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Gastroenterology and hepatology
Cohort profile
Coeliac disease in the Trøndelag Health Study (HUNT), Norway, a population-based cohort of coeliac disease patients
  1. Polina Lukina1,
  2. Ina Lervåg Andersen1,2,
  3. Petter Tinbod Eggen2,
  4. Patricia Gjertrud Mjønes3,4,
  5. Elin Rønne4,
  6. Nils Bolstad5,
  7. Rolf Anton Klaasen5,
  8. David J Warren5,
  9. Rasmus Iversen6,
  10. Kristian Hveem1,7,
  11. Tomm Bernklev8,9,
  12. Lars Petter Jelsness-Jørgensen10,11,
  13. Lise Pedersen12,
  14. Iris Jonkers13,
  15. Pernilla Lagergren14,15,
  16. Ludvig Magne Sollid6,16,
  17. Knut Lundin6,17,
  18. Eivind Ness-Jensen1,2,14
  1. 1HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway
  2. 2Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
  3. 3Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Trøndelag, Norway
  4. 4Department of Pathology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Trøndelag, Norway
  5. 5Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
  6. 6K.G. Jebsen Centre for Coeliac Disease Research, University of Oslo, Oslo, Norway
  7. 7K.G. Jebsen Centre for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Trøndelag, Norway
  8. 8Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  9. 9R&D Department, Vestfold Hospital Trust, Tønsberg, Vestfold, Norway
  10. 10Østfold University College, Halden, Østfold, Norway
  11. 11Department of Gastroenterology, Østfold Hospital Trust, Kalnes, Norway
  12. 12Norwegian Coeliac Society, Oslo, Norway
  13. 13Department of Genetics, University of Groningen, Groningen, Groningen, The Netherlands
  14. 14Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Stockholm, Sweden
  15. 15Department of Surgery and Cancer, Imperial College London, London, UK
  16. 16Department of Immunology, Oslo University Hospital, Oslo, Norway
  17. 17Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
  1. Correspondence to Dr Polina Lukina; polina.lukina{at}ntnu.no

Abstract

Purpose Coeliac disease (CD) is a common disorder and affects about 1% of the population worldwide. CD in the Trøndelag Health Study (HUNT) is a population-based cohort study which was established to provide new knowledge about CD that can improve the diagnostics and management, prevent the onset or progression and expand the knowledge about the role of genetics of the disease.

Participants The cohort is based on the fourth wave of the population-based HUNT study (HUNT4), Norway, performed during 2017–2019, also including linkage to hospital records and the Norwegian Patient Registry (NPR). A total of 54 541 HUNT4 participants with available sera were screened for CD by serology. All seropositive participants were invited to a clinical assessment, including endoscopy with duodenal biopsies, during 2019–2023.

Findings to date A total of 1107 HUNT4 participants (2%) were seropositive for CD and 1048 were eligible for clinical assessment, including biopsy. Of these, 724 participants attended the clinical assessment and 482 were identified with CD. In addition, 371 participants with CD were identified through the hospital records and NPR. In total, 853 participants in HUNT4 with biopsy-verified CD diagnosis were identified.

Future plans All participants in the study will be invited to a follow-up assessment after at least 1 year, including repeated standard serological testing, endoscopy and tissue sampling. The collected data and material will be used to establish the true population-based prevalence of CD. The consequences of CD, including symptoms, deficiencies and comorbidity, will be investigated and possible triggers and predictors, will be studied. With access to serum samples from the previous HUNT surveys in HUNT Biobank, serological signs of CD in prediagnostic samples of seropositive individuals will be used. Genetic studies will identify new CD markers, assess genotype–phenotype links and explore gene–environment correlations.

Registration clinicaltrials.gov identifier: NCT04041622.

  • Coeliac disease
  • EPIDEMIOLOGIC STUDIES
  • EPIDEMIOLOGY
  • REGISTRIES

Data availability statement

Data are available upon reasonable request. The study data and material are available for research through application to HUNT Research Centre, as for other data and material from the main HUNT studies (https://hunt-db.medisin.ntnu.no/hunt-db/). All variables from the clinical assessment and PROMs are collected in HUNT Databank and the biological materials are stored in HUNT Biobank. A web application to HUNT Research Centre through the following link is needed to access data from the CD in HUNT: https://hunt-db.medisin.ntnu.no/hunt-db/ .In the web-application, the available variables and material from all the HUNT studies can be searched and ordered. More information about data access and access to biological material is available at https://www.ntnu.edu/hunt/databank or by contacting kontakt@hunt.ntnu.no. Access to the clinical data is through application to the Research Department at Nord-Trøndelag Hospital Trust, contact email: forskningsavdelingen@hnt.no.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2023-077131

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • The population-based design with a high number of participants and high participation rate at baseline reduces selection bias.

