UMEÅ UNIVERSITY ISBN 978-91-7264-650-6
From the Departments of Food and Nutrition & Epidemiology and Public Health Sciences, Public Health and Clinical Medicine
Umeå University, SE-901 87 Umeå, Sweden
Celiac Disease in Swedish Children and Adolescents
Variations in Incidence and Essentials of Gluten-free Eating with a Youth Perspective
Cecilia Olsson
Umeå 2008
© Cecilia Olsson, 2008 Cover: Stina Johansson Printed in Sweden by Solfjädern Offset AB, Umeå 2008 ISBN 978-91-7264-650-6
The highest result of education is tolerance
Helen Keller
ABSTRACT
Background Sweden has experienced a unique epidemic of celiac disease (CD) in children younger than 2 years of age. The epidemic was partly explained by changes over time in infant feeding and indicated a multifactorial aetiology. In CD, a strict lifelong gluten-free diet (GFD) is crucial for health but noncompliance is often reported among adolescents. Knowledge is limited regarding their own perspectives and experiences of managing the disease and adhering to GFD. Objectives To analyse the incidence of CD in epidemic and post epidemic birth cohorts, and explore and understand how adolescents with CD perceive and manage their everyday lives in relation to the GFD. Methods A population-based incidence register of CD in children covering the entire nation from 1998 to 2003, and part of the country back to 1973. ESPGHAN diagnostic criteria for CD and NUTS classification of regions were used. Incidence rates for each year of diagnosis, age group, gender and region, and cumulative incidence by age for each birth cohort were calculated. Ten focus groups were conducted with 47 CD adolescents aged 15-18 years. Transcribed interviews were analysed to illustrate and explain adolescents’ own perspectives concerning life with a GFD, and to search for recurrent stigma-related themes across the groups. Results A considerable gap in the cumulative incidence of CD at comparable ages was demonstrated between birth cohorts of the epidemic and post-epidemic periods. The gap persisted during pre-school years, although it decreased somewhat with age. During the final years of follow-up there was again a gradual increase in incidence rate among children younger than 2 years of age. The childhood populations in ‘West Sweden’ and ‘Småland and the islands’ had a significantly higher incidence rate compared to ‘North Middle Sweden’ and ‘Stockholm’. CD adolescents described an awareness of being different from others produced by meal appearance and the poor availability of gluten-free (GF) food. Eating in public had the effect of making an invisible condition visible and thereby creating a context for felt or enacted stigma. Maintaining invisibility avoided the negative consequences of stigma. The probability of compliance with the GFD was compromised by insufficient knowledge of significant others, problems with the availability and sensory acceptance of GF food, insufficient social support and their perceived dietary deviance. Three different approaches to the GFD emerged: compliers, occasional non-compliers, and non-compliers. Conclusions The difference in CD risk between birth cohorts at comparable ages may suggest an opportunity for primary prevention. Based on post-epidemic incidence trends, the Swedish epidemic might not have been as unique as previously thought, even though its magnitude was striking. The regional variation in CD risk supports multifactorial aetiology. Continued efforts are warranted to define factors besides gluten exposure that modulate CD risk. CD adolescents experience various dilemmas related to the GFD. It can produce stigma experiences in adolescence, and dietary compliance (or lack of) can be understood in terms of dealing with GFD concealment and disclosure. The increase in CD prevalence over time and unmet needs in young celiacs require resources to attain adequate levels of dietetic provision, regulated subsidies for covering additional costs for GF food, evidence-based practice, and increased general CD awareness for optimum clinical outcomes.
LIST OF PUBLICATIONS
This thesis is based on the following papers, which will be referred to by their Roman numerals.
I. Olsson, C., Hernell, O., Hörnell, A., Lönnberg, G., Ivarsson, A. Difference in celiac disease risk between Swedish birth cohorts suggests an opportunity for primary prevention. Pediatrics. 2008; 122: 528-534.
II. Olsson, C., Stenlund, H., Hörnell, A., Hernell, O., Ivarsson, A. Regional variation in celiac disease risk within Sweden supports multifactorial disease aetiology. Acta Paediatrica. DOI: 10.1111/j.1651-2227.2008.01086.x.
III. Olsson, C., Hörnell, A., Ivarsson, A., Mattsson Sydner, Y. The everyday life of adolescent coeliacs – issues of importance for compliance with the gluten-free diet. Journal of Human Nutrition and Dietetics. 2008; 21(4): 359-67.
IV. Olsson, C., Lyon, P., Hörnell, A., Ivarsson, A., Mattsson Sydner, Y. Food that makes you different: the stigma experienced by adolescents with celiac disease. Qualitative Health Research. Accepted. Forthcoming.
Paper I was reprinted with permission of the American Academy of Pediatrics. Paper II and III were published by Blackwell Publishing and no permission to reprint them was needed. Paper IV was reprinted with permission of SAGE Publications.
ABBREVIATIONS
CD celiac disease CI confidence intervals EMA anti-endomysium antibodies ESPGHAN European Society for Paediatric Gastroenterology, Hepatology and Nutrition GF gluten-free GFD gluten-free diet HLA human leukocyte antigen IEL intraepithelial lymphocyte NUTS Nomenclature of Territorial Units for Statistics RR relative risk, rate ratio tTG anti-tissue-transglutaminase antibodies
CONTENTS
INTRODUCTION ...... 1 Celiac disease ...... 1 Clinical aspects ...... 1 Genetics ...... 2 Pathogenesis ...... 2 Diagnostic criteria ...... 2 Variations in disease occurrence ...... 3 A multifactorial aetiology ...... 5 Option for primary prevention ...... 5 Gluten-free diet ...... 5 The complexity of food choice ...... 7 Compliance with the gluten-free diet ...... 7 Living with celiac disease in adolescence ...... 8 OBJECTIVES ...... 10 METHODS ...... 11 Combining epidemiological and qualitative research methods 11 The National Swedish Childhood Celiac Disease Register ...... 11 Statistical analyses (I, II) ...... 15 Theoretical framework (III, IV) ...... 16 Qualitative data analysis (III, IV) ...... 18 Ethical considerations ...... 19 MAIN FINDINGS AND DISCUSSION ...... 20 Differences in celiac disease risk ...... 20 How unique was the epidemic? ...... 22 Increased disease occurrence over time ...... 24 A potential for primary prevention ...... 25 Everyday life of celiac adolescents ...... 28 Compliance problems ...... 28 Being different because of different food ...... 30 Noncompliance as a stigma-reducing possibility ...... 33 Clinical challenge ...... 34 Validity (I) ...... 36 Trustworthiness (III, IV) ...... 38 CONCLUSIONS ...... 39 POPULÄRVETENSKAPLIG SAMMANFATTNING ...... 40 ACKNOWLEDGEMENTS ...... 42 REFERENCES ...... 44 APPENDIX 1...... 57 APPENDIX 2...... 58 PAPERS I-IV
INTRODUCTION
INTRODUCTION
Celiac disease
Celiac disease (CD) is the most common food-related chronic disease in children (1). It is an inflammatory disorder with autoimmune features, triggered in genetically susceptible individuals by exposure to dietary wheat and related prolamines from rye and barley. In the following, these are collectively referred to as gluten. In individuals with CD, gluten causes an immune- mediated enteropathy of the small intestinal mucosa, and in contrast to other autoimmune diseases, the precipitating antigen, dietary gluten, has been identified. The aetiology is multifactorial with both genetic and environmental factors contributing. Untreated CD is associated with a variety of health problems related to immunological processes and impaired nutrient absorption (2). An effective treatment is available through a strict lifelong gluten-free diet (GFD), which results in restored intestinal mucosa and relief of symptoms.
Clinical aspects
In early childhood, CD typically presents with gastrointestinal symptoms and clinical manifestations related to nutrient malabsorption. However, the clinical picture has changed considerably over time. Today, classical symptoms at diagnosis, such as diarrhoea, abdominal distension and growth failure, are less prominent, and CD more often presents later in life with diffuse or extra-intestinal symptoms (3, 4). Evidently, most CD cases remain undiagnosed unless actively screened (5).
The risk for developing other autoimmune diseases such as type I diabetes and autoimmune thyroiditis is 5-10 times higher in the CD population (6). The extent, to which the increased risk is explained by a common genetic background, or by exposure to dietary gluten, has not yet been determined. Moreover, CD is associated with genetic diseases such as Down’s syndrome and Turner syndrome.
1 INTRODUCTION
Genetics
There is a strong genetic susceptibility to CD but it is not yet fully understood. Individuals with alleles encoding human leukocyte antigen (HLA) DQ2 or DQ8 molecules are predisposed to CD (7). The contribution of HLA molecules to the genetic component of CD is at least 40% (8). Non-HLA genes also need to be identified to explain the remaining 60% of the genetic component. However, each contributing non-HLA gene seems to explain only a small part (9). It has been suggested that development of CD involves a combination of genetic components, each of which is not necessarily unique to the CD population (10, 11).
Pathogenesis
Today, CD is the best understood HLA-linked disorder. The expression of the endomysial autoantigen tissue-transglutaminase (tTG) is increased in individuals with CD. Via its enzyme activity tTG modifies glutamine- and proline-rich gluten peptides usually resistant to degradation by proteases in the human intestine (12). The modification of the gluten peptides enhances their binding to HLA-DQ2 or -DQ8 molecules, which stimulate gluten-specific T- cells leading to production of Th1 proinflammatory cytokines (13), and the mucosal immune response characteristic for CD. The histopathological abnormality of the intestinal mucosa can vary from merely an increase of intraepithelial lymphocytes (IELs) to clear structural damage with crypt hyperplasia and various degrees of villous atrophy (14).
Diagnostic criteria
Enteropathy Since 1990, current diagnostic criteria according to the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) are based on an initial intestinal biopsy showing villous atrophy of the small intestinal mucosa while exposed to gluten, followed by clinical remission after exclusion of gluten from the diet (15). Before revision, the former ESPGHAN criteria from 1970 included two more biopsies, one to verify a normalized intestinal mucosa on a GFD, and another to verify villous atrophy following gluten challenge. Today, the second and third biopsies
2 INTRODUCTION
are considered obligatory only when there are doubts about the initial biopsy interpretation and/or the clinical response to a GFD.
