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Clinical and epidemiological aspects of childhood celiac disease
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Celiac disease (CD) is one of the most common chronic diseases in childhood in many countries. It is a small intestinal disease, caused by gluten in genetically predisposed individuals, but underlying immunological mechanisms are not exactly known. Gluten is found in wheat, rye and barley, and possibly in oats. The clinical presentation of CD varies from overt to no symptoms at all. Treatment with gluten free diet (GFD) heals the mucosa and symptoms disappear. The varying clinical presentation makes the evaluation of the "true" prevalence difficult. When screening with serum antibodies, similar prevalence is found in several countries. The reported increase of clinically detected cases among Swedish children in the mid 1980s attracted much interest and was publicly debated. Infant feeding changes was focused on, but new diagnostic tools were also introduced during this period.

Aims: To describe epidemiological changes in the county of Östergötland from 1980 to 2001. To analyse the possible influence of diagnostic activity and accuracy and the possible influence of certain infant feeding patterns on disease occurrence. To study gluten intake, clinical, histological and immunological parameters during gluten challenge. To evaluate the practical usefulness of the nitric oxide (NO) analysis in CD.

Material and methods: All children (0-17.9 years) investigated for suspected CD in the county of Östergötland 1980-2001 were studied regarding disease occurrence, diagnostic activity and accuracy. Data on infant feeding were analysed in 72 CD children and 288 agematched referents. During gluten challenge 25 children were studied regarding gluten intake, serum antibodies, NO products in the urine, clinical symptoms and mucosal histology. NO products were also measured at different stages of CD investigation in !37 children.

Results: The incidence rate of CD in small children has fluctuated over the study period. How, or whether, infant feeding and/or diagnostic tools have influenced this is not known.

CD children were significantly shorter breastfed, more seldom breastfed at gluten introduction, and started more often with follow-up formula than porridge. This could be interpreted in two ways. Breastfeeding per se could protect against CD, but it is also known that a breastfed baby consumes lower amounts of gluten at the time of introduction. The lower exposure can make symptoms more vague in early childhood and thus postpone the diagnosis.

Gluten intake during challenge varied a lot. Some CD children reacted to minute amounts of gluten. Despite the small amounts given, all children showed signs of relapse at a clinical, serological, or histological level.

CD children on a gluten containing diet have significantly higher levels of NO products in the urine, compared to reference children and to CD children on a GFD. NO products increased during gluten challenge, and doubled within four weeks of challenge. This is probably caused by iNOS activation and increased NO production in the diseased intestinal mucosa.

Conclusions: How, or whether, changes in infant feeding and/or new diagnostic tools influenced the fluctuating incidence of the disease is not known. Very small amounts of gluten caused relapse in CD children. NO products in the urine were elevated in CD children on a gluten diet, and doubled within four weeks of gluten challenge. NO analysis is simple and non-traumatic for the child, and could be of value as a diagnostic tool in celiac disease.

Abstract [en]

Bakgrund: Celiaki (glutenintolerans) är en av de vanligaste kroniska sjukdomarna hos barn, både i Sverige och i andra länder. Celiaki är en tunntarmssjukdom som orsakas av gluten hos personer med ärftlig benägenhet. Gluten finns i vete, råg, korn och kanske också i havre. Den bakomliggande immunologiska mekanismen är fortfarande inte helt känd. Celiaki kan ge varierande symptom, alltifrån kraftiga magtarmsymtom tiH nästan inga symtom alls. Om patienten håller glutenfri diet (GFD) läker tarmen och symtomen försvinner. Livslång GFD innebär fördelaktiga hälsoeffekter både på kort och på lång sikt.

Sjukdomens varierande symtomatologi gör det svårt att uppskatta den "sanna" förekomsten. Vid screening med serumantikroppar hittas ungefar samma förekomst av sjukdomen i olika länder. I mitten av 1980-talet ökade antalet kliniskt upptäckta fall bland svenska barn kraftigt. Detta rönte stort intresse och debatterades livligt, även i pressen. Förändringar i spädbarnsuppfödningen diskuterades som orsak, men nya diagnostiska metoder infördes också under perioden.

