antibodies
7 CD/220 AT (3.2%)
Test: EmA+tTG
Half of them with TSH and
Volta U et al., Digestion 2001, 64:61-5
hypothyroidism
Sategna-Guidetti C et al., for the Italian Small
Intestinal Club, AJG 2001, 96:751-7
Increased incidence of coeliac disease (CD) in type 1 diabetes mellitus (T1DM)
in the period 1994-2004 versus 1987-1994 in Italy

10
Diagnoses of
9 coeliac disease
in T1DM (%)
8
7

6
Enviromental factors as a
5 possible trigger of CD
4
Intestinal infections
3 (mainly viral)
2

1
0
1987- 1994-
1994 2004
(6/180 cases) (16/151 cases)
3% 10% Salardi S, Volta U, JPGN 2008,46:612-4
Selective IgA deficiency and celiac disease (CD)
Congenital immune disorder characterized by serum IgA
< 5 mg/dl

Frequent pulmonary and small intestinal infection due


to the lack of secretory IgA (protective mucosal role)

CD has been found in 4.3% of patients with IgA


deficiency

Antibody scrreening for CD is mandatory in pts with


selective IgA deficiency by means of IgG antitissue
transglutaminase and deamidated gliadin antibodies
Korponay-Szabo I , Gut 2003; 52:1567-71
Connective tissue disorders
and coeliac disease (CD)

The most frequent correlation is with Sjogren


syndrome where CD can be found up to 14%
of cases

The prevalence of Sjogren syndrome in CD


patients is about 1.5-3%

CD is rarely associated with SLE, rheumatoid


arthritis, systemic sclerosis and polymyositis

Volta U et al., BMC Gastroenterology 2014, 14:194


Antibodies to gliadin (AGA) and to Purkinje cells and
prevalence of coeliac disease in Gluten Ataxia

Cases AGA CD
N. N. (%) N. (%)

Hadjivassiliou M, 25 17 4
Lancet 1996 (68%) (24%)

Pellecchia MT, 24 3 3
JNNP 1999 (13%) (13%)

Luorostainen LK, 24 6 4
Ann Med 2001 (25%) (13%)

Burk K, 104 12 7
Brain 2001 (12%) (7%)
Antibodies to Purkinje cells are positive in
about 60% of gluten ataxia pts, often
associated wth anti-ganglioside antibodies
Volta U et al.,Scand J Gastroenterol 2002, 37:1276-81; Volta U et al., APT 2005,21:291-2
Autoimmune liver disorders and celiac disease

Autoimmune hepatitis Overlap syndrome Primary biliary cholangitis Primary sclerosing cholangitis

Volta U et al., Exp Rev Gastroenterol Hepatol 2013, 7253-61


Chromosomal disorders and celiac disease

The prevalence of CD in pts with


Downs syndrome varies from
3.6% to 4.6%
Gale L, 1997; Rumbo M 2002

CD has been found up to 6.4% of


patients with Turners syndrome:
prevalenza di celiachia 6.4% (25
casi su 389 pazienti) in uno studio
policentrico italiano.
Bonamico M, 2002

CD has been detected up to 9.5%


of pts with Williamss syndrome
Giannotti M, 2001
Diagnostic value of celiac
disease-related antibodies
Sensitivity % Specificity % Pos. pred. Neg. Pred.
Value % Value %
IgA tTGA 98 90 91 98

IgA EmA 95 100 100 95

IgA AGA 82 78
OBSOLETE 79
TEST 81

IgA tTGA as the first choice being the most sensitive test

IgA EmA as the confirmatory test in IgA tTGA positive cases


Antibodies to deamidated gliadin peptides
(DGP): doubts and certainties

In adults 10-15% cases show


an isolated positivity for DGP
and normal intestinal mucosa
85-90% 10-15% (false positives or potential
CD ? coeliac disease?)
Dahle C, APT2010
Lutteri L, AnnBiol Clin 2010

DGP IgG proved to be the most useful test for identifying


CD in IgA deficiency patients and in infancy
Mozo L, JPGN 2012; Amarri S Volta U, JCI 2013
Site and number of biopsies: at least 4 specimens (2 from the 2nd/3rd
duodenum portion and 2 from the bulb) must be taken.
Orientation of biopsy sample is essential for proper histological
assessment.
partial atrophy
Fig.
mild 2
atrophy Fig. 3
(type 3b)
(type 3a)

subtototal
Fig. 4
atrophy
(type 3c) The positive predictive value of villous
atrophy (with increased IEL) for CD is very
high, but we cant forget that there are other
conditions with non gluten dependent
villous atrophy.