Future criteria A new diagnostic approach has been advocated during recent decades because of the recognition of antiendomysium (EMA) and tTG antibodies, both characterized by high sensitivity and specificity. Improvements in the serological methods and more information on the genetic components are needed before the intestinal biopsy will be redundant as a diagnostic tool. However, considering the variety in intestinal histological changes and systemic manifestations related to immunological processes, current diagnostic criteria need to be revisited (16).
Variations in disease occurrence
During recent decades the European view on CD has changed from regarding it as a rare childhood disease to considering it a worldwide public health problem encompassing all age groups. Today, CD is estimated to affect about 1% of most populations (17- 22), except the Saharawi population where the prevalence is over 5% (23). The prevalence of CD varies among different European populations with higher figures in genetically isolated populations like Northern Ireland (24), Sardinia (25), and Finland (19).
Variations in the frequency of diagnosed CD over time have also been demonstrated. In the 1970s, the cumulative incidence of symptomatic CD in Swedish children was quite stable, followed by an increase in the mid 1980s from 1 to 4 per 1000 births (26, 27). In Finland, the incidence figures were about the same as in Sweden during the 1970s (1 per 1000), but a shift towards older age at diagnosis was demonstrated (28). In contrast, the incidence decreased rapidly in Ireland (29), Scotland (30), and England (31).
However, ascertaining the true CD prevalence, i.e. the prevalence of gluten-induced enteropathy, is difficult as the symptoms are often vague and the spectrum of symptoms is wide, leaving a large proportion of cases undiagnosed (4, 32). The epidemiology has been depicted as an iceberg, where the clinically diagnosed CD cases are visible above the waterline, and the remaining majority of the CD population, the silent (unrecognized) and latent cases are hidden below the waterline (33).
3 INTRODUCTION
The Swedish Epidemic Unique to Sweden, the incidence of CD in children younger than two years of age showed an epidemic pattern during the period 1984 to 1996, partly explained by changes over time in infant feeding (34, 35), and with a twofold higher risk in girls compared to boys (36). The annual incidence rates increased fourfold to 200- 240 cases per 100 000 person years, which were levels higher than ever reported for any population except the Saharawi’s (23). At that time, it was contended that CD was unavoidable when dietary gluten was introduced to genetically susceptible individuals. Thus, both the abrupt four-fold rise and the subsequent rapid fall to the level before the epidemic were unexpected in the genetically relatively stable population of Sweden. Most cases contributing to the rapid rise in incidence had obvious symptoms suggesting CD, and thus improved case ascertainment was not a sufficient explanation (37). The later rapid decrease in incidence happened even though awareness of CD and its possibly vague symptoms had increased considerably among both health care personnel and the general public.
Preceding the epidemic a recommendation to postpone intro- duction of gluten-containing foods from 4 to 6 months of age inadvertently resulted in a decreased proportion of children being breastfed at gluten introduction (34). For example, of children born in 1986, 68% were breastfed at 4 months of age compared to 48% at 6 months of age (38). At the same time, the gluten content in widely used commercially available milk cereal drinks and porridges increased twofold (34). This was mainly due to a decrease in milk and an increase in cereals for the purpose of decreasing the total amount of protein given to infants. Milk cereal drinks provided about half of the total intake of cereal protein in infants during that time period (39).
Coincident with the end of the epidemic, recommended age and mode for gluten introduction were changed again in 1996 for the purpose of reducing the risk of CD at the population level. The introduction of gluten-containing foods in gradually increasing amounts, preferably while the infant is still breastfed was recommended at 4 to 6 months of age. At the same time, the gluten content of commercially available milk cereal drinks and porridges was reduced by one-third. These changes resulted in a larger proportion of children gradually introduced to gluten while still being breastfed, a pattern expected to reduce CD risk (35, 40).
4 INTRODUCTION
A multifactorial aetiology
The substantial variation in frequency of CD both between countries and over time supports the notion that environmental factors contribute, thereby indicating a multifactorial disease aetiology (41). Half of the epidemic was explained by changes in infant feeding (35), and consequently, other environmental- and lifestyle-factors also contributed. Repeated infectious episodes early in life have been suggested to trigger CD, as such episodes might increase gut permeability resulting in increased antigen penetration and/or induce a Th1-mediated immune response typical of CD (42, 43). Hence, genetic susceptibility and environmental- and lifestyle exposures, as well as interactions between them, together shape the immunological response to gluten (44).
Option for primary prevention
As a result of changes in infant feeding over time, birth cohorts in Sweden differ with respect to gluten exposure early in life (34). A continued excess CD risk later in life in birth cohorts of the epidemic period indicate both short- and long-term consequences of infant feeding for CD risk, and possibly an option for primary prevention. The opportunity to monitor CD incidence over time in epidemic and post-epidemic birth cohorts in the Swedish childhood population provides a unique basis for further exploration of the contribution of environmental- and lifestyle factors.
Gluten-free diet
A strict, lifelong GFD is effective in most patients and restores the morphology of the intestinal mucosa, relieves symptoms, and reverses and prevents negative health consequences (45). Options for new, alternative treatments have been reported (46); however, the GFD is still the only accepted medical treatment for CD.
The basis of the GFD is exclusion of gluten proteins from the diet. Gluten proteins are found in the botanically related cereals wheat, rye, and barley. The most CD toxic components reside in the proline- and glutamine-rich prolamines, the alcohol soluble
5 INTRODUCTION
fractions of the proteins. In wheat these prolamines are called gliadins, and in rye and barley, hordeins and secalins, respectively. Pure oats are now considered to be tolerated by most children and adults with CD (47, 48), and have therefore been allowed in the GFD in Sweden and some other countries. However, an immune response to oats has been reported in a few CD cases (49).
Elimination of gluten from the diet most likely interferes with the dietary habits of an individual. Foods such as vegetables, fruits, rice, potatoes, legumes, dairy products, meats and fish, are inherently GF provided preparation and cooking are GF. However, cereals, especially wheat, are a staple food in most populations and a myriad of industrially processed foods contain wheat in varying amounts. Subsequently, knowledge and close attention are needed when reading the lists of contents as many gluten-containing foods are labelled with words not obviously indicating gluten.
Gluten-free substitutes GF substitutes are available for most gluten-containing foods such as pasta, bread, pizza and crackers. These substitutes are specifically manufactured with inherently GF flour, e.g. corn, rice, potatoes, and buckwheat, or purified wheat-starch meeting the Codex Alimentarius Standard for GF foods (50).
Nutritional features of a gluten-free diet In CD patients, exclusion of gluten-containing cereals indirectly results in a limited range of foods providing dietary fibre, B- vitamins, and minerals. GF substitutes, if nutrient-enriched, might compensate for this. However, lower intakes of B vitamins, dietary fibre, and iron, together with a higher percentage of energy derived from fat and less from carbohydrates than that of controls have been reported in both CD children and adults (51, 52). A comprehensive picture of nutrient intake in CD patients is still lacking.
6 INTRODUCTION
Sensory features of gluten-free food The elastic and viscous properties of gluten facilitate bread making by giving structure to both the dough and the baked bread (53). Bread making without gluten is challenging because of the liquid dough and the limited gas holding properties, resulting in bread with a crumbling texture and pale colour. In cereal-based GF- products, different ingredients such as starches, hydrocolloids and dairy products are used to improve the sensory properties by mimicking the properties of gluten. In recent decades the quality of these products has improved remarkably but the structure, taste, and appearance still differ from their gluten-containing counterparts.
The complexity of food choice
Theoretically, it is possible to compose a GFD that provides both macro- and micronutrients in accordance with national dietary guidelines. However, dietary habits and the underlying factors influencing what people really eat are complex and involve social, cultural, personal, and biological concerns that either facilitate or aggravate healthy eating (54, 55). Cultural norms shape food choices and food preferences on a broader level (56). On an individual level, food choice carries many different meanings (57) and is commonly characterized by motivational conflicts and ambivalence (58, 59). These conflicts are reinforced by the expanding range of novel food products and the increasing amount of food information (60).
The complexity of food choice affects CD individuals as well as other people. In addition to the challenge of composing a healthy diet with a limited range of food items, CD individuals are continuously confronted with the everyday decision of whether to comply with the GFD or not.
Compliance with the gluten-free diet
Definition of compliance A well defined and generally accepted definition of compliance with a medical treatment has not yet been established (61). Using dietary history, serological tests and intestinal biopsy, GFD
7 INTRODUCTION
compliance is operationalized as an outcome with different sensitivities and specificities (62). The concept of compliance can also be seen as a complex process involving a diversity of emotions, intentions and actions (61). To explore this process, other methods might be more suitable, e.g. qualitative interviews with CD patients. Using such a framework, the patients’ own descriptions of their actions are not necessarily correlated with the actual ingestion of gluten, but the complex process behind the decision to comply or not to comply with the GFD can be revealed.
Consequences of noncompliance Untreated CD is associated with a variety of health problems related to immunological processes and impaired nutrient absorption such as, diarrhoea, abdominal pain, anaemia, fatigue and osteoporosis (63, 64). The health risks with a gluten- containing diet for those who are screening-detected or have minor enteropathy need to be further explored (65). In addition, evidence suggests that some CD patients might develop tolerance for gluten later in life, at least transiently (66).
Noncompliance in adolescents In CD adolescents, 50 to 80 % are reported to be strictly compliant with the GFD (51, 67-74). Younger children have shown higher compliance rates than older children (71), and young adults diagnosed before 4 years of age comply better than those diagnosed at an older age (75). CD diagnosis confirmed by intestinal biopsy and not based only on clinical suspicion, increases the compliance rate (72, 76). Disease-related knowledge in CD adolescents (71), and in parents of children with CD (67, 70), has also been shown to increase compliance with a GFD. Decreased compliance over time has been reported in asymptomatic children diagnosed through screening (69).