Mål: Att beskriva förändringar i förekomst av celiaki hos barn i Östergötland under åren 1980 till 2001. Att analysera eventuellt inflytande av träffsäkerhet och intensitet i diagnostiken samt spädbarnsuppfödning på sjukdomens förekomst. Att studera glutenintag, kliniska, immunologiska och histologiska parametrar under glutenprovokationen. Att utvärdera den praktiska nyttan av att mäta kvävemonoxid (NO)-metaboliter i urinen hos celiakibarn,

Material och metod: Alla barn (0-17 .9 år) som undersökts för misstänkt celiaki i Östergötland under åren1980-2001 registrerades. De studerades med avseende på sjukdomsförekomst samt träffsäkerhet och intensitet i diagnostiken. Uppfödningsdata från 72 celiakibam och deras 288 åldersmatchade kontroller analyserades. Under glutenprovokationen studerades glutenintag, kliniska symtom, NO-metaboliter i urinen, tarmslemhinnans histologi och serumantikroppar. På 137 bam under olika skeden i celiakiutredningen mättes också NO-metaboliter.

Resultat: Antalet nyinsjuknade småbarn varierade mycket kraftigt under de 22 år vi studerat. Huruvida förändrad spädbarnsuppfådning, och/eller fårbättrade diagnostiska metoder har påverkat sjukdomens förekomst går ej att avgöra.

Celiakibam hade ammats kortare tid, ammades mer sällan vid glutenintroduktionen och fick oftare börja med välling än med gröt. Det kan tolkas antingen som att amning i sig skyddar mot celiaki, men det är också känt att ett barn som ammas får i sig mindre mängder gluten vid introduktionen. Denna lägre exponering skulle kunna ge lindrigare symtom, och på så sätt försvåra och fårsena diagnosen.

Mängden gluten som barnen åt under provokationen varierade kraftigt. Vissa barn reagerade på ytterst små mängder. Trots de små mängder barnen fick i sig visade alla tecken på återfall i sjukdomen, antingen kliniskt, serologiskt eller histologiskt.

Hos celiakibam som åt g!uten uppmättes signifikant högre värden av NO-metaboliter i urinen än hos kontrollbarn och celiakibarn som inte åt gluten. Det beror antagligen på enzymaktivcring med ökad NO-produktion i den sjuka tarmslemhinnan. Under glutenprovokationen fördubblas NO-mctabolitema inom fyra veckor.

Sammanfattning: Huruvida fårändringar i spädbarnsuppfödningen och/eller förbättrade diagnostiska metoder har påverkat den varierande förekomsten av celiaki hos småbarn i Sverige går ej att avgöra. Mycket små glutenmängder var tillräckliga för att orsaka återfall under provokationen. NO-metaboliter i urinen var signifikant högre hos celiakibarn som åt gluten, än hos kontrollbarn och celiakibarn som åt glutenfritt Under provokationen stiger värdena till det dubbla inom f)rra veckor. NO-analysen är enkel, billig och dessutom skonsam för barnet. Den skulle därfår kunna utgöra ett värdefullt tillskott i den diagnostiska arsenalen.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2002. , 104 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 746
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-26660Local ID: 11226ISBN: 91-7373-188-9 (print)OAI: oai:DiVA.org:liu-26660DiVA: diva2:247209
Public defence
2002-10-18, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-20Bibliographically approved
List of papers
1. Celiac disease in childhood in a Swedish county 1980-2001
Open this publication in new window or tab >>Celiac disease in childhood in a Swedish county 1980-2001
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The prevalence of celiac disease (CD) in Swedish children has attracted considerable interest during the last decades, and especially the influence of feeding habits on the increased incidence. A national study has reporled a trend of decreasing incidence in the last years after a change in infant feeding recommendations in 1996.