Volta U Villanacci V, Cell Mol Immunol 2011


Clas
Brown I, Arch Pathol Lab Med 2006

An isolated IEL increase (Marsh1) is not


specific for coeliac disease being also
found in many other conditions.

Elevated IEL counts are observed from


2.2% to 14.3% of patients undergoing a
duodenal biopsy for differeny reasons.

Only 10% of patients with Marsh 1 are or


will become coeliacs.

Upton MP, Arch Pathol Lab Med 2008


GENETICS: WHEN HLA TYPING IS INDICATED
AND ITS SIGNIFICANCE

HLA typing should be performed only when CD diagnosis is controversial


due to a discrepancy between histology and serology and in 1st degree
relatives of CD patients to evaluate the genetic predisposition for CD

The finding of DQ2 or DQ8 or DQB1*02 is never diagnostic for CD by itself


since 40% of the general population displays the same HLA pattern of CD
patients

The most important clinical message of the test comes from its negativity
since the absence of DQ2, DQ8 and DQB1*02 allows to exclude CD
(negative predictive value around 100%)
NEW ESPGHAN GUIDELINES FOR THE DIAGNOSIS
OF COELIAC DISEASE, JPGN 2012

Diagnosis of CD without biopsy

In symptomatic patients with high titer anti-TG2 (>10x), EmA


positivity and HLA/DQ2 or DQ8 finding.

Confirmatory criteria: antibody decline and clinical response to


GFD.

In our experience the application of the new ESPGHAN guidelines


would allow to avoid the duodenal biopsy only in 20-30% of
suspected CD cases

Open problems: lack of standardization of anti-TG2 tests (different


kits with variable cut-off

A multicenter European study in order to confirm the indications of


the new ESPGHAN guidelines
Come cambiata la presentazione clinica della celiachia negli
anni: 770 casi diagnosticata presso il Centro Celiachia del
Policlinico S.Orsola-Malpighi (1998-2013)

Celiachia Potenziale
10%

27%
21% Diarrea Celiachia sieronegativa
Senza sintomi Calo ponderale 2%
Malassorbimento Classica
Non Classica
52% Subclinica
Stipsi
Anemia
Osteoporosi precoce
Alterazioni epatiche 1998-2007
Aborti ricorrenti Classica Non classica Subclinica
47% 43% 10%
2008-2012
Classica Non classica Subclinica
Volta U et al., BMC Gastroenterology 2014, 14:194 14% 58% 28%
Celiachia Potenziale (CP)

Anticorpi antiendomisio Lesione Marsh 0-1 HLA-DQ2 / -DQ8

DQ2
a5
DQA1*05

DQB1*02
b2

Anticorpi anti TG2 DQ8

a3 DQA1*03

DQB1*0302
b302

Sebbene i criteri diagnostici siano ben definiti, la CP ancora unarea grigia


con molti punti da chiarire soprattutto per lapproccio terapeutico
Volta U et al, Clin Gastroenterol Hepatol 2015
Dieta senza glutine (GFD) o con glutine (GCD)
nella celiachia potenziale?

Una decisione difficile da prendere

Sintomatica GFD
Malassorbimento, anemia,
aborto ricorrente, bassa
Celiachia statura, atassia cerebellare.
rialzo transaminasi,
Potenziale osteoporosi inspiegabile

Asintomatica GCD + follow-up

Volta U et al, Clin Gastroenterol Hepatol 2015


Seronegative villous atrophy cases identified at CDC
of Bologna University in a 16-year-period (1998-2014)

50% n=14

40% 45 Total number= 31 cases


Affected patients

30%
n=6
20% n=5 20
16 n=3
10%
n=1 n=1 10 n=1
0% 3 3 3
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Volta U et al., DLD 2016;48:1018-1022


Seronegative villous atrophy diagnostic work-up
Seronegative villous atrophy

HLA typing
HLA-DQ2/DQ8 - HLA-DQ2/DQ8+
Ruled out CD Possible CD

GFD trial
Search for other disorders
Autoimmune enteropathy
Common variable immunodeficiency
Olmesartan enteropathy Clinical
No effects
SIBO and histological
Giardia lamblia infection improvement
HIV
Eeosinophilic enteritis
Whipple / Crohns disease etc. Seronegative CD
Volta U et al., DLD 2016;48:1018-1022
Causes of non-responsive celiac disease (NRCD)