Living with celiac disease in adolescence
It is obvious that individuals with symptomatic CD have impaired health and well-being prior to diagnosis. When GFD is implemented, most symptomatic CD cases experience improved health and well-being (77, 78). This is also likely to be evident for screening-detected CD cases because of the fact that many of them
8 INTRODUCTION
have simply been unrecognized, but not asymptomatic as previously presumed (44). On the other hand, CD patients diagnosed in early childhood, which is the case for a majority of the Swedish adolescent CD population today, represent a potentially different experience because of their young age at diagnosis.
Adolescence is a challenging period in life that is characterized by several biological, psychological, and social development issues (79). Rapid physical growth increases energy and nutrient needs and an inadequate diet could impair growth and delay the onset of puberty. For adolescents with a chronic disease such as CD, it might be even more difficult to deal with challenges like establishing independence, building relationships with others and becoming comfortable with their bodies (80).
Dealing with GFD dietary specifics augments the ‘normal problems’ of adolescent life with extra practical, emotional and social burdens. In a qualitative study on adults, dilemmas related to CD and GFD were reported, such as worries about ‘being a bother’, and having a restricted choice of food products (81). The adult celiacs interviewed often remembered the intense emotions they had experienced in social dilemmas that had occurred years earlier. Diverse feelings about CD and GFD, e.g. anger about having to follow a special diet and embarrassment about bringing GF foods to parties, were reported in a retrospective questionnaire- based study with a sub-set of younger children with CD (82).
Individuals with CD display no obvious external signs that would indicate their condition to others. However, interaction in different social contexts invariably results in circumstances where CD can be made visible to others, such as when GF food is not available unless it is requested, or where the only food available contains gluten (83). Conforming to the GFD might have social consequences, since normative social rules in relation to food and meals are not being followed when available food is refused (84). However, following those normative rules might have serious consequences for the dietary management of CD if it involves deviating from the GFD.
The lived experiences of everyday life for people with CD have been found to be more complicated than previously expected. However, few studies have directly addressed the actual practices typical of adolescents with the purpose of increasing our understanding of what it is like to be a celiac adolescent.
9 OBJECTIVES
OBJECTIVES
The general objectives of this thesis were to analyse the incidence of CD in epidemic and post epidemic birth cohorts of Sweden, and to explore and understand how adolescents with CD perceive and manage their everyday lives in relation to the GFD.
The specific objectives were to determine • whether birth cohorts representing different gluten exposure early in life continue to differ with respect to CD risk, thereby indicating an opportunity for primary prevention.
• trends in age-specific incidence rate of CD in children, more specifically whether the incidence in children younger than 2 years has stabilized on a lower level after the epidemic period, and whether there is an ongoing shift toward higher age at diagnosis.
• whether there is a regional variation in the incidence rate of childhood CD. further to explore and understand • tentative compliance problems with the GFD in CD adolescents.
• circumstances in the lives of CD adolescents where their medical condition becomes visible to others, and how they handle the consequences.
10 METHODS
METHODS
Combining epidemiological and qualitative research methods
The objectives of this thesis involve the examination of different phenomena. Consequently, it was necessary to choose methodological approaches and data collection tools that were best suited to the characteristics of the research questions and the data (85, 86). A quantitative, epidemiological approach was used to determine variations in CD incidence in the first follow-up of the Swedish epidemic of CD, encompassing the post-epidemic period (Papers I and II), and a qualitative approach was used to explore and understand essentials of GF eating with a youth perspective (Papers III and IV) (Figure 1). These methodological decisions were pragmatic and reflect a view that the dichotomy between quantitative and qualitative research methods mainly involves different characteristics and assumptions regarding the data and consequently what can be revealed (87).
The National Swedish Childhood Celiac Disease Register
The abrupt rise in the incidence rate of CD in the mid 1980s resulted in a decision by the Swedish Paediatric Association to support initiation of a CD epidemiological surveillance system. Through its Section for Gastroenterology, Hepatology, and Nutrition, the Epidemiology and Public Health Sciences, Umeå University, was given the assignment to operate a prospective incidence register of CD. This was initiated in 1991. The Swedish Working group for Celiac Disease in Children (Appendix 1) within the Section for Gastroenterology, Hepatology, and Nutrition was involved in the planning of the register, entitled the National Swedish Childhood Celiac Disease Register.
New clinically detected CD cases younger than 15 years of age were retrospectively recorded in the register from 1973 to 1990, and prospectively from 1991 to 1997, covering 15% and 40% of the population respectively (Figure 1). Since 1998, the register has been nationwide, and all 47 paediatric clinics in the country prospectively report to the register (Appendix 2). The following is
11 METHODS
recorded on a standardized form; gender, date of birth, place of residence, date of diagnosis, and pathological assessment of the mucosal findings.
1973 1991 1998 2003
The Swedish Childhood Celiac Disease Register
RetrospectiveProspective Nationwide
Focus groups
Upper Norrland
Middle Norrland
Paper I Paper III North Middle Sweden Difference in celiac disease risk The everyday life of adolescent between Swedish birth cohorts coeliacs – issues of importance suggests an opportunity for for compliance with the gluten- Stockholm primary prevention. free diet. East Middle Sweden
West Sweden Småland and the islands Paper II Paper IV Regional variation in celiac Food that makes you different: disease risk within Sweden the stigma experienced by South Sweden supports multifactorial disease adolescents with celiac disease. aetiology.
NUTS 2 division of Sweden (89).
FIGURE 1. Overview of the research project.
Case ascertainment (I, II) The National Swedish Childhood Celiac Disease Register was used for identification of new cases (Figure 1). The follow-up period was limited to the period from 1998 to 2003. The diagnostic criteria for CD according to the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (15) were used for case ascertainment.
From 1973 to 1997, 2151 children fulfilled the inclusion criteria (34). During the follow-up period from 1998 to 2003, 2922 new cases fulfilled the criteria and 295 were excluded, of whom 195 were excluded due to normal mucosa morphology in spite of
12 METHODS
increased IEL count (Paper I). Inclusion of the 295 children did not change the regional pattern of CD incidence, and there was no difference in distribution by gender and age group between included and excluded children. A recent report update of the excluded children is depictured in Table 1.
TABLE 1. Report of excluded children (n=295) updated from the National Swedish Childhood Celiac Disease Register in October 2008.
Report update of excluded children
Update Total Villous Diagnosis Diagnosis Diagnosis Diagnosis Exclusion criteria not (n) atrophya securedb likelyb doubtfulc excludedc reported Increased IEL count, normal morphology 195 19 30 39 24 2 81 Normal IEL count, normal morphology 4 2 1 1 Mucosa not possible to classify 29 2 2 6 3 16 Biopsy not yet classified 15 10 1 4 Biopsy not conducted 49 7 15 7 2 18 Missing date for initial biopsy 3 3 Total 295 43 48 52 29 3 120
aBased on classification of a new intestinal biopsy on a gluten-containing diet. ESPGHAN criteria for CD fulfilled. bBased on clinical remission only and/or together with normalized IEL count on a gluten-free diet. ESPGHAN criteria for CD cBased on vague or nonexistent clinical remission on a gluten-free diet.
Study population (I, II) The mid-year population for each region, gender, single-year age group, and year of diagnosis, using official population data from Statistics Sweden (88), were used to approximate the number of person-years at risk. The study base from 1973 to 1997 encompassed 598 262 births and ~8.9 million person years of follow-up, and the follow-up period from 1998 to 2003 involved 454 923 births and ~9.8 million person years of follow-up.
Regional classification (II) The classification of Swedish national areas according to the Nomenclature of Territorial Units for Statistics (NUTS 2) was used (Figure 1) (89). This is a geocode standard developed by the European Union (EU) for referencing the administrative division of countries for statistical purposes. This classification was used to enable comparisons with other European countries, and utilization of statistics supplied by the EU in further analyses.
13 METHODS
Informants (III, IV) Participants were purposively selected to gather data on actual adolescent experiences related to CD and the GFD. Inclusion criteria were confirmed CD based on the ESPGHANs criteria (15), 15-18 years of age, and a prescribed GFD for at least one year. The National Swedish Childhood Celiac Disease Register and local paediatric departments were used to identify potential participants. From these databases, 159 adolescents fulfilled the inclusion criteria, and were invited by letter, including information about the study, to participate, resulting in recruitment of 47 adolescents.
Ten focus group discussions were conducted with a total of 32 girls and 15 boys (Paper III), reflecting the gender distribution of the Swedish CD child population at the time of the study. For each focus group, 6-7 adolescents were invited, and 3-6 adolescents finally participated. The intention was to attain homogeneity concerning gender and age, but because of a limited recruitment base and for practical reasons, only three focus groups were single gender. The first recruitment generated six focus groups, but to obtain theoretical saturation (90, 91), a second recruitment was conducted that generated four additional groups. Participants were recruited from four geographical areas of Sweden. The participants were given assumed names, which were used during the interview, analysis, and report stages of the research. Within each focus group, assumed names started with the same letter.
Focus group discussions (III, IV) We decided to initiate focus group discussions because they are particularly useful when a considerable gap exists between participants and professionals concerning such factors as language, culture, education, and power (92). Furthermore, interaction between participants within a focus group highlights different views, values and beliefs in relation to a given topic (93). To be valued as an ‘expert’ when collaborating with researchers can also be empowering for many participants (94).
Dialogue with CD adolescents was promoted by encouragement to speak freely. Discussions focused on their everyday life, how they perceived and managed different situations and obstacles in relation to the chronic disease (CD) and dietary treatment (GFD) that they had in common.
14 METHODS
Before the focus group discussions started, the adolescents were requested to fill in a short form with topics including age, sex, place of residence, age at diagnosis, family relationships, presence of known CD in close relatives, and dietetic and medical provision related to CD within the last year. The first author acted as moderator in all focus groups, and one of the other authors took notes. Interviews lasted 60-80 minutes and were digitally recorded. During the discussions, the moderator referred back to what had been said in the conversations for confirmation of researcher understanding of the points expressed. A flexible topic guide was used to ensure that the experiences of the CD adolescents were captured (Paper IV). This comprised issues of everyday life with CD and a prescribed GFD in different contexts and in different interactional settings. The guide, with the core of topics, was used throughout the data collection, although the focus of discussion in each group was shaped by specific participant experiences.
