Gluten intake and gluten-free diet in the Netherlands
Cover illustration gluten structure obtained by washing out dough.
Cover design Anja Bakker
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Financial support for the publication of this thesis was kindly provided by Willem-
Alexander Kinder- en Jeugdcentrum (Leiden University Medical Center), Celiac Disease
Consortium, Dienst Diëtetiek (Leiden University Medical Center), Divisiebestuur Divisie
2 (Leiden University Medical Center), Nederlandse Coeliakie Vereniging, Friso
Kindervoeding, Mead Johnson Nutritionals, Nutricia Advanced Medical Nutrition,
Sorgente B.V., Nutri-akt b.v. - arbeidsmarktintermediair binnen Food, Technology,
Nutrition & Health.
© 2008 Erica Hopman. Niets uit deze uitgave mag worden verveelvoudigd en/of
openbaar worden gemaakt zonder voorafgaande schriftelijke toestemming van de auteur.
No part of this thesis may be reproduced in any form without written permission from
Gluten intake and gluten-free diet in the Netherlands
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof.mr. P.F. van der Heijden,
volgens besluit van het College van Promoties
te verdedigen op donderdag 25 september 2008
klokke 15.00 uur
Geertruida Dorothea Hopman
geboren te Den Burg, Texel
Promotor:Prof. dr. J.M. Wit
Copromotor: Dr. M.L. Mearin-Manrique
Referent:Prof. dr. C.J.J. Mulder (VU Amsterdam)
Overige leden:Dr. L.J.W.J. Gilissen (Wageningen Universiteit, Wageningen)
Prof. dr. D.W. Hommes
Prof. dr. J.A. Romijn
In herinnering aan mijn vader
Chapter 1General introduction, aim and outline of this thesis 9
Chapter 2Presence of gluten proteins in breast milk: implications for the 17
development of celiac disease
Chapter 3 Food questionnaire for assessment of infant gluten consumption 31
Clin Nutr 2007;26:264-71
Chapter 4 Nutritional management of the gluten-free diet in young people with 47
celiac disease in the Netherlands
J Pediatr Gastroenterol Nutr 2006;43:102-8
Chapter 5Tef in the diet of celiac patients in the Netherlands 61
Scand J Gastroenterol 2008;43:277-282
Chapter 6 Dietary compliance and health-related quality of life in patients with 73
Chapter 7 Gluten tolerance in adult patients with celiac disease 20 years after 85
Eur J Gastroenterol Hepatol 2008;20:423-9
Chapter 8 General discussion 101
Curriculum vitae 127
General introduction, aim and outline of this thesis
In the early 1930’s the Dutch paediatrician W.K. Dicke discovered that the elimination of
wheat from the diet was beneficial for celiac patients (1). This benefit was confirmed later
during the period of food shortage in the Second World War (1944-1945), during which
bread was unavailable, and Dicke observed that the clinical condition of the hospitalized
children with celiac disease improved. Further studies showed that gluten and specifically
its alcohol-soluble component, gliadin, was harmful for celiac patients (2). Gluten is the
storage protein of wheat and wheat-related grains and can be subdivided in the gliadin
and glutenin protein families, both of which are involved in celiac disease. Since then, a
gluten-free diet has been the basis of the treatment of celiac patients.
In celiac patients, gluten causes histological alterations of the small bowel that may lead
to disturbances in nutrient absorption and symptoms such as diarrhea, failure to thrive,
abdominal pain, and extraintestinal complications such as osteoporosis, infertility and
cancer (3). The treatment of celiac disease consists of a life-long gluten-free diet to heal
the duodenal mucosa, improve symptoms, and protect against development of
The diagnosis of celiac disease is based on characteristic histological alterations of the
small bowel mucosa during gluten consumption and clear clinical remission with a
gluten-free diet. In asymptomatic patients, however, a control biopsy is needed to prove
mucosal recovery after treatment (6). In earlier days, a third biopsy after gluten challenge
was needed to confirm the diagnosis in children (7).
Celiac disease is considered to be a life-long disorder, but there are studies describing
patients diagnosed with celiac disease in childhood who seem to tolerate gluten later in
life for an extended period of time (8).
Until now, the only effective treatment for the disease has consisted of a gluten-free diet
in which wheat, rye, barley, spelt, kamut, and products derived from these cereals are
avoided. To what extent oats belong to the list of banned cereals is still debated. Both
long-term follow-up studies (9-11) and laboratory studies on oats being less toxic than
wheat (12), support that oats are permitted in the gluten-free diet for adults and children.
However, some patients do show mucosal damage after oat consumption, and individual
differences in oat tolerance have been found (11,13). In the Netherlands, as in many
other countries, fear of wheat contamination in commercially available oat products has
led to a reluctance to recommend oats to celiac patients (14,15).
Wheat cereal is a staple food in many countries in Europe and is widely used in the food
industry. Therefore, wheat is difficult for celiac patients to avoid; hence, the prescription
to follow a gluten-free diet has a big impact on the patients’ daily and social life (16), and
even on the lives of family members. The availability of the gluten-free products is
limited, and consequently, celiac patients have difficulty finding gluten-free foods.
Furthermore, taste as well as higher expenses can be limiting factors for compliance. For
example, in the Netherlands, only a few health insurance companies contribute to the
added costs of the gluten-free products. All these factors may affect the health-related
quality of life of celiac patients (17,18). Furthermore, the nutritional value of gluten-free
food products is lower compared to the gluten-containing equivalents, which may lead to
inadequate nutrient intake (19-22).
Genetics play a role in the development of the disease: as much as 98% of the celiac
patients are HLA-DQ2 (95%) or –DQ8 (3%) positive. However, the majority of people
with these genetic factors do not develop celiac disease. This suggests that additional
genetic and/or environmental factors play a role in disease development.