    • The participants in the study are representative of the general population, and not selected for age, sex, health condition or social status.

    • The Norwegian birth number, unique to every Norwegian resident, provides an opportunity to link the HUNT data of every participant to his/her hospital records and national health registries to track his/her patient history, both in the past and in the future.

    • The ethnic homogenous population of Trøndelag leads to limited generalisability for people of non-European origin.

    • The study did not include participants below 20 years of age, so the paediatric and adolescent CD population is not included.

    Introduction

    Coeliac disease (CD) is an autoimmune condition triggered by the consumption of grains containing gluten in genetically predisposed individuals.1 Gluten is the main storage protein in wheat, barley and rye.2 Inflammation in the small intestine leads to villous atrophy and flattening of the intestinal mucosa.3 The most common symptoms of CD include abdominal pain, increased bowel movements, weight loss, osteoporosis, anaemia and weakness.4 The primary treatment for CD is a strict lifelong gluten-free diet.5

    CD exists worldwide where gluten is a part of the diet and is among the most prevalent autoimmune disorders, affecting 0.5–2.4% of the general population globally.6 Once considered as a condition in children of European origin, now CD is one of the most prevalent lifelong disorders, affecting individuals of all ages across the globe.7 Two systematic reviews conclude that the incidence of biopsy-confirmed CD is more common in women than men and approximately twice as common in children than in adults per 100 000 person years.6 8 A notable upward trend in CD incidence has been observed from the latter half of the 20th century and continues into the 21st century across Western countries.8 While CD was traditionally considered a paediatric disease, it is now diagnosed at any age.7 However, most adults diagnosed with CD do not have past serological tests and therefore we do not know the actual disease onset. Former studies have also indicated a high ratio of undiagnosed to diagnosed CD cases.9 10

    The pathogenesis of CD is a complex interaction between gluten, the immune response, and genetic and environmental factors.11 The HLA-DQ2 and HLA-DQ8 genotypes are strongly associated with CD.12 13 In addition, non-HLA genes have been identified, collectively explaining high heritability of the disease.14 15 While individuals with a genetic susceptibility have an increased risk, the development of CD also requires environmental triggers. Data about the role of environmental factors in the risk of developing CD in adults are still limited.16

    CD is associated with a higher occurrence of other autoimmune diseases.17 Additionally, the risk of developing small intestinal lymphomas and adenocarcinomas is increased in individuals with CD.18 However, due to these associations being established using hospital-based case series and a significant proportion of undiagnosed cases, the prevalence of comorbidity in the overall CD population is currently unknown.

    The aim of our study was to provide new knowledge about CD that can improve the diagnostics and management, prevent the onset or progression and expand the knowledge about the role of genetics of the disease.

    Cohort description

    Cohort basis

    CD in the Trøndelag Health Study (HUNT) was established based on the fourth wave of the HUNT study (HUNT4) performed during 2017–2019.19 The HUNT study is a population-based cohort study from former Nord-Trøndelag County, Norway (figure 1), established in the 1980s and is the largest collection of health data from the general population in Norway.20–22 The population of Nord-Trøndelag is representative of Norway and other Western populations, except for the lack of large cities and immigrant populations. The population is stable, with low migration, making it well suited for longitudinal studies. In 2017, the population of the county was nearly 137 000 residents.19 The study was designed to cover a broad range of health-related topics through repeated comprehensive questionnaires, clinical examinations, laboratory measurements and storage of biological samples. All individuals ≥20 years of age residing in the county were invited (online supplemental table S1). The HUNT data can be linked to national and local health registries by the unique identification number of all Norwegian residents (‘the birth number’).

    Figure 1
    Figure 1

    The former Nord-Trøndelag County, the Trøndelag Health Study’s geographic area (the Norwegian Mapping Authority, Kartverket).

