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ANTIBODIES ANTI-SACCHAROMYCES CEREVISIAE (ASCA) DO NOT DIFFERENTIATE CROHN’S DISEASE FROM CELIAC DISEASE

ANTIBODIES ANTI-SACCHAROMYCES CEREVISIAE (ASCA) DO NOT DIFFERENTIATE CROHN’S DISEASE FROM CELIAC DISEASE

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v. 47 – no.3 – jul./set. 2010Arq Gastroenterol  242
    A    R    T    I    G    O     O    R    I    G    I    N    A    L    /    O    R    I    G    I    N    A    L    A    R    T    I    C    L    E
ARQGA/1496
ANTIBODIES ANTI-
SACCHAROMYCES CEREVISIAE 
(ASCA) DO NOT DIFFERENTIATECROHN’S DISEASE FROM CELIAC DISEASE
Lorete Maria da Silva
 
KOTZE
1
, Renato Mitsunori
 
NISIHARA
2
, Shirley Ramos da Rosa
 
UTIYAMA
2
,Paulo Gustavo
 
KOTZE
1
, Petra Mirella
 
THEISS
1
and Márcia
 
OLANDOSKI
3
ABSTRACT
 – 
Context 
- Anti-
Saccharomyces cerevisiae
antibodies (ASCA), considered serologic markers or Crohn’s disease, weredescribed in patients with celiac disease, disappearing ater a gluten-ree diet.
Objectives
- Evaluation o ASCA positivity in patientswith Crohn’s disease and celiac disease in relation to healthy individuals.
Methods
- A total o 145 individuals were studied: 36 with
Crohn’s disease and 52 with celiac disease, that ullled the diagnostic criteria or both aections, and 57 healthy individuals or control.
The celiac patients were divided as ollow: group CeD I at diagnosis (n = 34), group CeD II with gluten-ree diet compliance (n = 13)and group CeD III with transgressions to the diet (n = 5). ASCA IgA and IgG were determined by ELISA.
Results
- With statistical
signicance, ASCA IgA were positive in Crohn’s disease, celiac disease at diagnosis and celiac disease with diet transgressions; ASCAIgG in Crohn’s disease and in all groups with celiac disease.
Conclusions
- The detection o ASCA in patients with celiac disease allows
to suggest that ASCA is not a specic marker or Crohn’s disease, but was associated with the infammation o the small intestine.The increased levels o positive ASCA may be due to genetic actors and increased intestinal permeability.
HEADINGS
 – 
Saccharomyces cerevisiae.
Crohn disease. Celiac disease. Diet, gluten-ree.
INTRODUCTION
Crohn’s disease (CD) is a chronic infammatorybowel disorder o uncertain etiology which clinical
course is characterized by relapsing and remittingchronic intestinal infammation. The way in which
environmental actors modiy the expression o genes
in susceptible individuals and modulate the eector
unction o the intestinal immune system is not yet well
known. Antibodies to bake yeast and brewer’s yeast
(anti-
Saccharomyces cerevisiae
or ASCA) directed
against cell wall oligomannosides epitopes have been
proposed as serological marker or Crohn’s disease
(CD) with 60% o sensitivity and 80% o specicity
(8)
.
In a Brazilian study, ASCA were positive in 80% o 40 patients with CD
(22)
.
 
In CD
 
ASCA seemed to have
most signicant association with small bowel disease,
brostenosis, internal perorations and small bowelsurgery
(15, 19)
. However, the cause o ASCA positivityis still unknown and some authors have considered
antibody ormation as a consequence o increased
mucosal permeability
(11)
. These changes are also ound
in 10%-20% o rst-degree relatives o patients withCD
(11, 12)
. ASCA are known to be positive in 0%-5%o healthy controls
(8, 20)
.
Celiac disease (CeD) is an immune-mediated enteropathy
that is precipitated by the ingestion o gluten in geneticallysusceptible individuals
(10)
. The diagnosis includes positivity
or serological tests as antiendomysium (IgA EmA)
(27)
 