NRCD % Non responsive celiac disease is a


Continued gluten ingestion 36-45% common problem affecting from
Incorrect CD diagnosis 12% 7% to 30% of celiac patients
despite being on a gluten-free
Irritable bowel syndrome 10- 22%
diet.
Bacterial overgrowth 6- 9%
The most common cause of NRCD
Refractory CD and other 9-10% is unintentional gluten intake,
complications
but etiologies can vary greatly.
Lactose intolerance 7-8%
Less than 10% of NRCD cases are
Inflammatory colitis 7% affected from refractory celiac
Microscopic colitis 6-11% disease including ulcerative
Eating disorders 2-4% jejunoileitis and small intestinal
lymphoma
CVID 1-2%

Leffler DA, Clin Gastroenterol Hepatol 2007, Dewar DH, World J Gastroenterol 2012
Complicated Celiac Disease
Refractory Celiac Disease Other complications
Type 1 Type 2
Ulcerative jejunoileitis
Severe villous atrophy yes yes
Collagenous sprue
Autoimmune disorders yes no
Small bowel adenoca.
HLA-DQ2 homozygosity rare common

Clonal TCR-/b gene + ++


Enteropathy associated T-
rearrangement cell non Hodgkin lymphoma
Aberrant T-cell phenotype 10%IEL 50% IEL
(EATL)
Chromosomal abnorfmalities no yes
Hyposplenism
Ulcerative jejunoileitis rare common

Resp. to immunosuppress. yes no A delayed diagnosis and a poor


Risk of EATL low 60% in 5 yrs compliance with the diet increase
the risk for complicated celiac
Mortality rate Slightly 5-yr survi-
increased val <50% disease.
The prevalence of complicated coeliac disease in Italy: a
multicenter study by Italian Coeliac Disease Foundation

Assessment of complicated celiac disease among celiac


patients directly diagnosed in 5 Italian referral centers
between September 1999 and October 2011
Pavia
Seventeen (12 F, mean age 595 yrs) out of 2242 celiac pts
Bologna
developed complications (overall prevalence 0.75%). Six had
RCD type 1, 2 RCD type 2, 3 ulcerative jejunal ileitis, 3 small
bowel adenocarcinoma and 3 enteropathy T-cell associated
Napoli lymphoma.
Salerno
In 14 cases the onset of complications followed the
diagnosis of celiac disease (21.4 yers) and in the remaining
Palermo 3 cases the two diagnosis wer almost at the same time

Complicated celiac disease was very rare, but its outcome


was poor with a high mortality (35.3%)

Biagi F, Volta U et al, Dig liver Dis 2014


Follow-up for Celiac Disease
Verification of the compliance First evaluation 6 months after
with the diet the diagnosis and then every18
months by means of:
Development of autoimmune
disorders Medical evaluation and dietary
interview
Metabolic abnormalities Blood absorption tests (ferritin, blood
count, folic acid, vitamine D and
other routine tests)
Early diagnosis and treatment of
neoplastic (lymphoma) and non- tTGA IgA (DGP IgG if IgA deficiency)
neoplastic complications TSH, anti-TPO, anti-TG
(refractory coeliac disease, Metabolic tests (cholesterol, HDL,
ulcerative jejunal ileitis, tryglicerides, glucose, transamin-
collagenous sprue) ases) in cases with a marked weight
gain after GFD
Gluten-free diet is the only effective
treatment for coeliac disease

LIGHTS SHADES
Disappearance of Mineral and vitamin
intestinal and extra-intestinal deficiency
symptoms Psychological problems
Normalization of duodenal Metabolic syndrome
histology Increased cardio-
Antibody disappearance vascular risk
Prevention of auto-immune
disorders
Protection against
complication (refractory CD,
intestinal lymphoma)
Terapie alternative alla dieta aglutinata
1. Inibizione selettiva dellassorbimento del glutine (pillola
antizonulina)
2. Terapie intraluminali
- Pillola con enzimi digestivi
- varianti di grano e modificazioni genetiche
- pre-trattamento delle farine of flours
- anticorpi neutralizzanti il glutine
3. Blocco della risposta immune adattativa
- inibitori della transglutaminasi
- inibitori delle molecole HLA-DQ2
4. Immuno-modulazione ed induzione della tolleranza
verso il glutine (vaccino)
5. Terapie modulanti le citochine (anti-IL15 o con
IL-10)
NCGS

CD IBS Non-Celiac Gluten Sensitivity


(NCGS)

Adverse reaction to gluten / other wheat proteins (ATIs)