    The HUNT4 study

    HUNT4 was performed between 29 August 2017 and 23 February 2019 with 56 042 participants out of 103 800 invitees (54.0% participation rate).19 About 19 000 individuals have participated in all HUNT1–4 surveys with a total follow-up history since 1984–1986. Almost half of the participants in HUNT4 have participated in three HUNT surveys, and 60% of the participants have been followed from the previous HUNT3 survey (online supplemental figure S1). More women (54.6%) than men participated in HUNT4, which was similar to the previous HUNT surveys. The highest participation was in the age group of 50–59 years for women (19% participation rate) and 60–69 for men (21.3% participation rate). The lowest was in the age groups 20–29 years and >80 years. The HUNT4 survey’s data collection included questionnaires and clinical measurements, in addition to collection of biological samples (blood, urine, faeces and saliva). A total of 849 different variables from HUNT4 are available in HUNT Databank. In addition, genetic material is available from almost all participants in HUNT2-4.23

    HUNT Biobank

    HUNT Biobank stores biological material from participants in HUNT2-4.24 25 The biobank has a fully automated storage system with temperatures at −80°C (Azenta)22 and a nitrogen storage unit which maintains a temperature of −187°C. The participants in HUNT4 provided blood samples at health examination stations in a non-fasting state. Fixed procedures for sampling, transport and storage were used. The blood samples were aliquoted and stored in the automated −80°C freezers at HUNT Biobank.

    Data collection

    The CD cohort was established based on the blood samples from the participants in HUNT4 (n=54 541) stored at HUNT Biobank (figure 2). Frozen serum from each participant was retrieved from HUNT Biobank and sent to Department of Medical Biochemistry, Oslo University Hospital for analyses with a new serological assay for simultaneous measurement of transglutaminase 2 (TG2) IgA and IgG antibodies.26 A total of 1107 individuals (2%) were seropositive. Of these individuals, 59 were dead, had moved or withdrawn their consent, leaving 1048 individuals eligible for clinical assessment, including endoscopy with duodenal biopsy. All seropositive participants eligible for the study were invited through an invitational letter, including information about the endoscopic procedure, additional investigations and a written informed consent. A total of 59 seropositive participants already had a CD diagnosis, 32 before participation in HUNT4 and 27 after participation in HUNT4, but still took part in the clinical assessment, except endoscopy.

    Figure 2
    Figure 2

    Number (n) of participants in each stage of the establishment of the coeliac disease cohort in the Trøndelag Health Study. aDead, moved or refused consent.

    The clinical assessment included clinical chemistry (online supplemental table S2) with repeated serological testing using commercially available serological assays (TG2 IgA and deamidated gliadin peptide IgG antibodies, EliA Phadia 250, Thermo Fisher Scientific) and upper endoscopy with small intestinal biopsies. The endoscopies were

    performed with standardised pictures taken from the duodenal pars horizontalis (D3) and the duodenal bulbus (D1) using Endobase (Olympus).27 Six single-bite biopsies were collected in formalin, four from pars horizontalis (D3) and two from bulbus (D1), and four biopsies in RNAlater, two from pars horizontalis (D3) and two from bulbus (D1). Histopathological and immunohistochemical (CD3 staining) examinations were performed on the formalin-fixated biopsies at the Department of Pathology, St. Olav’s Hospital, Trondheim University Hospital. As this was mass screening of the population and not case finding, strict criteria were used to diagnose CD. A diagnosis of CD required repeated positive serology at the time of endoscopy, Marsh grade 328 29 and exclusion of other possible causes of inflammation and atrophy, including infection with Helicobacter pylori by PCR testing of biopsies from the antrum and corpus of the stomach and use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid. Participants with Marsh grade below 3 were assessed as potential coeliacs and further recommended gluten-containing diet for a new diagnostic procedure after at least 1 year. The biopsies on RNAlater, in addition to serum, plasma, saliva and faeces were collected and stored at HUNT Biobank, which provided a source for future studies (online supplemental table S3a,b). The participants were also invited to bone mineral density measurements by dual-energy X-ray absorptiometry (DXA), performed at Levanger Hospital, Namsos Hospital or at Høvdinggården Medical Centre, Steinkjer, and to panoramic dental X-ray, orthopantomogram (OPG), performed at Levanger Dental Clinic. All participants in the clinical study were asked to fill in patient-reported outcome measures (PROMs; online supplemental table S4a–g). The PROMs included the Norwegian version of Short Form 36 Health Survey Questionnaire, Chalder Fatigue Scale, Hospital Anxiety and Depression Scale, Gastrointestinal Symptom Rating Scale-Irritable Bowel Syndrome, Coeliac Disease Symptom Index, Coeliac Disease Assessment Questionnaire and five in-house made questions about diet.30–35

    All clinical research data were registered in WebCRF, a resource for online collection of research data, provided by the Norwegian University of Science and Technology (NTNU), and thereafter imported to HUNT Databank.36 In addition, the clinical data were registered in DocuLive, the electronic hospital records at Levanger Hospital, and the endoscopic data were registered in Endobase (Olympus).27 37 Results of the clinical chemical analyses, DXAs and OPGs were imported directly to HUNT Databank. The participants are invited to a 1-year follow-up with repeated serological testing, upper endoscopy with tissue sampling, collection of biological material and questionnaires.