and/or anti-tissue transglutaminase (IgA anti-tTG)
antibodies
(6)
, and histological changes in small bowel
mucosa
(28)
. The treatment with a gluten-ree diet (GFD)
result in healing o the mucosa changes, improvemento the malabsorptive state and reversal o the majorityeects o the aection, including disappearance o theautoantibodies in the sera
(10)
. There are several studies
demonstrating increased permeability o the gut mucosa
in CeD by sugar absorption tests
(25, 26)
and the presence
o ood allergens. These changes also can disappear ater
a GFD. Probably the increased intestinal permeabilitymay be related to constitutional actors in susceptibleindividuals and may detect latent CeD
(7, 12)
.
Currently, there are reports o the presence o 
ASCA in the sera o patients with CeD at diagnosis and
disappearing ater a GFD, suggesting that ASCA can be
a sensitive marker o intestinal mucosa integrity
(5, 9, 23)
.
In the dierential diagnosis o intestinal disorders,
the presence o autoantibodies in the sera can be
helpul in the investigation o patients with unexplainedcomplaints. In this context, the aims o the present study
Prêmio da Federação Brasileira de Gastroenterologia como o melhor trabalho de Gastroenterologia na VIII Semana Brasileira do Aparelho Digestivo, Brasília, DF, Brasil, 2008.
This manuscript has not any potential conicts o interest regarding specifc fnancial interests (personal or institutional).
1
Hospital Cajuru, Pontifícia Universidade Católica do Paraná;
2
Laboratório de Imunopatologia Molecular, Hospital de Clínicas, Universidade Federal do Paraná;
3
Departamento de Estatística, Pontiícia Universidade Católica do Paraná, Curitiba, PR, Brazil.Correspondence: Pro. Lorete Maria da Silva Kotze - Rua Bruno Filgueira, 369 – cj. 1205 - 80240-220 – Curitiba, PR, Brazil. E-mail: loretekotze@hotmail.com
 
Kotze LMS, Nisihara RM, Utiyama SRR, Kotze PG, Theiss PM, Olandoski M. Antibodies anti-
Saccharomyces cerevisiae
(ASCA) do not dierentiate Crohn’s diseaserom celiac disease
Arq Gastroenterol 
243
v. 47 – no.3 – jul./set. 2010
were to evaluate the requency o ASCA in patients with CDand CeD (at diagnosis and in a GFD), comparing the results
with the data o healthy controls o the same geographic area.
METHODS
Controls and patients
The patients were studied at the Gastroenterology and
Coloproctology Services, Cajuru Hospital, Pontical Catholic
University o Paraná, Curitiba city, State o Paraná, SouthBrazil. The study was approved by the Ethical Committeeo the Institutions involved in the research.Demographic data o the studied groups are showed inTable 1. Fity-seven healthy individuals, 38 emale (66.7%)and 19 male (33.3%), mean age 38.9 years (range 14 to 67
years) were enrolled as controls. Thirty-six patients with
CD, 63.9% emale, 36.1% male, mean age 42.9 years (range16 to 83 years) were evaluated. Fity-two patients previously
diagnosed as having CeD, 38 (73%) emale and 14 (27%) male,
mean age 38.1 years (range 16 to 68 years) were divided asollow: 34 at diagnosis (Group CeD I) and 18 in a GFD, 13with strict compliance to the diet (Group CeD II) and 5 thatadmitted transgressions (Group CeD III).
RESULTS
All the controls, patients with CD and patients with CeD
adherent to a GFD (group CeD II) were negative or IgA
EmA and IgA anti-tTG; celiacs at diagnosis (group CeD
I) and patients with no compliance to a GFD (group CeDIII) were positive or both autoantibodies. The positivity o ASCA IgA and IgG or all the groups were summarized inTable 2. The statistical analysis is demonstrated in Table 3.
TABLE 1
– Demographic data o the controls and studied patients
GroupFemale%Male%Mean age (years)
Controls (n = 57)66.733.338.9 (14-67)CD (n = 36)63.936.142.9 (16-83)CeD I (n = 34)73.526.540.1 (19-65)CeD II (n = 13)76.923.135.4 (16-68)CeD III (n = 5)60.040.038.8 (30-56)
CD = Crohn’s disease; CeD I = celiacs at diagnosis; CeD II = celiacs adherent to a GFD;CeD III = celiacs with transgressions to a GFD
Methods
The serum samples o all the studied individuals, stored
at -80ºC, were submitted to antibodies evaluations in
the Laboratory o Immunopathology, Clinical Hospital,
Federal University o Paraná. The diagnosis o CeD wasbased on IgA antiendomysium (EmA) and IgA anti-tissue
transglutaminase (anti-tTG) serum positivity plus histological
ndings o the intestinal biopsies
(18, 28)
. An accurate dieteticinterview was used to register data related to the current dieto the celiac patients. The patients with CD were diagnosed
based on accepted clinical, endoscopic and radiological
criteria supported by histopathology
(19, 20, 21)
.
 
