Autismo ed intestino:
quale relazione?
CARLO CATASSI
Clinica Pediatrica, Università Politecnica
delle Marche, Ancona
Center For Celiac Research, Boston, MA,
USA
Autismo (Disturbi Spettro Autistico)
Disturbo dello sviluppo neurologico caratterizzato da
• deficit di comunicazione sociale: (1) deficit nella reciprocità
socio-emotiva, (2) deficit nei comportamenti di
comunicazione non verbale, (3) deficit nello sviluppare,
mantenere e comprendere le relazioni
• pattern ristretti e ripetitivi di comportamento, interesse o
attività: (1) movimenti stereotipati e ripetitivi, (2) modelli
ritualizzati di comportamento verbale e non, (3) abnorme
fissazione di interessi, (4) ipo- od iperreattività agli input
sensoriali
• Esordio precoce dei sintomi
• Rilevante compromissione clinica nelle sfere sociali,
occupazionali, etc
• I disturbi non sono spiegati da un ritardo globale dello
sviluppo ma i due aspetti possono coesistere
Criteri DSM-5
Autismo
• Prevalenza USA nel 2010 = 1 : 68
• La frequenza è aumentata di 10 volte
negli ultimi 20 anni
• Aumento in parte reale ed in parte
legato ad una maggiore attenzione
diagnostica
• Rapporto maschi/femmine = 4 : 1
• Nel bambino autistico i disturbi
gastrointestinali (DAR, stipsi, diarrea,
etc) sono frequenti
Autismo
• Nessuna causa identificata, nessuna terapia
conosciuta
• Il trattamento consiste in un programma
globale ed intenso di intervento educazionale,
terapie di sviluppo, e trattamento
comportamentale
• Diffuso impiego di terapie complementari ed
alternative (CAM)
MMR vaccine > ileo-colon NLH > autism ?
La truffa di Wakefield
Ann Pharmacother 2011
Comportamenti potenzialmente evocativi
di dolore addominale o altre turbe
dispeptiche nel bambino autistico
SMORFIE FACCIALI
STRINGERE I DENTI
SINGHIOZZO
SOSPIRO, PIAGNISTEO
LAMENTO, GEMITO
TRASALIRE
Consensus Report, Pediatrics 2010
The Reichelt hypothesis on
gut-to-brain connection in ASD
Inadequate catabolism of
gluten and casein peptides
Absorption across the
gut barrier (leaky gut)
high levels of peptides
In the urine
Crossing of the bloodbrain barrier
gliadorphin and casomorphin bind
with endogenous opioid receptors
negative effect on attention, brain
maturation, social interaction, and learning
Possibili connessioni tra leaky gut e
malattie pediatriche
Liu et al, Acta Pediatrica 2005
J Pediatr Gastroenterol Nutr 2010
Indirect evidence of leaky gut in autism
De Magistris et al,
Biomed Res Int 2013
Lau et al, PLoS One 2013
AGA-IgG sono presenti spesso
nei soggetti con NCGS
Sensibilità al glutine (NCGS)
Celiachia
Volta et al, BMC Gastroenterology 2014
La celiachia non è frequente nei bambini
autistici ma la familiarità celiaca sì
Atladóttir et al, Pediatrics 2009
The GFCFD in ASDs:
Cochrane Reviews 2004 and 2008
• From 1965 to 2007, 61 studies were identified
• Only 3 were considered to be of high enough quality to be included in
the analysis
• 2 small trials: the first with 10 participants in each arm and the second
with 15 participants total
• In the first study, GFCFD was reported to reduce the autistic traits of
“social isolation” and “bizarre behavior” at 12 months
• In the second study, there was no significant difference in outcome
measures between the diet group and the control group with regard
to cognitive skills at 12 months, motor ability at 12 months,
communication and language sampling at week 6
• These metaanalyses concluded that “this is an important area of
investigation and large scale, good quality randomized control trials
are needed»
Nutr Neurosci 2010
• Statement 11
Anecdotal reports have
suggested that there may
be a subgroup of
individuals with ASDs who
respond to dietary
intervention. Additional
data are needed before
pediatricians and other
professionals can
recommend specific dietary
modifications.