Aim: To evaluate, on a geographically defined area, the changes of incidence over time and the influence of the introduction of antibody analysis.

Material: All children investigated for suspected CD during 1980-2001 in the county of Östergötland in southeast Sweden. The population of children <18 years is 89,679 (Jan 1, 2001).

Results: 1901 children were investigated with small intestinal biopsy, yielding 472 CD cases. The area initially describes the same trends as the national study, hut the annual incidence rate is now increasing again. Median age at diagnosis has increased markedly since 1997 from less than 2 years to above 5 years. Cumulalive incidence is much higher for the birth cohorts 83-96 than 80-82 or 97-00. More biopsies were performed per 1,000 children after the introduction of anti-gliadin antibodies (AGA), and less biopsies after the introduction of antiendomysium antibodies (EMA). Diagnostic accuracy was significantly higher after AGA, and especially after EMA introduction.

Conclusions: The incidence rate of CD in small children has shown a large variation over the 22 years observed. Both feeding practice and methods of investigation have changed during the period. Annual incidence rate for the total child population in 2001 approaches the peak value observed in 1994. Median age at first biopsy has rnore than doubled in the last years. There were no conclusive results on whether antibody analyses influenced the diagnostic activity, but they seemed to have increased the diagnostic accuracy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81657 (URN)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2012-09-20Bibliographically approved
2. Infant feeding history shows distinct differences between Swedish celiac and reference children
Open this publication in new window or tab >>Infant feeding history shows distinct differences between Swedish celiac and reference children
Show others...
1996 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 7, no 1, 1-5 p.Article in journal (Refereed) Published
Abstract [en]

Infant feeding history was investigated in 72 celiac and 288 age-matched reference children in a retrospective questionnaire study. The reply rate was 100% in celiac and 91. 6% in reference children. The celiac children were breast-fed for a significantly shorter time than reference children, and they were less often breast-fed at the introduction of gluten. The age of the children at gluten introduction was similar, but the cellac children were significantly more often introduced by a gluten-containing follow-up formula, while the reference children more often started on a gluten-containing porridge. The results can be interpreted in two ways. First, it could be argued that breast milk per se protects against symptoms of celiac disease in childhood. It could, however, also be claimed that breast-feeding merely modulates the gluten introduction, causing a less abrupt introduction of gluten in the baby diet and thereby fewer overt symptoms of the disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81658 (URN)10.1111/j.1399-3038.1996.tb00098.x (DOI)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2017-12-07Bibliographically approved
3. Even small amounts of gluten cause relapse in children with celiac disease
Open this publication in new window or tab >>Even small amounts of gluten cause relapse in children with celiac disease
2002 (English)In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 34, no 1, 26-30 p.Article in journal (Refereed) Published
Abstract [en]

Background: Previously, a gluten challenge was customary to establish the diagnosis of celiac disease in children. There are no clear recommendations on how to perform this challenge or what markers to rely on for timing the biopsy after the challenge. The authors' aim was to monitor gluten intake, clinical symptoms, and antibody kinetics to evaluate the influence of gluten exposure during the challenge.

Methods: Twenty-five children under investigation for suspected celiac disease were challenged. One child was excluded because blood samples, food records, or biopsy was lacking. Median age at the postchallenge biopsy was 3.8 (2.7-8.8) years. The families kept daily records of the children's gluten intake and of symptoms that occurred. Blood samples were taken monthly for analysis of antigliadin and endomysium antibodies and total immunoglobulin A (IgA). A third biopsy was performed when clinical symptoms suggested a relapse.

Results: All 24 children showed deterioration of the mucosa or elevated antibodies during gluten challenge. Median duration of the challenge was 13 (5-51) weeks, and mean gluten intake was 1.7 (0.2-4.3) g/d and 0.1 (0.02-0.26) g/kg daily.