ASCA IgA andIgG were quantitated using a standard calibrated enzyme
linked immunosorbent assay (ELISA) commercially kits
and perormed according to the manuacturer’s instructions
(QUANTA Lite
TM
, INOVA, USA
®
). ASCA IgA and IgG cut
o values dening seropositivity were 20 U/mL.
Statistics
Results are presented as the absolute number and percentage
o patients that are positive or ASCAs. Dierences between
variables were evaluated by Fisher’s exact test:
P
values <0.05
were considered statistically signicant.
TABLE 2.
Percentage o ASCA positivity in the studied groups
GroupsASCAIgAASCAIgG ASCAIgA and IgG 
Controls (n = 57)5.21.70.0CD (n = 36)36.144.427.8CeD I (n = 34)61.788.255.8CeD II (n = 13)0.053.80.0CeD III (n = 5)40.060.00.0
CD = Crohn’s disease; CeD I = celiacs at diagnosis;CeD II = celiacs adherent to a GFD; CeD III = celiacs with transgressions to a GFD
 
TABLE 3.
Statistical analysis o ASCA positivity in the studied groups *
GroupsASCA IgAASCA IgGASCA IgA and Ig
CD x Control<0.001<0.001<0.001CD x CeD I0.055<0.0010.149CD x CeD II0.0110.7470.011CD x CeD III0.9960.6490.160CeD I x Control<0.001<0.001<0.001CeD II x Control1<0.001-CeD III x Control0.0480.001-CeD I x CeD II<0.0010.0170.001CeD I x CeD III0.6310.1610.047CeD II x CeD III0.0651-
*Fisher’s exact test (
P  
<0.05). In blot the data with statistical signifcanceCD = Crohn’s disease; CeD I = celiacs at diagnosis; CeD II = celiacs adherent to a GFD;CeD III = celiacs with transgressions to a GFD
DISCUSSION
The demographic data showed that both CD and CeDhad an young adult emale preponderance, as demonstratedby several authors in dierent countries
(2, 10)
.
Both CD and CeD can have similar gastrointestinal
presentation and are characterized by the presence o distinct
serological autoantibodies. The results o the present study
conrm that IgA EmA and IgA anti-tTG are the most sensitive
serological markers or CeD, being negative in the healthycontrols, in the CD patients and in the celiac patients withcompliance to a GFD
(13)
.The high prevalence o ASCA in CeD was previously
reported by Giaer et al.
(8)
, speciically ASCA IgG.
Damoiseaux et al.
(5)
reported positivity or ASCA IgA and/
or IgG in 30% o 37 patients with biopsy-conrmed CeD,
while Granito et al.
(9)
reported 59% o ASCA positivitywhen evaluated 105 CeD patients (adults and children).
In the present investigation, the positivity o ASCA wasunexpectedly increased in patients with CeD at diagnosis,showing ASCA IgA in 61.7%, IgG in 88.2% and both IgAand IgG in 55.8%, with statistical signicance in relationto controls and patients with CD (Table 3). These values
 
Kotze LMS, Nisihara RM, Utiyama SRR, Kotze PG, Theiss PM, Olandoski M. Antibodies anti-
Saccharomyces cerevisiae
(ASCA) do not dierentiate Crohn’s diseaserom celiac disease
Arq Gastroenterol  244v. 47 – no.3 – jul./set. 2010
are higher than the data obtained by the cited authors.
Mallant-Hente et al.
(17)
reported 18% o ASCA positivityin 83 children and 61% in 28 adults with CeD at diagnosis,
similarly to our results. The higher levels o ASCA observedat diagnosis o adults CeD patients probably may be related
to the act that they had been exposed to gluten or longerand thereore had more long-lasting damage
(1, 24)
 
