Research: Celiac Disease and Risk of Subsequent Type I Diabetes

Article Critiqued By Frugal Fitness From "The Journal of Diabetes Care"
About Celiac Disease

          Definition: Gluten Intolerance
          Not to be confused with a wheat allergy, body reacts to wheat protein only
          Autoimmune Disease of small bowel
          Reaction to gliadin, a gluten protein found in wheat and hybrid wheat/rye Triticeae proteins, some also react to oats due to cross-contamination with gluten containing products
          Occurs in about 1% of North American and European populations but increasing reports due to screening asymptomatic individuals

Cell-Mediated Immune Response
          Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein and immune system cross-reacts with bowel tissue, creating inflammation
          leads to flattening of the lining of the small intestine, significantly reducing nutrient absorption.

Symptoms of Celiac Disease
          Often diagnosed as IBS before proper screening
          Diarrhoea or constipation
          Weight Loss
          Stunted Growth in Children
          Primarily a bowel disease but these symptoms may be limited or absent
          Older children and adults have malabsorptive problems and anaemia due to reduced iron absorption
          Abdominal pain, cramping, bloating, abdominal distention due to gas production
          Mouth ulcers may be present
          Lactose intolerance can develop as symptoms worsen
          Longstanding disease may cause ulcering of the small bowels or stricturing (narrowing due to scarring)

Malabsorption-Related Problems
          Fatigue or lack of energy due to carbohydrate and fat malabsorption
          Reduced Vitamin D and Calcium absorption may lead to osteopenia or osteoporosis.
          10% of those with Celiac have coagulation problems due to decreased Vitamin K absorption
          Can potentially cause bacterial overgrowth of small intestine leading to further malabsorption even after treatment

          All tests lose there usefullness if patient consuming a gluten-free diet
          Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months, if no gluten consumed a 10g per day intake will elicit a proper diagnosis
          Serology by blood test is 98% effective, all positive blood tests must be followed by endoscopic examination and a biopsy of 4-8 sites in duodenum to be 100% sure
           Blood tests detect IgA against endomysium or tissue transglutaminase
          Some experts also require or encourage blood tests for electrolyte, calcium, liver enzymes, vitamin B12, and folic acid levels. Coagulation testing for Vitamin K deficiency, bone scan for checking Vitamin D or calcium deficiencies

          One study suggested that exposure to wheat, barley, or rye before full GI development caused five times the risk over those exposed at 4 to 6 months
          Another study contradicts these results and shows early exposure can be protective to disease development
          Breastfeeding may also reduce risk significantly for the first 6 months before gluten exposure
          Only  real “cure” is the preventative measure of a lifelong diet avoiding gluten although some major symptoms may still occur even with strict dieting
          Now there is a much higher selection of gluten-free foods at supermarkets, restaurants, etc.

          Looks at incidence of type 1 diabetes diagnosis prior to celiac diagnosis.
          Previous studies looked at prevalence of opposite scenario
          Focused on children diagnosed before the age of 20.
          Hypothesized that prior celiac diagnosis will result in significant increased risk for type 1 diabetes
          Majority of individuals with celiac disease exhibit HLA-DQ2, with a smaller group being positive for HLA-DQ8
          Studies have proven that children with diabetes are at increase risk for celiac disease (5 to 10 fold risk increased for celiac)
          It has also been suggested that early gluten introduction may be a common risk factor for both diseases.
          Cronin and Shanahan have demonstrated that some 15% of individuals with both diseases may first receive diagnosis of celiac disease.
          This study did not give incidence ratios
          It was unclear if individuals with type 1 diabetes and simultaneously diagnosed with celiac disease were included.
          The main objective was to estimate the association of celiac disease with subsequent type 1 diabetes (before 20yoa) p=9,243 with celiac disease compared with 45,680 age + sex matched individuals without celiac disease
          The second objective was to study the risk of type 1 diabetes stratified for age at diagnosis of celiac disease.
          Hypothesis: celiac disease diagnosed at early age and consequent early introduction of gluten-free diet would be associated with a lower risk of type 1 diabetes.

          Approved by research ethics committee of Karolinska Institute.
          No participants contacted, information was made anonymous before analysis
          Used hospital inpatient diagnosis of celiac disease between 1964 and 2003 through Sweedish national inpatient register.
          Celiac diagnosed by various ICD codes.
          For each individual with celiac disease, Statistics Sweden indentified up to five reference individuals matched for age, sex, calendar, year, and area of residence at time of diagnosis
          Restricted measurements to individuals diagnosed with type 1 diabetes before age of 20.