Conclusions: Gluten intake during the challenge varied widely, and the parents were unable to give their children the recommended amount. Despite the small amounts given, all children showed signs of relapse at a clinical, laboratory, or histologic level. Much smaller amounts of gluten than previously suggested seem sufficient to cause relapse during gluten challenge in children.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26463 (URN)10.1097/00005176-200201000-00007 (DOI)11011 (Local ID)11011 (Archive number)11011 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Significantly increased levels of nitric oxide products in urine of children with celiac disease
Open this publication in new window or tab >>Significantly increased levels of nitric oxide products in urine of children with celiac disease
Show others...
1998 (English)In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 27, no 2, 196-198 p.Article in journal (Refereed) Published
Abstract [en]

Background: Celiac disease is characterized by morphologic and functional aberrations of the small intestinal mucosa, i.e. crypt hyperplasia, villous atrophy, infiltration of intraepithelial lymphocytes, and alteration of permeability. Nitric oxide has been shown to affect mucosal permeability after ischemia-reperfusion, but little is known about the regulatory role of nitric oxide in celiac disease. The purpose of this study was to assess nitric oxide production in children with celiac disease and in control subjects.

Methods: The sum of nitrite and nitrate in the urine was measured with a colorimetric method in 137 children with a median age of 3 years, 84 patients and 53 reference children, all of whom underwent a small intestinal biopsy to confirm or overrule suspicion of celiac disease.

Results: Median urinary nitrite-nitrate concentration in celiac children was 3323µM (4147 ± 1102; mean ± SEM) at first clinical examination and 2501 µM (2939 ± 386) after gluten challenge, which was significantly higher than concentrations in reference children(1029 µM; 1174 ± 116) and in children with celiac disease on a gluten-free diet (882 µM; 1369 ± 360) (p< 0.0001).

Conclusions: A gluten-containing diet is associated with an increased nitrite-nitrate secretion in the urine in children with celiac disease, presumably as a result of nitric oxide synthase activation and nitric oxide production in the diseased small intestinal mucosa.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81659 (URN)10.1097/00005176-199808000-00013 (DOI)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2017-12-07Bibliographically approved
5. Increase in nitric oxide urinary products during gluten challenge in children with coeliac disease
Open this publication in new window or tab >>Increase in nitric oxide urinary products during gluten challenge in children with coeliac disease
2003 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 38, no 1, 55-60 p.Article in journal (Refereed) Published
Abstract [en]

Background: Coeliac disease is a gluten-sensitive enteropathy where pro-inflammatory cytokines and excess nitric oxide (NO) production can contribute to mucosal damage. NO urinary products are elevated in coeliac children on a gluten diet, but it is not known how rapidly this increase develops after gluten exposure.

Methods: Oral gluten challenge was performed in 25 children whose families kept a daily record of gluten intake and symptoms. Blood was analysed monthly for antigliadin (AGA) and endomysium antibodies (EMA). Urine was analysed every second week for NO products, i.e. the sum of nitrite and nitrate was measured with a colorimetric method. We performed a third biopsy when clinical symptoms indicated a relapse. Median age at the post-challenge biopsy was 3.8 (2.7-8.8) years.

Results: Signs of morphological or serological relapse were seen in all children. Mean daily gluten intake was 0.10 (range 0.02-0.26) g/kg bodyweight. Median NO level was doubled and significantly higher after 4 weeks of challenge but not after 2 weeks. EMA, but not AGA levels, correlated positively with NO. Intraepithelial lymphocyte count was significantly higher in the post-challenge biopsy, but did not correlate with the NO levels.

Conclusions: NO products in urine increased during gluten challenge. EMA levels reflected severity of mucosal damage, and NO products reflected the inflammatory response, which was doubled after 4 weeks of challenge. The NO analysis is simple and non-traumatic for the child. It can be performed repeatedly during investigation of children with suspected coeliac disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26466 (URN)10.1080/00365520310000447 (DOI)11016 (Local ID)11016 (Archive number)11016 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved

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