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
• Fatigue
• 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
Diagnosis
• 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
Prophylaxis/Treatment
• 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.
Introduction
• 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.
Research/Methods
• 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.
Methods
• 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.
Results
• 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
Conclusion
• 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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