Statistical analyses (I, II)
Measures of disease occurrence Children were grouped according to age: i) 0-1.9 years, ii) 2-4.9 years, and iii) 5-14.9 years. Incidence rates for each specific combination of region, gender, age at diagnosis, and year of diagnosis were calculated by dividing the number of new cases by the number of person years of follow-up, approximated by the mid- year population. The cumulative incidence for each birth cohort at a certain age was calculated by dividing the number of cases diagnosed up to this age by the total number of births in the cohort. Incidence rates are expressed as number of new cases per 100 000 person-years, and cumulative incidence as the number of cases per 1000 births.
Differences in disease occurrence Linear regression analysis was used to test for any difference in increase in cumulative incidence by age for different birth cohorts. Rate ratios (RR) were estimated to compare differences in incidence rates.
15 METHODS
Relative risks Poisson regression models were used to estimate the relative risk (RR) of CD in different regions. The model also included gender, age at diagnosis, and year of diagnosis. Bivariate analyses were followed by multivariate analysis. In the multivariate analysis, ‘Upper Norrland’ was used as reference to facilitate depiction of the data from north to south. RRs are graphically depicted on a logarithmic scale, which illustrates equal ratios as equal distances.
Statistical significance Statistical significance was defined as a p-value <0.05, and rate ratios (RR) with a 95% CI excluding 1.0.
Software Excel 2003 (Microsoft, Redmond, WA, USA) and SPSS 15.0 (SPSS, Chicago, IL, USA) were used for basic calculations.
Theoretical framework (III, IV)
My experience as a dietician in the clinical setting was the starting point of the research process. A conscious attempt to reflect on the preconceptions shaped by this professional perspective was made at every stage of the research process. The purpose was to keep an open and reflexive mind in order to reveal more than aspects already taken for granted (95).
The premise was that this knowledge was created in the specific social interaction between CD adolescents and the researchers, and the approach sought to reveal multiple views of being a CD adolescent and not to describe a single version of the ‘truth’ (96).
Initially, no certain concept or theory was applied as a frame of reference. An inductive approach was used in the primary analysis (Paper III) as we were interested in the natural variation in a substantially unexplored field such as CD adolescent experiences (97). However, relating to a pre-existing sociological theory can add a more comprehensive understanding of the data (96), and a theory driven analysis was therefore applied in the second analysis (Paper IV).
16 METHODS
Symbolic interactionism From a symbolic interactionist perspective (98, 99), people routinely construct social identities through their narratives, actions and personal information they reveal to others. Some personal characteristics, qualities or orientations are immediately visible, but some allow the possibility of discretionary disclosure so that not all information is made available to others in the same way, or at the same time. Either way, the consequences can vary from beneficial to unpleasant depending on what is revealed (100), so certain attributes might be hidden, or simply never referred to, out of concern for the personal difficulties that could ensue. However, an unplanned revelation of some aspect of one’s self not previously known to others might permanently and negatively change the way the individual is viewed.
Stigma Goffman (101) made a distinction between the original meaning of stigma, as a direct visible sign of something unusual enough to disqualify a person from full social acceptance and subsequent metaphorical use to include potentially discrediting attributes that are revealed indirectly. The depiction of stigma starts with social disapproval of an attribute that has the capacity to undermine an individual’s public identity. Such attributes range from collective identities to individual beliefs, behaviours and medical conditions, they may be ascribed or acquired, but they all share the enduring quality of adversely differentiating the individual from those who do not have the attribute. How stigma is experienced, and the strategies used to manage its effects, is shaped by how an individual defines the context and interprets others’ intentions, and the public perceptions of self in relation to the internal view of self (102). Furthermore, it is not always necessary that actual discrimination - enacted stigma – is encountered. Fear of possible consequences - felt stigma – is often sufficiently powerful to initiate avoidance behavior. Creating or maintaining the appearance of ‘normality’ therefore has considerable personal and social value. To this end, an individual can make use of a variety of information management strategies to conceal stigmatic symbols. This is termed ‘passing’ (103). Attributes that allow individuals to ‘pass as normal’ in most circumstances, by actual or contrived invisibility, also render them liable to having their apparently ‘normal’ status discredited (101). Such ‘discreditable’ people continually judge whether to reveal their condition, and thereby make visible the signs and symbols that carry the stigma. Thus,
17 METHODS
passing allows routine avoidance of adverse social reaction but entails the risk of ‘discovery’ and can therefore create stress in otherwise ‘normal’ situations.
Qualitative data analysis (III, IV)
Analysis focused on the problems that the CD adolescents described as most central and how they tried to solve these problems by using different strategies. The first author compiled field notes immediately after the focus group discussions and transcribed the digitally recorded audio interviews verbatim, as a part of the initial analysis.
Paper III Transcripts were read repeatedly by all the authors and thereafter analysed in three stages guided by the work of Strauss and Corbin (91). Open coding was first used to get an overview of the information, and content that shared a commonality was conceptualized and arranged into preliminary codes. During this data-near process, new codes emerged and some were renamed or modified while going back and forth in the transcripts. Based on the preliminary codes, a code tree for selective coding was developed and thereafter inserted in MAXqda2 (Verbi Software, Berlin, 2004), a software for qualitative data analysis. Transcripts were imported to the program and text segments were then organized in the code tree. Thereafter, coded text segments were extracted from the software, and grouped into categories. Finally, properties and dimensions were added to these categories and patterns explaining the main concerns and the variation of the adolescents’ own perspectives emerged.
Paper IV During the research process it became clear that the CD adolescents were relating GFD compliance problems illustrative of stigmatized interaction. Using that theoretical framework, the second analysis provided a more complete explanation of the phenomena made explicit in the focus group discussions.
While reading the transcripts, content in relation to stigma experiences was coded, conceptualized and thereafter arranged
18 METHODS
into preliminary codes. A code tree developed from the preliminary codes was constructed and thereafter inserted in MAXqda2 (Verbi Software, Berlin, 2004). Subsequently, transcripts were imported to the program and text segments organized in the code tree. In this process, new codes were chosen, and some were renamed or modified, to better represent the data. Thereafter, coded text segments were extracted from the software, and grouped into four categories including subcategories reflecting the relationship between adolescent experiences and the theoretical framework of stigma. After categorization, recurrent patterns across the groups emerged.
Ethical considerations
The prospective incidence register (UmU 101-2496-04) was approved by the Research Ethics Committees of all Swedish Medical Faculties. The Regional Ethical Board in Umeå approved the qualitative study, and informed consent was a requirement for participation. Papers I and II were based on register data not connected to individuals as date of birth was used in the calculations. Papers III and IV were based on focus group discussions. Focus groups are reported to empower participants if the issues being discussed are meaningful to them, and they believe that their contribution will make a difference (104). Furthermore, the potential reticence of adolescents in one-to-one interviews can be avoided with a focus group design.
19 MAIN FINDINGS AND DISCUSSION
MAIN FINDINGS AND DISCUSSION
Differences in celiac disease risk
Epidemic and post-epidemic cohorts (I) During the epidemic period, the cumulative incidence at two years of age was almost three times higher compared with the years before and after the epidemic (Figure 2). For the 1993 cohort, born during the peak of the epidemic, it reached 4.4 cases per 1000 births at two years. In contrast to the cohorts born before the epidemic period, for which the cumulative incidence more or less ceased to increase after two years of age, the cohorts born during and after the epidemic period also had a gradual increase after two years of age.
8
7 1993 1992 1989-90 1987-88 6 1991 1994 1985-86 5
4 1983-84 1995 3 1997 2000 1998 2001 1999 1996 1978-82
Cases per 1000 births 2 1973-77 2002 1
0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Age (years)
FIGURE 2. Cumulative incidence of celiac disease by age for the birth cohorts of 1973 to 2002. To reduce graph complexity, the cohorts 1973 to 1982 are aggregated in groups of five, the cohorts 1983 to 1990 in groups of two, while the cohorts of 1991 to 2002 are reported separately.
At six years of age, the longest follow-up so far available for post- epidemic cohorts, there was still a considerable difference in
20 MAIN FINDINGS AND DISCUSSION
cumulative incidence between birth cohorts of the epidemic and post-epidemic periods (Figure 2). For the 1993 cohort, born during the peak of the epidemic, it reached 4.4 cases per 1000 births at two years, 5.4 at six years and 6.6 at ten years of age. For the 1997 cohort, the first cohort born after the epidemic had completely abated, it reached 1.3 cases per 1000 at two years, increasing to 2.9 at six years of age, which at this point is the longest possible follow- up. The increase in cumulative incidence between two and six years of age was steeper in cohorts born after the epidemic period compared with cohorts born during the epidemic period. When comparing the cohorts of 1993 and 1997 this difference was significant (p=0.008).
Geographical regions (II) During the period 1998 to 2003, the incidence rate (cases per 100 000 person-years) was about twice as high in ‘West Sweden’ and ‘Småland and the islands’, with average incidence rates of 40 and 39, respectively, as compared with the central regions ‘North Middle Sweden’ and ‘Stockholm’, which had average incidence rates of 21 and 22, respectively. The remaining regions – ‘Upper’ and ‘Middle Norrland’, covering the northern half of the country, together with ‘East Middle Sweden’ and ‘South Sweden’, had incidence rates between 28 and 30.
The regional variation in incidence rates was statistically significant, as also confirmed by adjusted relative risks (RR) in a multivariate analysis with ‘Upper’ Norrland’ used as reference (Table 2). ‘West Sweden’ and ‘Småland and the islands’ had RRs of 1.37 and 1.38, respectively, as contrasted with the middle regions ‘North Middle Sweden’ and ‘Stockholm’, with adjusted RRs of 0.74 and 0.71, respectively. The regional variation in CD risk was largely the same for boys and girls, the different age groups, and for each calendar year.
21 MAIN FINDINGS AND DISCUSSION
TABLE 2. Risk for celiac disease in Sweden by region, gender, age at diagnosis, and year of diagnosis during the period of 1998 to 2003.