          Follow up time began 1 year after study entry.
          Ended on the date of first discharge diagnosis of type 1 diabetes, emigration, death, or age 20 years
          Identified 9,733 individuals with celiac disease between 1964 and 2003
          Excluded 233 individuals with type 1 diabetes diagnosed before celiac disease.
          Study based upon 9,243 individuals with celiac disease diagnosed before 20yo and 45,680 age, period, and sex matched individuals without celiac disease

All participants were type 1 free at start of follow up
          Used cox regression to estimate association of celiac disease with type 1 diabetes.
          Estimated the risk of ketoacidosis before age 20 years.
          Individuals only compared with matched reference individuals
          Stratification for sex and age was chosen <2 or 3 years to maximize study power
          Individuals  diagnosed with celiac disease between 0-1yo were used as the reference category and compared with those between 1 and <2yo

At a significance level of 5% the study had an 80% power to detect an increased risk of subsequent type 1 diabetes.

          Median age was 1 year (range 0-19).
          Majority was female.
          Median age at first diabetes diagnosis was 10 years (2-19)
          The median duration from diagnosis of celiac to diagnosis of diabetes was 8.1 years
          Children with celiac disease were at increased risk of type one diabetes (based upon 300 positive results)
          Age of first celiac diagnosis displayed no significance to subsequent diagnosis of diabetes (p=.211)
          Risk estimates after stratification for age at diagnosis and sex were similar to risk estimates for type 1 diabetes before age of 20.
          Individuals with celiac disease were at a significantly increased risk of subsequent ketoacidosis. (based upon 13 positive results)
          Results were only significant for females

          The study found a statistically significant positive association of celiac disease with subsequent type 1 diabetes and with ketoacidosis before the age of 20.
          There was no statistically significant difference in risk of subsequent type 1 diabetes between individuals with a diagnosis of celiac disease at 0-2 years and those diagnosed after 2 years of age.
          To knowledge of authors, there exists only one previous similar study though no incidence ratios were given.
          The significance of the studies results is only further enhanced by the use of several reference individuals for each of the studied individuals.
          The large population provided high statistical power and allowed for sub analysis.
          Increased risk of diabetes was seen (300 cases) 2-3 fold greater than reference individuals
          Could be attributed to various factors such as environmental or genetic susceptibility.
          Gluten is a necessary trigger for celiac disease so feeding pattern may have been a factor.
          Daisy and BABY DIAB studies found a four to fivefold increase risk in children exposed to gluten before age of 4 months.
          Risk estimates were substantially lower than prior findings of diabetes diagnosis followed by celiac disease
          An explanation could be that those with more severe autoimmune disease have an earlier symptomatic onset of type 1 diabetes.
          An alternative explanation is that the inflammation associated with celiac disease remained for a period after diagnosis.

No strong evidence suggested that early diagnosis of celiac disease could help protect against type 1 diabetes

          The association could be a result of shared HLA characteristics or an interaction between food introduction and genetic susceptibility.
          Approximately 1/3rd of celiac patients are positive for HLA-DQ2 and this is a positive risk factor for type 1 diabetes so the increased risk could be attributed entirely to HLA characteristics.
          False negative celiac disease is unlikely since <1% of reference population should be affected by celiac disease.
          All children in Sweden are hospitalized upon diagnosis of type 1 diabetes so sensitivity to diabetes should be high in this study.
          In conclusion, the cohort study found a 2-3fold risk increase of type 1 diabetes before age of 20. Shared nutritional factors and common HLA profiles may explain the significance.
          The risk increase for type 1 diabetes is low considering that 95% of individuals with celiac disease are HLA-DQ2 positive.

Experiment Critique
          Family history of subjects not taken into account
          Many subjects taken from decades ago and the diagnosis of type 1 diabetes may have been inconsistent with rates from the last few years
          Study isolated to a set of hospital records in Sweden, primarily Caucasian and middle class.
          Subjects were anonymous so there was no telling what these subjects diet consisted of.
          Also the prevalence of celiac disease within the subjects siblings and parents could not be noted.

Further Experimentation
          Use more current records to account for present day type 1 diabetes diagnosis, compare rate of increased susceptibility from this study to a current one
          Focus on other geographical or demographical areas
          Take more detailed records of subjects to determine secondary variables that could account for different results

Works Cited
          Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, Eisenbarth GS: One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. ] Autoimmun 13:143-148, 1999.
          Dube C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, Sampson M, Zhang L, Yazdi F, Mamaladze V, Pan I, Macneil J, Mack D, Patel D, Moher D: The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 128: S57-S67, 2005
          Ekbom, Anders; Jonas F Ludvigsson, Johnny Ludvigsson, Scott M Montgomery. Celiac Disease and Risk of Subsequent Type 1 Diabetes: A general population cohort study of children and adolescents. J. Diabetes Care. Alexandria: Nov 2006. Vol. 29, Iss. 11; pg. 2483.
          Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, Neugut AI: Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 96:126-131, 2001
          Murray JA: Celiac disease in patients with an affected member, type 1 diabetes, irondeficiency, or osteoporosis? Gastroenterology 128:552-556, 2005
          Rapoport MJ, BistritzerT, Vardi O, Broide E, Azizi A, Vardi P: Increased prevalence of diabetes-related autoantibodies in celiac disease. J Pediatr Gastroenterol Nutr 23:524-527,1996  

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