Many genetic and immunological studies have been performed in an attempt to unravel
the complexity of this multi-factorial disease (23-25). In addition, the possible role of
environmental factors, such as early feeding, in the development or prevention of celiac
disease has been studied (26-28). The Swedish ‘experiment of nature’ causing the rise and
fall of ‘an epidemic’ of gluten intolerance after changes in infant feeding suggests that
early feeding may be an important factor (26). Breastfeeding at the time of gluten
introduction, ongoing breastfeeding while gluten is already being consumed, as well as
timing and amount of gluten introduced into the diet, may play a preventive role in the
development of celiac disease (27-29).
Breastfeeding and weaning influence the development of the gastro-intestinal tract, and it
is possible that gradual introduction of antigens will lead to the development of oral
tolerance (30,31). It is also likely that the response of the immune system to gluten is
modified by breastfeeding (32,33). The presence of gluten peptides in breast milk leading
to an early exposure to gluten, even before gluten is introduced into the infants’ diet, has
been studied as a possible factor in the development of oral tolerance (34,35).
AIMS OF THIS THESIS
Gluten is essential for the development of celiac disease: in the absence of gluten, celiac
disease will not be expressed. The aims of this thesis were to explore the relationship of
celiac patients with gluten and the gluten-free diet at different ages, their ability to
develop tolerance to gluten, and the impact of the gluten-free diet on health-related
quality of life. Furthermore, this thesis also aims to measure some of the environmental
factors such as breastfeeding and gluten intake in early life considered to play a role in the
prevention of celiac disease and in the possible development of oral tolerance.
Chapter 1 consists of a general introduction and description of the aims and outline of
the thesis. In chapter 2, the implication of the presence of gluten proteins in breast milk
for the development of celiac disease is discussed. This relates to one of the aims of the
study, i.e. to measure some of the environmental factors possibly involved in celiac
disease, such as early feeding. Breastfeeding has been shown to prevent, or at least delay,
the development of celiac disease (28). Breast milk contains many immunological factors
that stimulate the infant’s immune system, but its exact role in the prevention of celiac
disease is not known. Furthermore, breast milk contains small amounts of food antigens,
like gluten peptides, that may contribute to tolerance induction. As the first contact with
gluten may be important in this respect and the level of gluten peptides in breast milk
may vary with intake of gluten by the mother, we studied the level of gluten peptides in
breast milk of mothers on a gluten-containing diet and of mothers on a gluten-free diet.
Expecting to find gluten peptides in the breast milk of mothers on a normal diet, but not
in the breast milk of mothers on a gluten-free diet.
In chapter 3 we describe the development and testing of a food questionnaire to assess
gluten intake, since another possible factor in the development of oral tolerance is the
timing of gluten introduction and the quantity of gluten consumption in early life.
However, this hypothesis is only based on observational studies. The role of gluten
introduction should be confirmed by intervention studies before cause-effect conclusions
can be drawn and changes in advice considering early infant feeding can be proposed.
For such studies, it would be necessary to have an instrument available to assess the
amount of gluten consumed. Such an instrument should be accurate, easy to use, and
should be easily accessible by both researchers and parents. Since such an instrument was
lacking, we developed and validated one for this purpose.
In exploring the attitude of celiac patients towards the gluten-free diet, we studied the
management of the gluten-free diet by adolescent celiac patients. The results of that study
are described in chapter 4. Until now, the gluten-free diet was the only effective
treatment for the disease. From the perspective of the celiac patient, this treatment is
quite a burden. Gluten intake is difficult to avoid since wheat is the cereal most used in
staple food and widely used in the food industry. Furthermore, adherence to a gluten-free
diet may have negative nutritional consequences. Dietary compliance in adolescents with
celiac disease has been studied frequently and was shown to vary between 52% and 81%
in European countries. In the Netherlands, however, we did not have information on
this topic. Therefore, we studied the situation of dietary compliance in our country and
the consequences for the nutrient intake in young celiac patients.
In an attempt to enlarge the gluten-free food choices, we studied whether the (new)
naturally gluten-free cereal, tef (Eragrostis tef) can be safely used by celiac patients (Chapter
5). Adherence to the diet is often reported as being difficult. Next to the aforementioned
aspects, the limited availability, the variety and the taste of gluten-free food products may
have negative effects on the compliance with the gluten-free diet. A greater variety of
tasteful products may contribute to a better compliance with the diet.
We studied the health-related quality of life (Chapter 6) in an adult population of celiac
patients. Having a chronic disorder as well as having to adhere to a dietary regimen may
affect quality of life. The health-related quality of life of celiac patients adhering to the
gluten-free diet has been frequently studied in children as well as in adults. The adult
population we studied was recruited for the study described in chapter 7 and consisted of
celiac patients with strict adherence to the gluten-free diet and of celiac patients with
gluten transgression or consuming a normal gluten-containing diet. This gave us the
opportunity to compare the results of the health-related quality of life survey between
compliers and non-compliers.
In chapter 7 we describe the results of a study on possible development of tolerance to
gluten. As celiac disease is considered to be a permanent disorder, the diet has to be
followed for life. However, patients consuming gluten without developing symptoms or
signs of the disease have been described. Therefore, it is important to investigate which
factors (genetic, immunologic or environmental) determine which patients with celiac
disease remain intolerant to gluten for life and which few may regain tolerance. We
studied the possible existence of adult celiac patients developing tolerance to gluten in
the Netherlands and whether we could identify immunological or genetic factors that
might contribute to this.
Finally, the overall results of the studies described in this thesis are discussed in chapter
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