Bivariate analysesa Multivariate analysisb Independent variables RRc 95% CId RR 95% CI
Regione Upper Norrland 1.00 - 1.00 - Middle Norrland 0.94 0.62-1.42 1.00 0.77-1.28 North Middle Sweden 0.76 0.51-1.12 0.74 0.59-0.92 Stockholm 0.74 0.52-1.07 0.71 0.58-0.86 East Middle Sweden 1.05 0.73-1.51 0.99 0.82-1.20 West Sweden 1.44 1.01-2.05 1.37 1.14-1.64 Småland and the islands 1.51 1.04-2.19 1.38 1.13-1.68 South Sweden 1.23 0.85-1.76 1.05 0.86-1.27
Gender Boys 1.00 - 1.00 - Girls 1.84 1.55-2.19 1.74 1.60-1.89
Age at diagnosis 0-1.9 years 1.00 - 1.00 - 2-4.9 years 0.53 0.44-0.64 0.54 0.48-0.60 5-14.9 years 0.33 0.28-0.40 0.34 0.31-0.38
Year of diagnosisf 1998-2003 1.20 1.15-1.27 1.19 1.16-1.22
aPoisson regression analyses based on 2,922 cases and 9,8 *103 person-years of follow-up. bLikelihood ratio statistics (LRS) on 393.1 degree of freedom (DF)=11, p<0.001 cRelative risk d95% confidence intervals eNUTS 2 regions in Sweden f Continuous variable
How unique was the epidemic?
During the epidemic, the incidence rate in children younger than 2 years of age reached levels around 200 cases per 100 000 person- years, with a maximum of 241 in 1994 (Figure 3) (34). From 1997, the incidence rate was fairly stable at about 50 cases per 100 000 person-years (34). A significant, gradual increase in incidence rate among children younger than 2 years of age was once again
22 MAIN FINDINGS AND DISCUSSION
revealed during the last years of follow-up (Paper I). In 2001, it started to increase and in 2003 it had almost doubled to 98 cases per 100 000 person-years (RR 2.00, 95% CI 1.55-2.57).
300
0-1.9 years 250 2-4.9 years 5-14.9 years 200
150
100
50 Cases per 100 000 person-years 100 per Cases 0 1975 1980 1985 1990 1995 2000 Year of diagnosis
FIGURE 3. Annual incidence rates of celiac disease in children from 1973 to 2003. During the period 1973 to 1990 calculations were based on retrospective data covering 15% of the Swedish childhood population, from 1991 to 1997 on prospective data covering 40%, and from 1998 to 2003 on nationwide coverage.
The increase in incidence rates in children younger than 2 years of age seen between 2000 and 2003 might be a sign of a new epidemic approaching. However, the steepness of the increase was far from that of the epidemic period, and only a longer follow-up will reveal if it is an ongoing trend or not. In addition to the Swedish epidemic in young children, it is noteworthy that fluctuations over time in CD frequency have also been reported from other European countries (30, 31, 105, 106). The magnitude of the Swedish epidemic was striking compared to these other fluctuations, but the epidemic, or the “Swedish case”, might not have been as unique as we previously assumed.
23 MAIN FINDINGS AND DISCUSSION
Increased disease occurrence over time
During the follow-up period from 1998 to 2003, the annual incidence rate in the total childhood population increased twofold; from 19 cases per 100 000 to 44, i.e. the same level as during the epidemic years, but with a shift toward higher age at diagnosis (Figure 4).
50
40
30
20
10 Cases per 100 000 person-years 000 Casesper 100 0 1975 1980 1985 1990 1995 2000 Year of diagnosis
FIGURE 4. Annual incidence rate of celiac disease in children 0-14.9 years of age from 1973 to 2003.
Since the beginning of the 1980s, the cumulative incidence of clinically detected CD in 10-year-olds tripled, and in 2003 it reached almost 7 cases per 1000 for children born 1993 (Figure 2, p. 20). A cross-sectional screening of the same cohort at 12 years of age revealed a further 20 cases per 1000 (107). By comparison, we observed a prevalence of 5 cases per 1000 in a screening-study of a middle-aged population in the mid 1990s (5). Thus, our findings clearly demonstrate an increase in disease occurrence over time, assuming unchanged mortality from CD, which has also been observed in the Finnish adult population (108). The rising trend in CD occurrence is therefore not unique to Sweden, nor to the disease itself as an increase in incidence has also been observed for other autoimmune diseases such as type I diabetes and Crohn’s disease (109).
24 MAIN FINDINGS AND DISCUSSION
The median age at diagnosis in Swedish children has increased since the early 1970s. Between 1973 and 1994 it was 1.2 years (interquartile range 1.0 – 1.7 years), in 1997 it was 3.7 years (interquartile range 1.3 – 8.9 years) (34), and during the period 1998 to 2003 it increased to 5.8 years of age (interquartile range 1.9 – 9.8 years). The upward shift in age at diagnosis is partly explained by the fact that children carrying excess risk for CD, i.e. children originating from the cohorts born during the epidemic period were older at the time of follow-up. Increased awareness of the disease, resulting in the diagnosis of CD in children previously undiagnosed because of the milder clinical symptoms, typical for older children, as well as screening of siblings could also have contributed. Moreover, less obvious symptoms at diagnosis have also been implicated in younger children (3), which could account for delayed diagnosis among the youngest children and consequently also contribute to the shift toward higher age at diagnosis.
A potential for primary prevention
The considerable gap in cumulative incidence at comparable ages between birth cohorts of the epidemic and post-epidemic periods might indicate both short- and long-term consequences of infant feeding on CD risk, and if so, might suggest an opportunity for primary prevention. The difference in CD risk was still striking at six years of age, although it decreased somewhat with age. Hence, not all cases were permanently prevented, and the onset or diagnosis of CD was merely delayed for some individuals.
The decreased gap in cumulative incidence at comparable ages between the cohorts could indicate that, with time, the cumulative incidence in the cohorts born after the epidemic might reach the same level as the epidemic cohorts. If so, a favourable exposure with regard to infant feeding (35) only delays the diagnosis because of milder symptoms and/or those individuals at risk contract the disease at a higher age. This would support the view that given a genetic susceptibility, CD cannot be avoided in individuals exposed to gluten. An Italian study has shown a pair wise concordance rate of 71% in monozygotic twins (110), which supports the strong genetic impact, although monozygotic twins commonly also share the same environmental exposures. However, about 20-30% of the population carry genes encoding HLA-DQ2 or -DQ8 molecules, and most of them never develop CD. Furthermore, both innate and
25 MAIN FINDINGS AND DISCUSSION
adaptive immunity seem to be involved in disease development (111, 112). Consequently, genetic susceptibility is a prerequisite but possibly not sufficient for CD development (46). Indeed, the difference in CD risk between birth cohorts at comparable ages persisted during preschool years. Moreover, the cross-sectional screening study of 12-year-olds born in 1993, representing a cohort with unfavourable infant feeding, revealed a CD prevalence of 3%, with two thirds undiagnosed prior to screening (107). In addition, a recent screening study in pre-school children in Sweden indicated a lower prevalence of screening-detected CD after the national change in infant feeding recommendations in 1996 (113). These findings support the potential role of environmental exposure in primary prevention of CD. The rapid changes in incidence over time also support the notion that environmental factors contribute, as population-wide genetic changes do not develop that quickly. A repeated cross-sectional screening of 12-year-olds born in 1997, representing a cohort with favourable infant feeding, will be conducted during 2009 to 2010. Subsequently, we will be able to evaluate to what extent the differences in early exposure have influenced the clinical expression of CD, and thereby the proportion of diagnosed cases, and to what extent cases have been truly prevented.
Regional variation in CD risk also supports multifactorial disease aetiology, although regional clustering of families with a strong genetic susceptibility for CD could theoretically be one contributing factor. Detailed geographic distribution of genes encoding HLA- DQ2 and -DQ8 molecules, which are crucial for CD development (9), is largely unexplored, but variations exist between countries (114). However, geographical mapping with respect to genes encoding HLA-DQ2 and -DQ8 molecules is not yet available at population level. In addition, contributing non-HLA genes also need to be identified and geographically mapped (11).
Environmental and life-style contributions are largely unexplored regarding the multifactorial aetiology of CD, and the option of primary prevention therefore needs to be further explored (44). Modes of gluten introduction and infectious agents have been suggested to play a role early in life. There is ample evidence that ongoing breastfeeding at the time of gluten introduction reduces CD risk in children younger than 2 years of age (35, 40). The duration of this protection is not clear, but the difference in CD risk between Swedish birth cohorts differing with respect to infant feeding supports a long-term preventive effect. A critical age interval for introduction of gluten to infants with respect to CD risk
26 MAIN FINDINGS AND DISCUSSION
has also been advocated (115), although this is still a controversial issue (41). Moreover, abrupt introduction of gluten, i.e. intake of gluten-containing foods in large amounts, as compared to small or medium amounts, the first 2 weeks of consumption is an independent risk factor for CD in children younger than 2 years of age (35). CD development triggered by infectious agents is supported by a seasonal pattern in CD risk with respect to month of birth (116), and an increased CD risk in children experiencing three or more infectious episodes before 6 months of age, with a significant further increased risk if gluten was abruptly introduced (44). Moreover, it was recently reported that rod-shaped bacteria were frequently associated with the mucosa of CD patients diagnosed during the epidemic, and that certain carbohydrate structures of the glycocalyx/mucous layer might facilitate this bacterial adhesion (112). Frequent rotavirus infections have also been suggested to increase the risk of CD autoimmunity (117).
CD risk is most likely modulated by environmental and life-style exposures operating during different periods of the whole life span (41). Interestingly, the total per capita consumption of bread and cereals in Sweden increased by 30% from 1980 to 2003 because of a remarkable increase in the consumption of processed cereal- based foods (118), and a similar pattern has been seen worldwide (41). These dietary changes highlight the potential role of gluten load during the whole life span as a contributor to CD risk. Furthermore, sensitized individuals respond dose-dependently to gluten (14), and there is an interaction between HLA-DQ expression and the available number of T-cell stimulatory gluten peptides (119). Besides the quantitative load of gluten, the processing of cereal-based and other foods might increase CD risk by amplifying the immunogenicity of dietary gluten (120).
