Dietary antibodies and gluten related seromarkers in children and young adults with cerebral palsy

106 Pages·2012·1.65 MB·English

Dietary antibodies and gluten related seromarkers
in children and young adults with cerebral palsy
To the children and youth with cerebral palsy and their families.

The long and winding road, that leads to the door……
(Lennon/McCartney)
To the children and youth with cerebral palsy and their families. Örebro Studies in Medicine 72

REIDUN STENBERG

Dietary antibodies and gluten related seromarkers

in children and young adults with cerebral palsy

The long and winding road, that leads to the door……
(Lennon/McCartney)
To the children and youth with cerebral palsy and their families.

The long and winding road, that leads to the door……
(Lennon/McCartney)

© Reidun Stenberg 2012
Title: Dietary antibodies and gluten related seromarkers
in children and young adults with cerebral palsy.

Publisher: Örebro University 2012
www.publications.oru.se
[email protected]

Print: Ineko, Kållered 08/2012
ISSN 1652-4063
ISBN 978-91-7668-884-7
To the children and youth with cerebral palsy and their families.

Abstract

Reidun Stenberg (2012): Dietary antibodies and gluten related seromarkers in
children and young adults with cerebral palsy. Örebro Studies in Medicine 72.
The long and winding road, that leads to the door……
(Lennon/McCartney) Background&Aims; Cerebral palsy (CP), the most common physical disorder in
children that affect motor function, is associated with a low weight and height.
Celiac disease (CD), an autoimmune disorder precipitated by ingestion of gluten,
is another common chronic disease in children that has a negative impact on
growth. Based on our findings in a small pilot study, antibodies against gluten,
dietary antigens and antibodies against transglutaminase 6(TG6) a new possible
gluten related neurological marker have been investigated in an extended group
of children with CP. The main aim of this thesis was to find out if the children
with elevated gluten related antibodies have enteropathy consistent with CD and
if they have antibodies to other dietary antigens as well. We further wanted to
study if elevated levels of antibodies were associated to their weight, subtypes of
CP and also to investigate if there were an association between the brain damage
seen in CP and antibodies against TG6.
Methods; Ninety nine children with CP and matched (study4) controls (study3)
were analysed for antibodies against gluten, TG6, egg white, lacto-globulin, casein
and wheat. Small bowel biopsies were analysed in the majority of the children with
antibody positivity, both by routine procedures and by extended analyse (study 2).
Results; Significantly elevated levels of gluten related seromarkers and antibodies
against casein, lacto globulin and egg white were found in the CP-group compared

to matched controls. The overall elevated levels of antibodies were more frequent in

the tetraplegic (TP) and dyskinetic (DK) CP -subtypes having the most severe neuro-
logic handicap and undernourishment. Routine and extended small bowel biopsies
analysis did not indicate an increased prevalence of CD. Elevated antibodies against
TG6 were found in the CP-group and significantly in the tetraplegic CP-subgroup.
© Reidun Stenberg 2012
Conclusion Children with CP do not have increased prevalence of celiac disease
but have elevated levels of gluten related seromarkers as well as antibodies against
Title: Dietary antibodies and gluten related seromarkers
other dietary proteins compared to matched controls. There was a correlation
in children and young adults with cerebral palsy.
between underweight, CP-subtypes (TP/DK) and occurrence of the tested antibod-
Publisher: Örebro University 2012 ies suggesting disturbed intestinal permeability related to underweight. Compared
www.publications.oru.se to controls TG6 autoantibodies were found in the TP-subtype of CP that could
[email protected] be a result due to the brain damage.

Keywords: Cerebral palsy, children, celiac disease, glutensensitivity, brain,
Print: Ineko, Kållered 08/2012 transglutaminase 2 and 6, malnutrition, casein, eggwhite laktoglobulin.

ISSN 1652-4063 Reidun Stenberg, School of Health and Medical Sciences/Clinical Medicine,
ISBN 978-91-7668-884-7 Örebro University, SE-701 82 Örebro, Sweden, [email protected]

List of papers
This thesis is based on the following original papers.

I. Stenberg R, Dahle C, Lindberg E, Schollin J. Increased prevalence of
anti-gliadin antibodies and anti-tissue transglutaminase antibodies in chil-
dren with cerebral palsy. J Pediatr Gastroenterol Nutr 2009;49(4):424-9.

II. Stenberg R, Kaukinen K, Bengtsson M, Lindberg E, Dahle C. A study on
early developing celiac disease in children with cerebral palsy. J Pediatr
Gastroenterol Nutr 2011; 53(6):674-8.

III. Stenberg R, Hadjivassiliou M, Aeschlimann P, Hoggard N, Aeschli-
mann D. Transglutaminase 6 antibodies in children and young adults with
Cerebral Palsy. 2012 [Submitted].

IV. Stenberg R, Magnuson A, Dahle C, Hellberg D, Tysk C. Antibodies
against dietary proteins in children and young adults with cerebral palsy.
2012[Submitted].