Statement 12
Available research data do
not support the use of a
casein-free diet, a gluten-free
diet, or combined glutenfree,
casein-free (GFCF) diet as a
primary treatment for
individuals with
ASDs.
Pediatrics 2010
A strange case of NCGS
Alessia, first seen at 13 yrs of age
• Past history: unremarkable
• Family history: autoimmune thyroid disease (mother)
• Weight loss, headache, behavioural problems
(unmotivated crying, troublesome mind
concentration, confusion), intestinal dispepsia
• After a couple of months: visual hallucinations
• Treated with steroids, aloperidol and bromazepam
Lionetti et al, Nutrients 2015
May 2014: Alessia is seen by a pediatric
gastroenterologist
• No celiac disease: celiac serology negative, HLA
compatible
• No wheat allergy: negative RAST, Immunocap ISAC Tri
a 19 (alfa-gliadin) and Tri a 14 LTP (gluten) Tri a 36
• Resolution of both intestinal and neuropsychiatric
symptoms with the GFD
SUSPECTED NCGS
Diagnosis confirmed by the DBPC gluten challenge
Clinical manifestations of NCGS
Frequency
Very Common
Common
Undetermined
Intestinal
Extra-intestinal
Bloating
Abdominal pain
Diarrhea
Epigastric pain
Nausea
Aerophagia
GER
Aphtous stomatitis
Alternating bowel habits
Constipation
Hematochezia
Anal fissures
Lack of wellbeing
Tiredness
Headache
Anxiety
Foggy mind
Numbness
Joint/muscle pain
Skin rash/dermatitis
Weight loss
Anemia
Loss of balance
Depression
Rhinitis/asthma
Weight increase
Interstitial cystitis
Ingrown hairs
Oligo or polimenorrhea
Sensory symptoms
Disturbed sleep pattern
Hallucinations
Mood swings
Autism
Schizophrenia
The Salerno NCGS diagnostic criteria (Nutrients, 2015)
La diagnosi differenziale dei disturbi glutine-indotti
History and Physical Exam - Initial Evaluation –
Consider Differential Diagnosis
Celiac Disease (CD)
Gluten Sensitivity (GS)
Wheat Allergy (WA)
•
•
•
•
•
•
Specific skin prick tests
Wheat specific serum IgE
Gluten challenge
Tests +
Challenge +
NO
WA
ruled out
tTG IgA +/- EMA + total IgA
Deamidated AGA IgA
AGA
tTG and/or
dAGA+
NO
Suspected
GS
YES
YES
EGD with
biopsies
WA diagnosis confirmed
Gluten
challenge +
YES
Potential CD
NO
Biopsy
positive
YES
CD diagnosis
confirmed
GS diagnosis
confirmed
NO
GS ruled out
Consider other
diagnoses
NCGS diagnosis: the flow diagram
STEP 1
STEP 2
Start
GFD
GFD +
A or B
E E E E E E E
improved
1 week
GFD
GFD +
B or A
Stop
E
E
E
1 week
1 week
NCGS
confirmed or
excluded
Suspect
NCGS
gluten-containing
diet > 6 weeks
6 weeks
not
improved
NCGS
excluded
The Salerno NCGS diagnostic criteria (Nutrients, 2015)
ADSs and the gluten connection
• ADS is an heterogeneous group of disorders that is related
to multiple genetic and environmental factors
• No clearcut relationship between ADSs and celiac disease
• Gastrointestinal dysfunctions and associated symptoms
are common in ADS children
• Some evidence of a leaky gut and of a therapeutic effect
of the GFCFD in a sub-group of children with ADSs is
available (non celiac gluten sensitivity?), but further data
are needed
• Double-blind, placebo-controlled studies are required to
evaluate the effect of the GFCFD treatment in ADSs
children
Il sistema astronomico delle intolleranze al glutine
autism
Healthy population
(gluten tolerant)
W
A
(subgroup)
NCGS
IBS
(subgroup)
D
H
Celiac
disease
G
A