    Data linkage

    To identify all participants in HUNT4 with CD, data were retrieved from the patient records at Nord-Trøndelag Hospital Trust (HNT; ie, Levanger Hospital and Namsos Hospital), St. Olav’s Hospital and from NPR on all HUNT4 participants by linkage using the birth number (unique personal identification number).

    At HNT and St. Olav’s Hospital, the medical, surgical and radiological procedures performed are registered using the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures (NCSP) since 2006. The NCSP codes UJD02 (gastroscopy) and UJD05 (gastroscopy with biopsy) were used to identify HUNT participants with a possible CD diagnosis. Before 2006, rate codes were used to register the endoscopic procedures performed. Rate codes were part of the activity-based payment system for hospital care in Norway and were used to refund costs for medical procedures performed at the outpatient clinic.38 39

    The NPR contains health information about all individuals who have received treatment or who are waiting for treatment in the specialist healthcare service in Norway.40 The registry was searched for both primary and secondary diagnoses with the International Classification of Disease (ICD-10) diagnostic code for CD (K90.0).

    Follow-up

    All participants in the clinical study will be invited to a 1-year follow-up with repeated endoscopy and biopsy, in addition to repeated sampling of the biological material and repeated reporting on the questionnaires.

    Patient and public involvement

    The Norwegian Coeliac Society provided financial support for the project and has been involved in the planning of the study, but not the implementation or analyses.

    Findings to date

    Of the seropositive participants in HUNT4, 450 participants with a new, previously unknown CD diagnosis were identified after participation in HUNT4, in addition to 32 participants with known, previously diagnosed CD before participation in HUNT4 (table 1). Data on 16 213 HUNT4 participants were retrieved from the hospital records and a CD diagnosis was confirmed by histology in 312 individuals who were seronegative or without serum samples in HUNT4. In addition, 56 individuals that were seropositive in HUNT4 but did not attend the clinical assessment were identified with a histologically confirmed CD diagnosis through the hospital records. Of these 56, 20 individuals got their CD diagnoses after participation in HUNT4 and were defined as new CD cases, while the remaining 36 had already a known CD diagnosis before participation in HUNT4. The NPR accommodated data from 54 799 HUNT4 participants, collected from somatic hospitals and clinics (n=53 580) and from contract specialists in somatic disciplines (n=38 943). Of these, 341 individuals who were seronegative or without serum samples in HUNT4 were identified with a CD diagnosis, but only three participants with CD not already identified by the hospital record searches.

    View this table:
    Table 1

    The number of participants in the fourth Trøndelag Health Study (n=56 042) with a CD diagnosis, by identifying data source

    Collaboration

    The CD project in HUNT4 was initiated in 2019 as a collaboration between researchers at NTNU, Levanger Hospital, St. Olav’s Hospital, University of Oslo, Oslo University Hospital, Østfold University College, Karolinska Institute, Sweden, University of Groningen, the Netherlands and the Norwegian Coeliac Society.

    Further details

    Future plans

    All seropositive participants, both those with confirmed and not confirmed CD, will be invited to a follow-up assessment after at least 1 year, including repeated standard serological testing, upper endoscopy and tissue sampling. Currently, the first clinical assessment is complete, and the follow-up assessment will be completed during 2024. The collected data will be used to establish the total population-based prevalence of CD. The serological data from the cohort will be analysed, including as part of a no-biopsy approach in diagnosing CD in adults, as in the paediatric population. The identification of all CD cases in an unselected population, including both the previously diagnosed and newly diagnosed cases, in addition to individuals with potential CD, is a unique resource for unbiased assessments of CD. The consequences of CD, including symptoms, deficiencies and comorbidity will be investigated, and possible triggers and predictors, both genetic and environmental, will be studied. Paediatric cohorts suggest that CD usually has its onset during childhood.41 However, most adults diagnosed with CD do not have previous serological tests to assess if the disease might have occurred earlier in life. With access to serum samples from the previous HUNT2 and HUNT3 surveys in HUNT Biobank, serological signs of CD in prediagnostic samples of seropositive individuals will be used to assess if CD might have occurred in adulthood or if there have been signs of the disease one to two decades ago in time.