Negative serology / histology (not diagnostic for CD)
Negative specific IgE to wheat / gluten and prick tests
Gastrointestinal (IBS like) and extra-intestinal symptoms
Improvement with a gluten/wheat free diet / challenge re-
evokes symptoms

3rd Consensus Conference on Gluten Related Disorders, Salerno 2014


4th Consensus Conference on Gluten Related Didorders, Merano 2016
Non-Celiac Wheat Sensitivity (NCWS):
a more appropriate/alternative term for NCGS

Gluten has been confirmed as a


trigger of NCGS /NCWS by DBPCC
(although only in 20% of cases)
Gluten
Other potential triggers involve:
amylase trypsyn inhibitors (ATIs)
Other
NCGS/NCWS wheat and fermentable oligo-, di-,
Triggers proteins, monosaccharides and polyols
i.e.ATIs (FODMAPs) and many others
likely not identified

FODMAPs In addition to gluten, both ATIs


and FODMAPs are contained in
wheat
Volta U De Giorgio R. Nat Rev Gastroenterol Hepatol 2012; 9:295-9
Volta U, De Giorgio R. Exp Rev Gastroenterol Hepatol 2017, 11:9-18
Innate more than adaptive immunity is involved
in NCGS
Innate Adaptive
2Cytokines
4CD4+ T-cells

gluten-stimulated cytokine 5,6B-cells

secretion from PBMC IFN-

1TLRs

6Bacterial translocation
3Innate
AGA IgG
lymphoid cells AGA IgM
(ILC1)
intestinal
expression Abs to microbial antigens
ILC1 with
gluten intrarectal
challenge

1Sapone A., et al., BMC Medicine, 2011; 9:23 4Brottveit M., et al., AJG 2013; 108:842-50
2Vazquez-Roque M.I.et al., Gastroenterology, 2013; 144:903-11; 5Volta U., et al., J Clin Gastro 2012; 46:680-5;

3Di Liberto D., et al., Clin Transl Gastroenterol, 2016; e-pub 6Uhde M., et al., Gut, 2016; e-pub
Increased small bowel permeability in NCGS

Increased small intestinal permeability by lactulose- Zonulin up-regulation/disassembly of intercellular tight


mannitol test in DQ2/DQ8+ IBS gluten-sensitive patients junctions in NCGS intestinal biopsies exposed to
gliadin
Microbiome and NCGS

Experimental data in HLA-


DQ8 mice sensitized by
gliadin showed that gut
microbiome might contribute
to enhance the inflammatory
response to gluten

IBS/IBD Celiac Disease NCG/WS


Proven in humans Proven in humans Tested in mice
Microbiome Saulnier DM et al
Gastroenterology 2011 M
association de Palma G et al, BMC Natividad JM et al,
Manichanch C et al
NRGH 2012 Microbiol 2010 PLoS One 2009

Dysbiosis may potentially trigger clinical manifestations in NCGS


Epidemiology of NCGS:
still undefined and largely variable

USA Primary Care USA Tertiary Care Italian Tertiary


Care
NHANES based on Center for Celiac Multicenter study in
interview, biochemi- Disease University tertiary care centers
stry and physical of Maryland from coordinated by Bologna
examination 2009/10 2004 to 2009 University 2012/13

49 NCGS/7762 347 NCGS/5896 391 NCGS/12255


patients (0.6%) patients (6.0%) patients (3.2%)

1 in 158 subjects 1 in 17 subjects 1 in 31 subjects

Di Giacomo D et al, Sapone A et al, Volta U et al,


Scand J Gastroenterol 2013 BMC Medicine 2012 BMC Medicine 2014
Gastrointestinal symptoms in NCGS
F/M 5.4:1
Mean age
38 years
(range 3-81)
Extra-intestinal manifestations in NCGS:
Three main targets
No correlation between NCGS
and HLA-DQ2/DQ8
%
100
90
80
70
60
NCG/WS
50
Celiac Disease
40
General population
30
20
10
0
DQ2/DQ8 DQ2/DQ8 DQ2/DQ8

and HLA-DQ2
Volta U et al, J and/or DQ8 2012
Clin Gastroenterol
Intestinal
biopsy Marsh 1
not done 184/486
Marsh 0

Intestinal 93/302 Intestinal


biopsy 209/302 biopsy
done 302/486

0 20 40 60 80

CD3+ T lymphocytes:
linear distribution in the deeper part
of the mucosa and clusters in the villi

Possible histological pattern of NCGS?