All previously published papers were reproduced with permissions from
the publisher.
Abbreviations

AGA = anti-gliadin antibody
A = ataxic
BMI = body mass index
BSA = bovine serum albumin
CD = coeliac disease
CI = confidence interval
CP = cerebral palsy
CRM = celiac disease-related marker
CT = computed tomography
DGP = deamidated gliadin peptide
DK= dyskinetic
DP = diplegic
ECM = extracellular matrix
ELISA = enzyme-linked immunosorbent assay
EMA = endomysial antibody
EDCD =early developing coeliac disease
FEIA = fluorescence enzyme-linked immunosorbent assay
GERD = gastroesofageal reflux disease
GMFCS = Gross Motor Function Classification System
GS = gluten sensitivity
HLA = human leukocyte antigen
HP = hemiplegic
IF: immunofluorescence
IEL = intra-epithelial lymphocyte
IgA = immunoglobulin A
IgG = immunoglobulin G
IQR = interquartile range
IP = intestinal permeability
MRI = Magnetic Resonance Imaging
NSAID = non-steroidal anti-inflammatory drug
OR = odds ratio
PVL = periventricular leukomalacia
PPI = proton pump inhibitor
SD = standard deviation
TBS = Tris-buffered saline
TG = transglutaminase
tTG /TG2= tissue transglutaminase 2
TP = tetraplegic
Abbreviations Table of contents

AGA = anti-gliadin antibody PREFACE ................................................................................................ 13
A = ataxic
BACKGROUND ...................................................................................... 15
BMI = body mass index
Introduction ............................................................................................. 15
BSA = bovine serum albumin
Cerebral palsy (CP) .................................................................................. 15
CD = coeliac disease
Prevalence ............................................................................................ 16
CI = confidence interval
Definition of cerebral palsy .................................................................. 16
CP = cerebral palsy
Classification of cerebral palsy ............................................................. 16
CRM = celiac disease-related marker
The Gross Motor Function Classification System ................................ 17
CT = computed tomography
Aetiology.............................................................................................. 17
DGP = deamidated gliadin peptide
Comorbidity ........................................................................................ 19
DK= dyskinetic
Growth and feeding problems .............................................................. 19
DP = diplegic
Gastrointestinal problems .................................................................... 21
ECM = extracellular matrix
Treatments and life expectancy ............................................................ 22
ELISA = enzyme-linked immunosorbent assay
Coeliac disease (CD) ................................................................................ 22
EMA = endomysial antibody
Classification of Coeliac Disease .......................................................... 22
EDCD =early developing coeliac disease
Early developing coeliac disease. .......................................................... 23
FEIA = fluorescence enzyme-linked immunosorbent assay
Genetics ............................................................................................... 24
GERD = gastroesofageal reflux disease
Diagnosis ............................................................................................. 26
GMFCS = Gross Motor Function Classification System
Laboratory test .................................................................................... 26
GS = gluten sensitivity
Criteria................................................................................................. 26
HLA = human leukocyte antigen
Symptoms ............................................................................................ 26
HP = hemiplegic
Gut permeability ...................................................................................... 27
IF: immunofluorescence
Gluten sensitivity (GS)/ non-coeliac glutensensitivity ............................... 28
IEL = intra-epithelial lymphocyte
Extraintestinal manifestations of CD and or GS ...................................... 29
IgA = immunoglobulin A
Neurologic and neuropsychiatric aspects ............................................. 29
IgG = immunoglobulin G
Ataxia .................................................................................................. 32
IQR = interquartile range
Epilepsy ............................................................................................... 32
IP = intestinal permeability
Autism ................................................................................................. 33
MRI = Magnetic Resonance Imaging
The transglutaminases .............................................................................. 34
NSAID = non-steroidal anti-inflammatory drug
Malnutrition ............................................................................................ 35
OR = odds ratio
Stunting (H/A) ..................................................................................... 35
PVL = periventricular leukomalacia
Wasting (W/H) ..................................................................................... 35
PPI = proton pump inhibitor
Underweight (W/A) .............................................................................. 35
SD = standard deviation
Weight and height recordings............................................................... 35
TBS = Tris-buffered saline
Effect of malnutrition on intestinal function ........................................ 36
TG = transglutaminase
Malnutrition and cerebral effects ......................................................... 37
tTG /TG2= tissue transglutaminase 2
The tested dietary antigens in the thesis ................................................... 38
TP = tetraplegic
Gluten .................................................................................................. 38
Milk ..................................................................................................... 38
Casein .................................................................................................. 38
Beta-lactoglobulin ................................................................................ 39
Egg white ............................................................................................. 39
AIMS OF THIS THESIS ........................................................................... 40
DEFINITIONS ......................................................................................... 41
METHODS .............................................................................................. 42
Subjects .................................................................................................... 42
Study 1 ................................................................................................. 44
Study 2 ................................................................................................. 44
Study 3 ................................................................................................. 44
Study 4 ................................................................................................. 45
Control groups ..................................................................................... 45
Study 3 ................................................................................................. 45
Study 4 ................................................................................................. 45
Weight Height and BMI ....................................................................... 45
Serological analyses .............................................................................. 45
Study 1 ................................................................................................. 46
Study 3 ................................................................................................. 47
Study 4 ................................................................................................. 48
Small bowel Biopsies ............................................................................ 49
Study1 .................................................................................................. 49
Study 2 ................................................................................................. 49
STATISTICAL METHODS ...................................................................... 51
ETHICAL CONSIDERATIONS .............................................................. 51
RESULTS ................................................................................................. 52
Study 1 ..................................................................................................... 56
Study 2 ..................................................................................................... 57
Study 3 ..................................................................................................... 58
Study 4 ..................................................................................................... 59
DISCUSSION ........................................................................................... 61
Methodological considerations................................................................. 61
The cohort ........................................................................................... 61
Study design ............................................................................................. 61
Study 1 ................................................................................................. 61
Study 2 ................................................................................................. 61
Study 3 ................................................................................................. 62