The level o the ASCA also has been helpul in
monitoring celiac patients or compliance to the GFD.Mallant-Hent et al.
(17)
reported disappearance o ASCAin children (1%) and a decreased in the adults (29%) inGFD. In children the disappearance o ASCA positivitywas more pronounced and this can be explained by thewell-known act that gut permeability normalizes betterin children than in adults. Granito et al.
(9)
reported that
the disappearance o ASCA IgA (93%) was more requent
than that o ASCA IgG (17%) ater GFD. In our studywe also nd no ASCA IgA and only ASCA IgG in thepatients with diet compliance (Table 2). By other hand,
in the patients with transgressions to the GFD, the ASCA
IgA was positive in 40% and IgG in 60%, conrming
that this determination can help in monitoring the diet,in spite the low number o individuals evaluated (Table2). IgA is known to be a mucosal immunoglobulin andthereore may recover aster than the more systemic IgG
(immunological memory). The positivity and the levels o 
ASCA IgG in treated patients with CeD with complianceto the diet or that admitted transgressions, were similar.
This suggest that the period o gluten exposure is only one
o the determinants o the mucosal changes (individualor genetic actor?).
ASCA can be a marker used in the dierentiation o 
infammatory bowel diseases (IBD). According to Saibeni et
Kotze LMS, Nisihara RM, Utiyama SRR, Kotze PG, Theiss PM, Olandoski M. Anticorpos anti
-Saccharomyces cerevisiae
não dierenciam doença deCrohn de doença celíaca. Arq Gastroenterol. 2010;47(3):242-5.
RESUMO
 – 
Racional 
- Anticorpos anti-
Saccharomyces cerevisiae
antibodies, considerados marcadores sorológicos para a doença de Crohn, oramdescritos em pacientes com doença celíaca, desaparecendo após dieta isenta de glúten.
Objetivos
- Avaliação da positividade de anti-
Saccharomycescerevisiae
antibodies em pacientes com doença de Crohn e doença celíaca, em relação a indivíduos sadios da mesma área geográca.
Métodos
- Foramestudados 145 pacientes, 36 com doença de Crohn e 52 com doença celíaca que preencheram os critérios diagnósticos para ambas as aecções, e 57indivíduos sadios para controle. Os pacientes celíacos oram divididos como segue: ao diagnóstico (grupo doença celíaca I: n = 34), obedientes àdieta isenta de glúten (grupo doença celíaca II: n = 13) e não-aderentes à dieta isenta de glúten (grupo doença celíaca III: n = 5). Anti-
Saccharomycescerevisiae
antibodies IgA e IgG oram determinados por ELISA.
Resultados
- Anti-
Saccharomyces cerevisiae
antibodies IgA oi positivo na doençade Crohn, nos celíacos ao diagnóstico e nos transgressores à dieta, com signicado estatístico. Anti-
Saccharomyces cerevisiae
antibodies IgG oipositivo na doença de Crohn e em todos os grupos de celíacos, com signicado estatístico.
Conclusões
- A detecção de anti-
Saccharomyces cerevisiae
 antibodies em pacientes com doença celíaca permite sugerir que o mesmo não seja marcador especíco para a doença de Crohn, mas que estejaassociado à infamação do intestino delgado. A positividade de anti-
Saccharomyces cerevisiae
antibodies pode ser decorrente de atores genéticos eaumento da permeabilidade intestinal.
HEADINGS
 – 
Saccharomyces cerevisiae
. Doença de Crohn. Doença celíaca. Dieta livre de glúten.
al.
(21)
in the dierential diagnosis o IBD, double positivity
or ASCA IgA and IgG identies with certainty the presence
o CD, as demonstrated in our study: ASCA IgA has beenpositive in 36.1% o the patients, ASCA IgG in 44.1% and
both in 27.8%, with statistical signicance in relation to
controls (Tables 2 and 3).
The high positivity detected in CeD patients at diagnosis,
in a GFD and with diet transgressions (Tables 2 and 3),
emphasizes that ASCA do not allow dierentiate DC romCeD. Similarly, Makharia et al.
(16)
reported that ASCA donot dierentiate CD rom intestinal tuberculosis.
The protective unction o the intestinal mucosa is
called “permeability”
(12)
. When the intestinal mucosal
barrier is broken, with junctions-mediated barrier deects,an infux o luminal antigens may result in infammation,even by chronically stimulating resident, with consequentrecruitement o immunocompetent cells rom the lamina
propria
(3, 7)
. In patients with autoimmune diseases, like
CD, or in inectious disease, and in various other clinicalconditions, ASCA can be positive. The presence o ASCAmay refect a shared permeability disorder, leading to theenhanced exposure to various antigens that, depending onthe genetic background, may provoke various or multiple
autoimmune disorders.
(3, 4, 5, 7, 9, 14)
. The antibodies in the sera
o the analysed ASCA positive cases proved a systemic
immune response against
Sacharomyces cerevisiae
(generally
accepted as not a pathogen)
 
and suggested the end o theoral tolerance against the yeast’s antigens
(3)
.In conclusion, the results show that ASCA was ound
in patients with CeD and disappear ater a GFD. So, it
is presumed that ASCA positivity is not a specic markeror Crohn’s disease but correlates with the (auto) immuneinfammation o the small intestine.

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