Celiac Disease: Complications and the Role of Infection in Pathogenesis

Background: Celiac disease (CD) is an autoimmune disorder occurring worldwide with a prevalence of about 1% of the Western population. The classic presentation comprises symptoms of malabsorption such as diarrhea and weight loss, but the spectrum of symptoms is wide, including asymptomatic disease. CD is induced by dietary gluten in genetically susceptible individuals. The pathogenesis of CD has not been fully elucidated, and although environmental factors such as infant feeding practice and infectious disease have been suggested, results are inconclusive. Treatment of CD consists of a life-long gluten-free diet (GFD). Individuals with CD suffer increased risk of a number of comorbid conditions, including diabetes mellitus type 1, depression and certain malignancies. Aims: The aim of this thesis was to investigate the risk of venous thromboembolism (VTE), end-stage renal disease (ESRD), and IgA nephropathy (IgAN) in individuals with CD. These studies were carried out with the objective to obtain increased knowledge regarding CD characteristics, in order to optimally design the care of individuals with CD and identify possible groups with increased risk of CD. A separate aim of this thesis was to further investigate the pathogenesis of CD, by assessing the effect of infectious disease at time of gluten introduction in infants on the risk of future CD. Materials and methods: The risk of VTE was assessed in a cohort of 14,207 individuals with a discharge diagnosis of CD recorded in the Swedish hospital discharge register. When investigating renal complications (ESRD and IgAN), studies were based on a CD cohort identified through Swedish biopsy registers (about 29,000 individuals). Reference individuals, matched for age, sex, calendar period and county, were selected (five per index individual with CD) from the Swedish total population register. Cox regression was used to investigate the associations between CD and outcome data in these population-based cohort studies. We used the All Babies in Southeast Sweden (ABIS) population-based cohort study, where the parents of all children born in 1997-1999 in the area were invited to participate. Parents of 9,849 children prospectively completed a diary with feeding data and parent-reported infections during the child’s first year of life. The pediatric departments in the area reported children diagnosed with CD. Cox regression was used to assess the risk of CD in children with infection at time of gluten introduction. Results: Among individuals with a discharge diagnosis of CD, 406 (2.6%) suffered subsequent VTE, compared with 1105/76,910 (1.4%) of reference individuals, corresponding to a modestly increased risk of VTE in CD (Hazard ratio, HR, 1.86; 95% Confidence interval, CI, 1.54-2.24). This risk increase was limited to individuals diagnosed with CD in adulthood. Individuals with biopsy-verified CD suffered a threefold increased risk of future ESRD (HR, 2.87; 95% CI 2.22-3.71). The estimate remained significant in analyses where we adjusted for the presence of type 1 diabetes mellitus, and after restricting the outcome to ESRD recorded in the Swedish patient register and in the Swedish renal register. Individuals with biopsy-verified CD also suffered increased risk of future biopsy-verified IgAN (HR, 3.03; 95% CI 1.22-7.56). This risk increase was only seen in men with CD. Although parent-reported infections were more common among children with CD (p=0.035), we found no increased risk of CD among children with any reported infection (HR, 1.8; 95% CI 0.9-3.6) or gastroenteritis (HR, 2.6; 95% CI 0.2-30.8) at time of gluten introduction (analyses adjusted for age at gluten introduction, age at end of breastfeeding, and age at any infection). The majority of Swedish children were breastfed for more than 9 months. Conclusions: CD is modestly associated with future VTE, likely due to a combination of chronic inflammation and surveillance bias. CD is a risk factor for future ESRD and IgAN. Although absolute risks are low, our findings warrant increased awareness regarding renal function in the care of individuals with CD. Future studies should evaluate the effect of adherence to a gluten-free diet and risk of future renal disease to potentially identify individuals at risk. Infection at time of gluten introduction does not seem to be a major risk factor for future CD. In a setting where adherence to infant feeding guidelines is high, duration of breastfeeding and age at gluten introduction are no major risk factors for CD. Future studies should include longer follow-up to assess long-term effects of environmental factors during the first year of life. LIST OF PUBLICATIONS I. Ludvigsson JF, Welander A, Lassila R, Ekbom A, Montgomery SM. Risk of thromboembolism in 14,000 individuals with coeliac disease. British Journal of Haematology 2007;139:121-7. II. Welander A, Prutz KG, Fored M, Ludvigsson JF. Increased risk of end-stage renal disease in individuals with coeliac disease. Gut 2012 Jan;61(1):64-8. Epub 2011 Aug 3. III. Welander A, Sundelin B, Fored M, Ludvigsson JF. Risk of IgA nephropathy in individuals with celiac disease (submitted). IV. Welander A, Tjernberg AR, Montgomery SM, Ludvigsson J, Ludvigsson JF. Infectious disease and risk of later celiac disease in childhood. Pediatrics; 2010 Mar;125(3):e530-6. Epub 2010 Feb 22.