Towards a diagnosis of NCGS
based on positive criteria
Evaluation of symptom variation after GFD by
modified version of the Gastrointestinal Symptom
Rating Scale (GSRS) integrated with extraintestinal
manifestations

Identification of biomarkers

Standardization of double-blind, placebo-controlled


(DBPC) trial as confirmatory diagnostic test

3rd Consensus Conference on NCGS, Salerno 2014


Modified version of GSRS for NCGS
(3rd Consensus Conference on NCG/WS)

Patient assessed by the questionnaire


at baseline on gluten-containing diet
Symptoms were scored from 1 (mild)
to 10 (severe)
At least 6 weeks of verified GFD
Data recording: weekly completion of
the questionnaire from week 0 to 6
Responders are those patients showing
30% reduction of three symptoms
Biomarkers for NCGS:
Where are we? Many attempts, but no diagnostic tests
Volta et al, JCG 2012;46:680-5 Valerii et al, Food Chem 2015;176:167-74 Mast cells density
100
90
80
70
AGA IgG
60
AGA IgA
50
DGP IgG
40 NF 200 kDa
tTGA IgA
30 EmA IgA
20 Tryptase+
10
0
NCGS CD
Close vicinity of mast cells to nerves

16-5-14
Zonulin ng/ mg total proteins

0.10

0.08

0.06
***
0.04
# **
*
0.02

0.00
C S S D
H IB CG
C
N

Barbaro et al, UEJG 2014; 2(suppl 1) A555

Giancola, Volta, Caio, De Giorgio unpublished


Gut 2016 July 25

AGA IgM LBP sCD14

Principal score analysis by


means of 6 biomarkers
EndoCAB Abs to flagellin FABP-2
DBPC trials for NCGS
Study design Patients Gluten/wheat vs Results
placebo
Crossover DBPC 8 pts with diarrhea Tomato soup without or Symptom worsening induced
Cooper, 1980 responding to 46-month-GFD with gluten (20g/d) by gluten in 6 pts

DBPC no crossover 34 IBS pts (Rome III) Bread/muffin without or Symptom worsening indu-
Biesiekierski, 2011 responding to 6-week-GFD with gluten (16g/d) ced by gluten in 13/19 pts

Crossover DBPC 276 IBS pts (Rome II) Capsules with wheat Symptom worsening induced
Carroccio, 2012 improved after GFD flour (13g/d) or xylose by wheat in 25% pts
Crossover DBPC 37 IBS pts (Rome III) High -(16g/d) / low- Symptom worsening induced
Biesiekierski,2013 responding to 6-week-GFD gluten diet (2g/d) vs low by gluten in 8% pts
FODMAP diet Response to low FODMAP
Cross-over DBPC 61 pts with NCGS/NCWS Capsules with gluten Symptoms worsening
Di Sabatino, 2015 responding to 2-year GFD (4.375g/d) / rice starch induced by gluten in 16% pts

Cross-over DBPC 35 pts with NCGS/NCWS Gluten containing flour/ Symptom worsening induced
Zanini et al. 2015 responding to 6-month-GFD gluten free flour by gluten in 34% pts
Cross-over DBPC 98 IBS pts (Rome III) Capsules with gluten (5.6 Symptom worsening induced
Elli L et al, 2016 responding to 3-week-GFD g/d) /rice strcrh by gluten in 28% pts
DBPC cross-over trial
Gluten-containing capsules (4.375 g/d) vs placebo (rice starch)
in 61 NCGS patients
(University of Pavia and Bologna, Italy)

Di Sabatino A., Volta U., et al., Clin Gastroenterol Hepatol 2015


Take home message
La patologia da glutine oggi sicuramente in aumento

Accanto alla celiachia oggi non pu pi essere ignorata lesistenza


della sensibilit al glutine non celiaca

Mentre la celiachia oggi una patologia ben definita nelle sue


caratteristiche clinico-diagnostiche, la sensibilit al glutine una
entit clinica che presenta ancora molti aspetti da chiarire

In attesa di definire specifici biomarker il gold standard per la


diagnosi di sensibilit al glutine rimane il trial in doppio cieco con
placebo, che peraltro necessita di essere standardizzato in modo
che i risultati siano riproducibili
Acknowledgments
Celiac Disease Center, Columbia University New York (USA)
Melanie Uhde and Peter H Green

Prof. Armin Alaedini

The Gluten-Related Disease Research Program


University of Bologna, Italy

Prof. Roberto De Giorgio

Dr. Giacomo Caio Fiorella Giancola, Tennekoon B. Karunaratne, Elisa Boschetti,


Elena Bonora, Alessandra Gori