Further studies are needed to explore the role of potentially contributing and protective exposures operating during different periods of the life span. If primary prevention of CD is possible, strategies such as rotavirus vaccination may open new perspectives (121). The possible role of the increasing consumption of wheat- based food, and processing of cereals and other foods, should be given priority. If general dietary habits can be identified as contributors to increased CD risk, implementation of dietary guidelines and/or modification of food processing might have considerable public health effects.
27 MAIN FINDINGS AND DISCUSSION
Everyday life of celiac adolescents
The everyday life of adolescents with CD involved different social settings such as being at home, at school, with friends, eating out and travelling, each of which presented or precluded opportunities for dealing with the GFD. At home, GF alternatives were normally easily available; family members were well acquainted with the GFD, and both GF food items and cooking were described as integral parts of the various households. In contrast, situations outside the home were more troublesome. Overall, there was a yearning to be like all the others and situations where the adolescents felt that the GFD set them apart were troublesome.
Dissatisfaction with both the availability and the sensory characteristics - taste, texture and visual appearance - of GF food items or meals was also an integral part of everyday life when having meals at school, and when eating out with friends.
Compliance problems
The decision to comply with the GFD was complex and to a considerable degree dependent on the social setting. How adolescents perceived and managed these social settings was influenced by factors such as limited knowledge negatively affecting their confidence in the treatment, poor availability and low sensory acceptance of GF food, insufficient social support, and social inconvenience (Figure 5). This concurs with earlier studies indicating that factors affecting compliance in adolescents with chronic diseases are multiple and overlapping (61).
Three approaches to the prescription of a GFD emerged from focus group interviews: i) compliers strictly following a GFD, ii) occasional non-compliers mostly adhering to a GFD and purposely eating gluten containing food only in problematic situations, and iii) non-compliers mainly eating an ordinary diet including gluten.
A conscious stance on how to manage the disease and dietary treatment, including an acceptance of their chronic condition, seemed to be something the compliers had in common.
‘I’m not so sensitive but I never eat normal food. If I do I get a little stomach ache and such, but I think it’s unnecessary to
28 MAIN FINDINGS AND DISCUSSION
eat it because I will only be tempted to continue and eat more food with gluten in.’
Availability of gluten- Knowledge Social support free alternatives
Sensory characteristics Symptoms after gluten Social setting of gluten-free food ingestion
Compliance with the gluten-free diet
FIGURE 5. Issues of importance for compliance with the gluten-free diet in 47 adolescents with celiac disease.
Occasional non-compliers usually chose a GF alternative if it was easily available and lack of GF alternatives was an excuse for noncompliance, although sometimes mitigated by choosing the alternative with the smallest amount of gluten.
‘Mostly, it happens when you’re at a café, when the only pastries you can choose from are the ones you aren’t allowed to eat. Then it’s difficult not to want to have something. The others just sit there and gobble, and I only have my cup of coffee…’
Among non-compliers, sensory aspects of GF foods seemed to have a greater impact on compliance than the availability of GF alternatives.
‘I cheat all the time… see, you know how different foods taste so you choose the one that tastes the best, at least that’s what I do.’
Commonly, the presence of immediate symptoms after gluten ingestion was expressed as a motivator for the decision to comply, and their absence was an excuse for noncompliance. However, absence of immediate symptoms existed among compliers and immediate symptoms existed among non-compliers. Non- compliers also denied experience of immediate symptoms, or
29 MAIN FINDINGS AND DISCUSSION
perceived them as more bearable than avoiding normal food in socially troublesome situations where there was poor availability of palatable GF alternatives. In fact, treatment compliance has earlier been shown to be related to whether or not serious noncompliance consequences or symptoms were experienced (61). Moreover, decreased compliance rates over time have been reported in asymptomatic children with CD diagnosed through screening (69).
Irrespective of the approach to a prescribed GFD, dietary treatment often involved the social embarrassment of being marked out as different from other people. For non-compliers and occasional non-compliers, this could be avoided by eating normal food. By contrast, compliers seemed to believe that following the GFD was an investment in long-term good health, despite social and practical inconveniences and dissatisfaction with the sensory characteristics of GF food.
Being different because of different food
An invisible problem made visible Adolescents with CD experienced enacted and felt stigma in everyday life. The foods they ate, or were trying to obtain, constituted an attribute that made them visible in public.
Sometimes when I’m eating my food it’s as if everyone’s staring at me… “What kind of strange and disgusting food are you eating?”… They probably don’t think so but that’s how I feel.
Feelings associated with social deviance and the discomfort of visibility were described as being more pronounced at primary school age, but were still something that made adolescents feel awkward. Differences in the appearance of GF meals, and the generally poor availability of GF food, increased the negative consequences of this visibility.
The centre of attention Stigmatization was more likely to occur in contexts outside the immediate domestic environment. The request for a GFD meal, or its appearance, often made adolescents the centre of attention in a way that was unwelcome because it publicly reinforced their
30 MAIN FINDINGS AND DISCUSSION
difference from others. Lack of knowledge, misconceptions, and carelessness on the part of others had the effect of either diminishing or amplifying the importance of their condition and prescribed treatment, and gave rise to both enacted and felt stigma. This can be understood in terms of the concept of reflected appraisal, when others’ perceptions of one’s self are experienced as inconsistent with one’s internal view of self (122). It was demanding and embarrassing to be seen as ‘special’ in the eyes of others, even when reactions were interpreted as misplaced kindness by people who became too concerned about accommodating their needs.
They make such a big deal of it… those who feel sorry for you… It’s just a drag [i.e. burdensome]…
By contrast, minimizing the importance of their condition was experienced when others publicly challenged or neglected their dietary needs. Often this was related to a limited understanding of the potential consequences of deviating from the GFD. Some adolescents explained that they had to bring their own food to particular school events, celebrations and parties to make sure that they would have something to eat. In school, kitchen staff did not always remember who the CD adolescent was, or confused them with other pupils and other special diets. The requested GF dish was therefore incomplete or not available. Difficulties related to public situations have previously been reported in both children and adults with CD (82, 123). In contrast to problematic settings outside the home where the adolescents were challenged to improvise a definition of the situation (124), circumstances at home were routine and more predictable (125). The propensity to assimilate the GFD into family practices has been reported previously (126), although this assimilation does not exclude practical, social, and personal dilemmas among family members (127).
Facing dietary deviance Adolescents’ stigma management strategies were selective and to a considerable degree dependent on the risk of stigmatization in a given context or situation. They often made use of humour, irony and sarcasm when describing discrimination and sensory qualities of GF foods. The use of humour helped to relieve embarrassment in stigmatizing situations, as has been reported more generally (128). Moreover, selective social comparisons (129), contrasting
31 MAIN FINDINGS AND DISCUSSION
themselves with people suffering from conditions with poorer outcomes, protected them from focusing too much on their negative experiences of stigma. These strategies could not actually prevent feelings of being different once other people were aware of their condition, but each represented a way of deflecting or contextualizing interactional difficulties.
Concealment of their condition, either by passing or avoidance behaviour, was described as a situation-based solution to circumvent embarrassment.
… You just want to stop the fuss or you don’t want other people to stare too much. That’s why you just take it [gluten- containing food].
They did not want other people to stare and ask too many questions, and often thought that disclosing the condition in a given situation would make others feel sorry for them or believe that they would not be able to eat anything, or even that other people would fake kindness without really caring.
In an ideal world Adolescents with CD identified certain stigma-reducing possibilities in everyday life. They wanted other people to be aware of – and familiar with – their dietary needs, and act and react in a supporting way that would help them to pass as normal. Central to this was the belief that GF alternatives should be available in an easy, safe way with a minimum of comments or questions. Generally, other people’s awareness of their dietary needs reduced feelings that they were in some way socially deviant. In school, some adolescents believed that this could be achieved if one specially trained person among the kitchen staff was responsible for special diets. When eating out, the adolescents believed that skilled chefs with knowledge of GF cooking, and clear statements on menus that a meal was GF or could be easily adjusted, would provide assurance that the food was GF. The adolescents also found that awareness on the part of significant others, for example when eating out, was supportive and reduced feelings of being different.
Furthermore, by meeting contemporaries with CD, they found help on how to manage the stigma.
32 MAIN FINDINGS AND DISCUSSION
“Oh, a gluten friend, my Glutis!”… You get like “One more, how nice, there are more people like me!”
With these other CD adolescents they had the opportunity to share common experiences of having CD and eating a GFD. In addition, friends with CD facilitated everyday life because GF food was always available when they visited them, and it was safe and easy to eat. Indirectly, this empowering interaction could help them to develop a shared language about the stigma with alternative and positive interpretations (101, 130).
Noncompliance as a stigma-reducing possibility
It is evident that CD adolescents’ decision to comply or not to comply with the GFD can be understood in terms of dealing with the problems of concealment and disclosure of their special dietary needs.
Invisibility was both a positive and a negative characteristic of CD adolescents’ experience. It was positive in the sense that it made passing in everyday life easy – except when they had to reveal their special dietary requirements, which placed them at risk of social devaluation. However, invisibility was also negative. Other people could not see their condition so they could think the adolescent was ‘making it up’ or ‘being self important’ about something that did not actually matter. Although this might possibly sound inconsequential to others, it is an intriguing insight into the inner contradictions of life as a CD adolescent. Keeping to a GFD in public generated feelings of guilt if it meant offending expected norms and relationships when people offer you food. These internalized norms are very strong (131), and apply to people with special dietary needs as much as they do to others.
Passing behaviour draws on negative reflected appraisals and can be understood as a situational identity negotiation with the purpose of generating the most comfortable presentation of their identity to others (132). Internal negotiation preceding the decision to pass mainly comprised scenarios expected to amplify the visibility of their condition and themselves as victims. It reflected the danger that amplifying their condition would produce a more uncomfortable sense of incongruity between the internal and external view of self as compared to ‘playing down’ their condition.
