Celiac Disease and Risk Celiac Disease and Risk of Subsequent Type I of Subsequent Type I Diabetes: A general Diabetes: A general

population cohort study population cohort study of children and of children and

adolescentsadolescents

Journal of Diabetes CareJournal of Diabetes Care

Mike Schiemer and Ryan Mike Schiemer and Ryan BlaneyBlaney

Celiac DiseaseCeliac Disease• Aka: Gluten IntoleranceAka: Gluten Intolerance• Not to be confused with a wheat allergy, Not to be confused with a wheat allergy,

body reacts to wheat protein onlybody reacts to wheat protein only• Autoimmune Disease of small bowelAutoimmune Disease of small bowel• Reaction to gliadin, a gluten protein found in Reaction to gliadin, a gluten protein found in

wheat and hybrid wheat/rye Triticeae wheat and hybrid wheat/rye Triticeae proteins, some also react to oats due to proteins, some also react to oats due to cross-contamination with gluten containing cross-contamination with gluten containing productsproducts

• Occurs in about 1% of North American and Occurs in about 1% of North American and European populations but increasing reports European populations but increasing reports due to screening asymptomatic individualsdue to screening asymptomatic individuals

Cell-mediated Immune Cell-mediated Immune Responses Responses •Upon exposure to gliadin, the Upon exposure to gliadin, the

enzyme tissue transglutaminase enzyme tissue transglutaminase modifies the protein and immune modifies the protein and immune system cross-reacts with bowel system cross-reacts with bowel tissue, creating inflammationtissue, creating inflammation

•leads to flattening of the lining of leads to flattening of the lining of the small intestine, significantly the small intestine, significantly reducing nutrient absorption. reducing nutrient absorption.

Symptoms of Celiac DiseaseSymptoms of Celiac Disease• Often diagnosed as IBS before proper screeningOften diagnosed as IBS before proper screening• Diarrhoea or constipationDiarrhoea or constipation• Weight LossWeight Loss• Stunted Growth in ChildrenStunted Growth in Children• FatigueFatigue• Primarily a bowel disease but these symptoms may be Primarily a bowel disease but these symptoms may be

limited or absentlimited or absent• Older children and adults have malabsorptive problems Older children and adults have malabsorptive problems

and anaemia due to reduced iron absorptionand anaemia due to reduced iron absorption• Abdominal pain, cramping, bloating, abdominal Abdominal pain, cramping, bloating, abdominal

distention due to gas productiondistention due to gas production• Mouth ulcers may be presentMouth ulcers may be present• Lactose intolerance can develop as symptoms worsenLactose intolerance can develop as symptoms worsen• Longstanding disease may cause ulcering of the small Longstanding disease may cause ulcering of the small

bowels or stricturing (narrowing due to scarring)bowels or stricturing (narrowing due to scarring)

Malabsorption-Related Malabsorption-Related ProblemsProblems

• Fatigue or lack of energy due to Fatigue or lack of energy due to carbohydrate and fat malabsorptioncarbohydrate and fat malabsorption

• Reduced Vitamin D and Calcium absorption Reduced Vitamin D and Calcium absorption may lead to osteopenia or osteoporosis.may lead to osteopenia or osteoporosis.

• 10% of those with Celiac have coagulation 10% of those with Celiac have coagulation problems due to decreased Vitamin K problems due to decreased Vitamin K absorptionabsorption

• Can potentially cause bacterial overgrowth Can potentially cause bacterial overgrowth of small intestine leading to further of small intestine leading to further malabsorption even after treatmentmalabsorption even after treatment

DiagnosisDiagnosis• All tests lose there usefullness if patient consuming a All tests lose there usefullness if patient consuming a

gluten-free dietgluten-free diet• Intestinal damage begins to heal within weeks of Intestinal damage begins to heal within weeks of

gluten being removed from the diet, and antibody gluten being removed from the diet, and antibody levels decline over months, if no gluten consumed a levels decline over months, if no gluten consumed a 10g per day intake will elicit a proper diagnosis10g per day intake will elicit a proper diagnosis

• Serology by blood test is 98% effective, all positive Serology by blood test is 98% effective, all positive blood tests must be followed by endoscopic blood tests must be followed by endoscopic examination and a biopsy of 4-8 sites in duodenum to examination and a biopsy of 4-8 sites in duodenum to be 100% surebe 100% sure

• Blood tests detect IgA against endomysium or tissue Blood tests detect IgA against endomysium or tissue transglutaminasetransglutaminase

• Some experts also require or encourage blood tests Some experts also require or encourage blood tests for electrolyte, calcium, liver enzymes, vitamin B12, for electrolyte, calcium, liver enzymes, vitamin B12, and folic acid levels. Coagulation testing for Vitamin and folic acid levels. Coagulation testing for Vitamin K deficiency, bone scan for checking Vitamin D or K deficiency, bone scan for checking Vitamin D or calcium deficienciescalcium deficiencies