    Strengths and limitations

    A major strength is the population-based design with a high number of participants and high participation rate at baseline, reducing selection bias. The participants in the study are representative of the general population, and not selected for age, sex, health condition or social status. However, the ethnic homogenous population of Trøndelag leads to limited generalisability for people of non-European origin.19 The Norwegian birth number, unique to every Norwegian resident, provides an opportunity to link the HUNT data of every participant to his/her hospital records and national health registries to track his/her patient history, both in the past and in the future. Nearly 30 000 participants in HUNT4 have participated in more than one HUNT survey and have historical data and biological material stored in HUNT Databank and Biobank, respectively. This gives the possibility to study CD in a longitudinal and prospective manner. Participants in HUNT may also be recontacted for future studies, including collection of biological material.

    The study was limited to the residents of Nord-Trøndelag County. The county is mainly representative of the Norwegian population, but the absence of a larger city causes low representation of a population in urban constituency. The study results may also be influenced by the lower level of participation by men in comparison with women, as well as the overall lower participation rate observed among both younger and older age groups.19 The most represented age group was 40–79 years (78.6% of all women and 71.7% of all men participated). The study did not include participants below 20 years of age, so the paediatric and adolescent CD population is not included. The representation of participants >80 years of age in the clinical part of the study was low, reducing the validity of the results in the oldest population. Reasons for non-participation in this age group included long distance to the hospital, comorbidity and death before invitation to the clinical part of the study. Despite the possibility to link data from primary healthcare, it was not possible to identify participants with CD from this data source as the International Classification of Primary Care code for CD is D99, which includes several conditions and diseases unrelated to CD. However, in Norway, the CD diagnosis in adults is only confirmed in secondary healthcare after histological verification, minimising the effect of this limitation.

    Data availability statement

    Data are available upon reasonable request. The study data and material are available for research through application to HUNT Research Centre, as for other data and material from the main HUNT studies (https://hunt-db.medisin.ntnu.no/hunt-db/). All variables from the clinical assessment and PROMs are collected in HUNT Databank and the biological materials are stored in HUNT Biobank. A web application to HUNT Research Centre through the following link is needed to access data from the CD in HUNT: https://hunt-db.medisin.ntnu.no/hunt-db/ .In the web-application, the available variables and material from all the HUNT studies can be searched and ordered. More information about data access and access to biological material is available at https://www.ntnu.edu/hunt/databank or by contacting kontakt@hunt.ntnu.no. Access to the clinical data is through application to the Research Department at Nord-Trøndelag Hospital Trust, contact email: forskningsavdelingen@hnt.no.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the Regional Committee for Medical and Health Research Ethics, Central (reference number 7943). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    The HUNT study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology NTNU), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. We thank the administration and staff at HUNT Research Centre for help with implementation of the project, ideas and feedbacks. We thank all participants in HUNT4 for their participation, including donation of biological material and participation in the clinical study. We thank the staff at the Gastroenterology Laboratory at Levanger Hospital, Nord-Trøndelag Hospital Trust for the contribution in the clinical study, the Research Department at Nord-Trøndelag Hospital Trust for the support and collaboration and the Norwegian Coeliac Society for the support in the project.

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    Footnotes

    • Twitter @lars_jelsness

    • Contributors Study design: ILA, LMS, KL, EN-J. Directing of the study’s implementation: EN-J. Study conception: ILA, KH, TB, LPJ-J, LP, IJ, PeL, LMS, KL, EN-J. Data collection: PoL, ILA, PTE, PGM, ER, NB, RAK, DJW, RI, EN-J. Data analysis and interpretation: PoL, EN-J. Manuscript writing: PoL. Supervision: LMS, KL, EN-J. Critical revision of the article: PoL, ILA, PTE, ER, PGM, NB, RAK, DJW, RI, KH, TB, LPJ-J, LP, IJ, PeL, LMS, KL, EN-J. Final approval of the version to be published: PoL, ILA, PTE, ER, PGM, NB, RAK, DJW, RI, KH, TB, LPJ-J, LP, IJ, PeL, LMS, KL, EN-J. The guarantor: EN-J.

    • Funding This work was funded by the Research Council of Norway (grant number 288308), the Liaison Committee for Education, Research and Innovation in Central Norway, Samarbeidsorganet (grant numbers 17/38297 and 18/42795) and the Norwegian Coeliac Society.

    • Map disclaimer The inclusion of any map (including the depiction of any boundaries therein), or of any geographic or locational reference, does not imply the expression of any opinion whatsoever on the part of BMJ concerning the legal status of any country, territory, jurisdiction or area or of its authorities. Any such expression remains solely that of the relevant source and is not endorsed by BMJ. Maps are provided without any warranty of any kind, either express or implied.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.