33 MAIN FINDINGS AND DISCUSSION
In contrast to concealment, disclosure reflected positive reflected appraisals – others’ perceptions of them – matching their self- view. It might also be the case that these interpretations of others’ appraisals were manipulated to deny seeing themselves as victims (133).
Clinical challenge
The increasing trend in CD incidence over time directly implies an increased prevalence and coincidently an accumulation in clinical load. At population level, the twofold increase in the annual incidence rate during the follow up period from 1998 to 2003 indicates that almost 700 new annual CD cases below 15 years of age were diagnosed in 2003 (Figure 6). The annual number of cases corresponds to figures during the epidemic years, but with a shift toward higher age at diagnosis. Any move toward introduction of mass-screening for CD also needs to be considered with regard to clinical load (134, 135). GFD compliance and normalization of the intestinal mucosa is crucial for long-term health (136), and thus, there is a need to consider resource implications and evidence-based practice for optimum clinical outcomes (137).
800
600
400 5-14.9 years
New cases 2-4.9 years 200 0-1.9 years
0 1973 1983 1993 1997 2003 Year of diagnosis
FIGURE 6. New clinically detected cases of celiac disease in the Swedish childhood population in five different years. Calculations were based on births per year approximated to 100 000, and retrospective incidence data covering 15% of the Swedish childhood population 1973 and 1983, and on prospective data covering 40% for 1993 and 1997, and on data with nationwide coverage for 2003.
34 MAIN FINDINGS AND DISCUSSION
The GFD is the only accepted and effective medical treatment for CD and in a multidisciplinary approach, specially trained dieticians play an important role regarding the safe and successful initial implementation and regular follow-up of the treatment (136). In the UK, the current level of dietetic provision within the healthcare system varies regionally and is far from the required level (138). Clinical views indicate that this might also be the case in Sweden.
Experiences of GFD compliance problems and stigma in CD adolescents are evident even in a country like Sweden, which by international standards is judged as good in terms of general CD awareness and availability of GF food (139, 140). Moreover, a majority of CD adolescents in the present study had been clinically diagnosed in early childhood presumably facilitating acceptance of the restrictions of a GFD later in life (75). In screening-detected CD cases, which are commonly diagnosed later in childhood, everyday life with a GFD can become even more problematic. Non- compliance with the GFD has been shown to be more common in screening-detected cases than in clinically detected cases. (69).
In addition to providing professional dietetic education, there is a need to consider the personal and social consequences of being faced with a chronic disease and life-long dietary restrictions. This is especially important if young people with CD receive no medical or dietary supervision after transition to adulthood, a reality for most CD patients that was revealed in an Irish study (141). The focus group discussion was described by the adolescents as a stigma-reducing experience. Opportunities to articulate the complications of their lives with others in the same situation were not common and, for many they were unique. This indicates the need of CD adolescents to talk among themselves about their condition and to develop their capacities to deal with social dilemmas. The potential for empowerment through discussion might therefore be useful in clinical practice.
Perceptions of the social inconvenience of GFD and the need for avoidance behaviours can probably also be reduced by adequate social support and better availability of palatable GF alternatives outside the home. For this to happen, an increased level of disease- and treatment-related knowledge is necessary not just among significant others but more widely in the social settings frequented by adolescents. In fact, a lack of knowledge about CD among chefs was reported in a study from the UK (142). In addition, the unequal subsidies for covering additional costs for GF foods between different regions in Sweden need to be adjusted and regulated.
35 MAIN FINDINGS AND DISCUSSION
The gender of adolescents might have an impact on the management of the disease in a similar way to that of other chronic diseases, such as type I diabetes (143), and it is important to explore any differences in the CD experiences of boys and girls. If there are gender differences in the ability to adapt to life with CD and a GFD, and in the interpretation of stigma, boys and girls might use different strategies and need somewhat different types of support in order to make it easier to comply with the GFD.
Future research could usefully explore how best to reduce general compliance problems, amplify confidence and reduce dietary stigma in the different social settings of CD adolescent life.
Validity (I)
Diagnostic accuracy Case ascertainment was based on the ESPGHAN criteria for diagnosis including a small intestinal biopsy with villous atrophy on a gluten-containing diet, and not only relying on elevated serological markers indicative of the disease (15). Nowadays, the CD diagnosis is sometimes considered verified in cases with only an increased number of IELs but normal mucosa morphology, provided there are positive serological markers indicative of the disease, even though this is not universally accepted. However, inclusion of the 195 children with an increased number of IELs but otherwise normal mucosa morphology on a gluten-containing diet did not significantly change the results.
Case ascertainment General CD screening of the population has not been adopted in Sweden, and the majority of the CD cases reported to the ‘National Swedish Childhood Celiac Disease Register’ were consequently detected clinically. In addition to liberal serological testing of clinically suspected CD cases, the national guidelines for childhood CD emphasize the increased susceptibility in high risk populations like siblings of patients and children with type I diabetes or Down’s syndrome. Nevertheless, CD screening of these high risk children is not yet an established clinical practice. Further, when performed, such screening is likely to be conducted after 2 years of age, and therefore does not explain the variation in incidence over time in the youngest children.
36 MAIN FINDINGS AND DISCUSSION
It could be argued that the regional variation reported in Paper II merely reflects a variation in case ascertainment. There might also be differences between regions in the probability that diagnosed cases were reported to the register. However, the recent cross- sectional CD screening study of 12-year-olds in five Swedish cities, representing regions from North to South, revealed differences in total prevalence of enteropathy between the study sites (107). This supports the notion that the risk of developing gluten-induced enteropathy has a regional variation.
Study population Paper I confirmed the reliability of monitoring CD incidence over time with a prospective population-based register, despite extended population coverage over time. When comparing incidence rates based on 40% population coverage, i.e. the catchment area for the period 1991 to 1997, and 100% coverage for each year from 1998 to 2003, there was no significant difference for the age groups 0-1.9 and 2-4.9 years, and for the 5-14.9 year age group there was a difference only in 1999 (RR 1.29, 95% CI 1.02 to 1.63). Although nationwide coverage is not required for estimation of CD incidence, it allows more-detailed analysis of variations in disease occurrence according to time, place, and person and serves as an excellent base for in-depth studies.
Age grouping The age groups; 0-1.9, 2-4.9, and 5-14.9 years were used to facilitate direct comparisons with previous years, particularly the epidemic period when most cases were diagnosed before 2 years of age (34). During the follow-up period from 1998 to 2003, the number of CD cases in the 5-14.9 year age group was twice as high as in the 0-1.9 and 2-4.9 age groups, respectively. Division of the oldest age group might therefore have been applicable. When this 5-14.9 year age group was divided in two groups, 5-9.9 and 10-14.9 years, the average incidence rate for the study period from 1998 to 2003 was significantly higher in children 5-9.9 years of age compared to children 10-14.9 years of age, with incidence rates of 25 and 20, respectively (RR: 1.26; 95% CI: 1.15-1.40). However, the magnitudes were similar, and the increase in annual incidence rates from 1998 to 2003 was significant in both age groups.
37 MAIN FINDINGS AND DISCUSSION
Trustworthiness (III, IV)
Complex realities of life are socially and contextually constructed (102), and thus the findings and interpretations are necessarily incomplete reconstructions of CD adolescent life. To enhance credibility (144), categories derived from the data were continuously compared to clarify and refine the classification, and all authors were involved in the backwards and forwards process of categorization and interpretation of the data until agreement was achieved. Moreover, possible biases and limitations originating from researcher beliefs and preconceptions were discussed as a part of the process (145).
Despite incomplete homogeneity in the groups regarding gender and age, a sense of community was created in the group conversations, and extensive interaction took place between participants when sharing the specific experiences of having CD. While the fact that most focus groups were mixed gender might have influenced expression of sensitive information (146), a sense of shared experience was evident in the group conversations. The fact that noncompliance existed among the CD adolescents was not controversial but their perspectives and behaviours were socially situated, and influenced by personal and environmental factors. Transferability is contextually and culturally dependent (95), but the breadth of the discussions suggests transferability of the findings to the CD adolescent population in Sweden. It is also likely that the results can be applied to broadly comparable countries as well, especially the findings covering interactions in social settings generally frequented by adolescents.
To allow judgement of authenticity and transferability, ‘thick’ descriptions (147) was provided by direct quotations and in Paper IV also by disclosure of categories. The adolescents’ own descriptions of their behaviour were not necessarily correlated with the actual ingestion of gluten, but the focus group discussions revealed common dilemmas, and demonstrated unmet needs for adolescents with CD.
38 CONCLUSIONS
CONCLUSIONS
A considerable difference in celiac disease risk at comparable ages between birth cohorts of the epidemic and post-epidemic periods suggests an opportunity for primary prevention of CD. The gap in incidence was still striking at six years of age, although it decreased somewhat with age. During the final years of follow-up there was a significant, successive increase in incidence rates in all age groups. The increase in incidence among children younger than 2 years of age might indicate that the Swedish epidemic was not as unique as previously thought, even though its magnitude was striking. At the end of the follow-up, the annual incidence rate in the total childhood population reached the same level as during the epidemic years but with a shift toward higher age at diagnosis. The regional variation in CD risk within Sweden supports a multifactorial aetiology with contribution of environmental and life-style factors in addition to genetic susceptibility and a gluten- containing diet.
In everyday life, young celiacs experience various dilemmas and compliance problems related to the GFD. CD and particularly the GFD can produce experiences of stigma during the sensitive years of adolescence. It is evident that their decision to comply or not to comply with the GFD can be understood in terms of dealing with the problems of concealment and disclosure of their special dietary needs.
The increase in CD prevalence over time and unmet needs in young celiacs require resources to attain adequate levels of dietetic provision, regulated subsidies for covering additional costs for GF food, evidence-based practice, and increased general CD awareness for optimum clinical outcomes. Continued efforts are warranted to define factors, besides gluten exposure, that modulate CD risk during different periods of the life span. If contributing and protective exposures can be identified, implementation of primary preventive initiatives might have considerable public health effects.