Pathology determined by the "Marsh classification”:Pathology determined by the "Marsh classification”:• Marsh stage 0: Normal mucosa Marsh stage 0: Normal mucosa • Marsh stage 1: Increased number of intra-epithelial Marsh stage 1: Increased number of intra-epithelial

lymphocyteslymphocytes• Marsh stage 2: Proliferation of the crypts of LieberkuhnMarsh stage 2: Proliferation of the crypts of Lieberkuhn• Marsh stage 3: Partial or complete villous atrophyMarsh stage 3: Partial or complete villous atrophy• Marsh stage 4: Hypoplasia of small bowel architectureMarsh stage 4: Hypoplasia of small bowel architecture

Prophylaxis/TreatmentProphylaxis/Treatment• One study suggested that exposure to wheat, One study suggested that exposure to wheat,

barley, or rye before full GI development caused barley, or rye before full GI development caused five times the risk over those exposed at 4 to 6 five times the risk over those exposed at 4 to 6 monthsmonths

• Another study contradicts these results and Another study contradicts these results and shows early exposure can be protective to shows early exposure can be protective to disease developmentdisease development

• Breastfeeding may also reduce risk significantly Breastfeeding may also reduce risk significantly for the first 6 months before gluten exposurefor the first 6 months before gluten exposure

• Only real “cure” is the preventative measure of a Only real “cure” is the preventative measure of a lifelong diet avoiding gluten although some major lifelong diet avoiding gluten although some major symptoms may still occur even with strict dietingsymptoms may still occur even with strict dieting

• Now there is a much higher selection of gluten-Now there is a much higher selection of gluten-free foods at supermarkets, restaurants, etc.free foods at supermarkets, restaurants, etc.

IntroductionIntroduction

• Looks at incidence of type 1 diabetes Looks at incidence of type 1 diabetes diagnosis prior to celiac diagnosis.diagnosis prior to celiac diagnosis.

• Previous studies looked at prevalence Previous studies looked at prevalence of opposite scenarioof opposite scenario

• Focused on children diagnosed before Focused on children diagnosed before the age of 20.the age of 20.

• Hypothesized that prior celiac diagnosis Hypothesized that prior celiac diagnosis will result in significant increased risk will result in significant increased risk for type 1 diabetesfor type 1 diabetes

IntroductionIntroduction• Majority of individuals with celiac disease Majority of individuals with celiac disease

exhibit HLA-DQ2, with a smaller group being exhibit HLA-DQ2, with a smaller group being positive for HLA-DQ8positive for HLA-DQ8

• Studies have proven that children with Studies have proven that children with diabetes are at increase risk for celiac diabetes are at increase risk for celiac disease (5 to 10 fold risk increased for celiac)disease (5 to 10 fold risk increased for celiac)

• It has also been suggested that early gluten It has also been suggested that early gluten introduction may be a common risk factor for introduction may be a common risk factor for both diseases.both diseases.

• Cronin and Shanahan have demonstrated Cronin and Shanahan have demonstrated that some 15% of individuals with both that some 15% of individuals with both diseases may first receive diagnosis of celiac diseases may first receive diagnosis of celiac disease.disease.

IntroductionIntroduction

• This study did not give incidence This study did not give incidence ratiosratios

• It was unclear if individuals with type It was unclear if individuals with type 1 diabetes and simultaneously 1 diabetes and simultaneously diagnosed with celiac disease were diagnosed with celiac disease were included.included.

IntroductionIntroduction• The main objective was to estimate the The main objective was to estimate the

association of celiac disease with subsequent association of celiac disease with subsequent type 1 diabetes (before 20yoa) p=9,243 with type 1 diabetes (before 20yoa) p=9,243 with celiac disease compared with 45,680 age + celiac disease compared with 45,680 age + sex matched individuals without celiac sex matched individuals without celiac diseasedisease

• The second objective was to study the risk of The second objective was to study the risk of type 1 diabetes stratified for age at diagnosis type 1 diabetes stratified for age at diagnosis of celiac disease.of celiac disease.

• Hypothesis: celiac disease diagnosed at early Hypothesis: celiac disease diagnosed at early age and consequent early introduction of age and consequent early introduction of gluten-free diet would be associated with a gluten-free diet would be associated with a lower risk of type 1 diabetes. lower risk of type 1 diabetes.

Research/MethodsResearch/Methods

• Approved by research ethics committee of Karolinska Approved by research ethics committee of Karolinska Institute.Institute.