39 POPULÄRVETENSKAPLIG SAMMANFATTNING
POPULÄRVETENSKAPLIG SAMMANFATTNING
Celiaki (glutenintolerans) har utvecklats till ett globalt hälsoproblem. Vid celiaki skadas tunntarmsslemhinnan av gluten som återfinns i sädesslagen vete, råg och korn. En effektiv behandling finns dock genom att livslångt utesluta vete, råg och korn.
Under perioden 1984 till 1996 nådde insjuknandet av celiaki hos små barn epidemiska nivåer i Sverige. Den kraftiga ökningen och lika abrupta minskningen i insjuknande var unik och kunde delvis förklaras av förändringar i spädbarnskosten. De barn som föddes under den så kallade epidemin har nu blivit tonåringar och unga vuxna. En strikt glutenfri kost är betydelsefull för deras hälsa på både kort och lång sikt. Det är dock vanligt att tonåringar inte följer den ordinerade glutenfria kosten och kunskapen är begränsad om hur de själva uppfattar och hanterar sin vardag i relation till sin sjukdom och behandling.
Baserat på data från ett nationellt register för celiaki hos barn har vi under perioden 1998 till 2003 fortsatt att studera insjuknandet i celiaki hos barn upp till 15 år i årskullar som föddes under och efter epidemin. Genom att intervjua ungdomar med celiaki har vi också utforskat hur de upplever och hanterar sin vardag i relation till den ordinerade glutenfria kosten.
Barn som föddes under epidemin fortsatte under förskoleåldern att ha markant ökad risk att insjukna i celiaki i jämförelse med barn som föddes efter epidemin. Denna skillnad i risk vid jämförbar ålder mellan olika årskullar – som också skiljer sig åt med avseende på kost under spädbarnsåren – tyder på att det kan finnas en möjlighet att förebygga insjuknande i celiaki. Insjuknandet hos barn yngre än 2 år började återigen öka under de sista årens uppföljning. Detta kan innebära att den svenska epidemin inte var så unik som vi tidigare trott, även om insjuknandenivåerna under epidemin var markant högre. Det fanns en regional variation i risken att utveckla celiaki. De två regionerna Västsverige och Småland inklusive Öland och Gotland hade ett högre insjuknande än regionerna Norra Mellansverige och Stockholm. Stora variationer i insjuknande av celiaki mellan olika årskullar kan inte enbart förklaras av ärftliga faktorer och glutenexponering. Det är därför angeläget att fortsätta att
40 POPULÄRVETENSKAPLIG SAMMANFATTNING
identifiera miljö- och livsstilsfaktorer som ökar eller minskar risken att insjukna i celiaki under olika delar av livet.
Ungdomar med celiaki upplever praktiska och sociala problem relaterade till den glutenfria kosten. Att äta utanför hemmet synliggjorde deras annars osynliga sjukdom och bidrog till att skapa en upplevelse av att inte vara som alla andra. Genom att inte synliggöra sin kostbehandling kunde de undvika de negativa konsekvenserna av att känna sig socialt avvikande. Valet att följa eller inte följa kostbehandlingen kunde därför förklaras som ett ställningstagande mellan att avslöja eller dölja sitt behov att äta glutenfri kost. Möjligheterna att följa den glutenfria kosten påverkades också negativt av begränsad kunskap hos dem själva och hos personer i deras omgivning, bristande tillgänglighet av glutenfria alternativ, svårigheter att acceptera smak, konsistens och utseende på den glutenfria maten samt otillräckligt socialt stöd. Till viss del påverkades följsamheten till kosten också av i vilken grad de upplevde symptom vid intag av gluten. Tre olika förhållningssätt till den glutenfria kosten kunde urskiljas: de som strikt följde kosten, de som i princip följde kosten men beroende på situation och omständigheter ibland valde att äta mat med gluten, samt de som valde att äta mat med gluten som en del av sin vardag.
Den ökade förekomsten av celiaki över tid samt de problem och behov som finns hos ungdomar med celiaki behöver uppmärksammas. Tillgång till kontinuerlig och evidensbaserad kostbehandling, subventionering av fördyrade matkostnader samt generellt ökad kunskap om innebörden och betydelsen av glutenfri kost behöver säkerställas för att bidra till god livskvalitet och minimera medicinska komplikationer hos unga med celiaki.
41 ACKNOWLEDGEMENTS
ACKNOWLEDGEMENTS
The research presented in this thesis is a result of a multidisciplinary collaboration between the Departments of Food and Nutrition, Public Health and Clinical Medicine, Epidemiology and Public Health Sciences, and Clinical Sciences, Paediatrics. First and foremost the gratitude must go to all the collaborators at paediatric clinics in Sweden for reporting incident cases, and to the adolescents sharing their experiences with us. Without their help this project has been impossible. Many people have been in involved in various ways along the way and I wish to express my genuine thanks and respect to the following:
First of all I want to thank my supervisors for all your deep knowledge, experience, support, attention, constructivism, inspiring discussions, and for always believing in me. I have experienced my self lucky to have access to all of you during this process. You have always been available for discussions and guided me with lots of confidence along the way.
Ylva Mattsson Sydner, my main supervisor, for taking me deeper into the field of qualitative research methods, and for extending the critical mass by inviting me to our sister-department in Uppsala. I miss you here in Umeå!
Agneta Hörnell, my co-supervisor, for your deep knowledge in infant nutrition and your ability to see the important details.
Anneli Ivarsson, my co-supervisor, for generously inviting me to the research fields of epidemiology and celiac disease.
Olle Hernell, my co-supervisor, for your impressive skills in seeing the wide perspectives.
Phil Lyon, my unofficial supervisor, for your excellent knowledge in sociology, for extending my English vocabulary, improving my English writing skills, and for fruitful guidance.
My colleagues at the department of Food and Nutrition for always encouraging me and for creating lots of funny coffee breaks. Special thanks to the girls born around the 60s for being my supporting sisters and for sharing so much joy, thoughts, and fellowship. But also Lisette Eriksson for skilful handling of the
42 ACKNOWLEDGEMENTS
economical matters, and Seppo Salonen for always keep my computer in good shape.
Hans Stenlund and Marie Lindkvist, for skilful guidance and explanations in biostatistics.
Susanne Walther, research administrator, for her patience and competence in the administrative work with the register.
All co-workers in the ‘Celiac disease Group’ at Epidemiology and Public Health Sciences, for professional work and help in completing the reports to the register.
The Swedish Paediatric Association´s Working Group on celiac disease for support.
My fellow doctoral students at the department of Food and Nutrition and the ‘Celiac disease Group’ at Epidemiology and Public Health Sciences, for stimulating discussions and friendship.
Lasse, my beloved man and soul mate, for all your love, respect, and optimism.
Erik, Oskar, and Mattias, my lovely sons, for being the most fantastic boys on Earth and for making me a happy and proud mother.
My mother Ullabritt, and sister Maria, for love and support. Although my father Melvin is no longer here with us, I am sure he would be proud.
My niece Stina, for catching all the young characters on the cover of this thesis. You are a real good photographer! I also thank the beautiful girls and boys on the cover for accepting to be photographed.
‘Matlaget’ for lifelong friendship and for sharing almost 500 fantastic meals with you.
All my friends for giving me the opportunity to sometimes focus on other things in life.
43 REFERENCES
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56 APPENDIX 1
APPENDIX 1.
The Swedish Working group for Celiac Disease in Children.*
Members Paediatric department Daniel Agardh Malmö Lars Browaldh Stockholm Peter Elfström Örebro Lena Grahnquist Stockholm Audur Gudjonsdottir Göteborg Lotta Högberg Norrköping Anneli Ivarsson (chair) Umeå Eva Lindberg Örebro Steven Lucas Uppsala Kerstin Nivenius Lund Olof Sandström Umeå Lars Stenhammar Norrköping
* Appointed by the Swedish Paediatric Association through its Section for Gastroenterology, Hepatology, and Nutrition.
57 APPENDIX 2
APPENDIX 2.
The National Swedish Childhood Celiac Disease Register: Participating paediatric departments by region, and the paediatricians and nurses responsible for case reporting at the end of the study period.
Region Paediatric department Paediatrician/Nurse
Upper Norrland Gällivare Åke Stenberg Sunderbyn Mats Bjerner Skellefteå Rickard Larsson Umeå Göte Forsberg
Middle Norrland Härnösand Kristina Hemmingson Sollefteå Britta Björsell Sundsvall Jonas Wållinder Örnsköldsvik Ove Ljungdahl Östersund Urban Tirén
North Middle Sweden Falun Bengt Korlén Gävle Niklas Nyström Hudiksvall Thomas Hägg Karlstad Gudrun Jonsell
Stockholm Astrid Lindgrens Barnsjukhus Anna Killander/Hans Hildebrand Huddinge Petter Malmborg Norrtälje Lars Danielsson Sachsska barnsjukhuset Lars Browaldh
58 APPENDIX 2
Region Paediatric department Paediatrician/Nurse
East Middle Sweden Eskilstuna Fredrik Lindgren Katrineholm Lars Anderzén Linköping Karin Fälth-Magnusson Motala Louise Forslund Norrköping Lars Stenhammar Nyköping Fredrik Lundqvist Uppsala Anders Dannaeus Västerås Urban Myrdal Örebro Eva Lindberg
West Sweden Borås Fredrik Lundberg Falkenberg Anita Öckner Göteborg Henry Ascher Halmstad Birgitta Bårdén Kungsbacka Kerstin Nydahl-Persson Lidköping Björn Kornerup Skövde Eric Ronge Trollhättan Nils Wramner Uddevalla Mats A Eriksson Varberg Ingrid Winbo
Småland and the islands Jönköping Ulf Jansson Kalmar Pär Ansved Visby Magnus Fredriksson Västervik Jan-Åke Hammersjö Växjö Eva Karlsson
South Sweden Helsingborg Jan Neiderud Karlskrona Martin Lindqvist Kristianstad Roland Schmidt Lund Kerstin Nivenius Malmö Daniel Agardh Ängelholm Christina Andersson
59