• No participants contacted, information was made No participants contacted, information was made anonymous before analysisanonymous before analysis

• Used hospital inpatient diagnosis of celiac disease Used hospital inpatient diagnosis of celiac disease between 1964 and 2003 through Sweedish national between 1964 and 2003 through Sweedish national inpatient register.inpatient register.

• Celiac diagnosed by various ICD codes.Celiac diagnosed by various ICD codes.

• For each individual with celiac disease, Statistics Sweden For each individual with celiac disease, Statistics Sweden indentified up to five reference individuals matched for indentified up to five reference individuals matched for age, sex, calendar, year, and area of residence at time of age, sex, calendar, year, and area of residence at time of diagnosisdiagnosis

• Restricted measurements to individuals diagnosed with Restricted measurements to individuals diagnosed with type 1 diabetes before age of 20.type 1 diabetes before age of 20.

MethodsMethods• Follow up time began 1 year after study entry. Follow up time began 1 year after study entry. • Ended on the date of first discharge diagnosis Ended on the date of first discharge diagnosis

of type 1 diabetes, emigration, death, or age of type 1 diabetes, emigration, death, or age 20 years20 years

• Identified 9,733 individuals with celiac disease Identified 9,733 individuals with celiac disease between 1964 and 2003between 1964 and 2003

• Excluded 233 individuals with type 1 diabetes Excluded 233 individuals with type 1 diabetes diagnosed before celiac disease. diagnosed before celiac disease.

• Study based upon 9,243 individuals with celiac Study based upon 9,243 individuals with celiac disease diagnosed before 20yo and 45,680 disease diagnosed before 20yo and 45,680 age, period, and sex matched individuals age, period, and sex matched individuals without celiac diseasewithout celiac disease

• All participants were type 1 free at start of All participants were type 1 free at start of follow upfollow up

MethodsMethods

• Used cox regression to estimate association of celiac Used cox regression to estimate association of celiac disease with type 1 diabetes.disease with type 1 diabetes.

• Estimated the risk of ketoacidosis before age 20 Estimated the risk of ketoacidosis before age 20 years.years.

• Individuals only compared with matched reference Individuals only compared with matched reference individualsindividuals

• Stratification for sex and age was chosen <2 or 3 Stratification for sex and age was chosen <2 or 3 years to maximize study poweryears to maximize study power

• Individuals diagnosed with celiac disease between 0-Individuals diagnosed with celiac disease between 0-1yo were used as the reference category and 1yo were used as the reference category and compared with those between 1 and <2yocompared with those between 1 and <2yo

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

ResultsResults

• Median age was 1 year (range 0-19).Median age was 1 year (range 0-19).

• Majority was female.Majority was female.

• Median age at first diabetes Median age at first diabetes diagnosis was 10 years (2-19)diagnosis was 10 years (2-19)

• The median duration from diagnosis The median duration from diagnosis of celiac to diagnosis of diabetes was of celiac to diagnosis of diabetes was 8.1 years8.1 years

Table 1Table 1

Atopic Dermatitis of the Arm (celiac patient)

ResultsResults• Children with celiac disease were at Children with celiac disease were at

increased risk of type one diabetes (based increased risk of type one diabetes (based upon 300 positive results)upon 300 positive results)

• Age of first celiac diagnosis displayed no Age of first celiac diagnosis displayed no significance to subsequent diagnosis of significance to subsequent diagnosis of diabetes (p=.211) diabetes (p=.211)

• Risk estimates after stratification for age at Risk estimates after stratification for age at diagnosis and sex were similar to risk diagnosis and sex were similar to risk estimates for type 1 diabetes before age of estimates for type 1 diabetes before age of 20.20.

• Individuals with celiac disease were at a Individuals with celiac disease were at a significantly increased risk of subsequent significantly increased risk of subsequent ketoacidosis. (based upon 13 positive results)ketoacidosis. (based upon 13 positive results)

• Results were only significant for femalesResults were only significant for females

ConclusionConclusion• The study found a statistically significant positive The study found a statistically significant positive

association of celiac disease with subsequent type 1 association of celiac disease with subsequent type 1 diabetes and with ketoacidosis before the age of 20.diabetes and with ketoacidosis before the age of 20.

• There was no statistically significant difference in risk of There was no statistically significant difference in risk of subsequent type 1 diabetes between individuals with a subsequent type 1 diabetes between individuals with a diagnosis of celiac disease at 0-2 years and those diagnosis of celiac disease at 0-2 years and those diagnosed after 2 years of age.diagnosed after 2 years of age.

• To knowledge of authors, there exists only one previous To knowledge of authors, there exists only one previous similar study though no incidence ratios were given.similar study though no incidence ratios were given.

• The significance of the studies results is only further The significance of the studies results is only further enhanced by the use of several reference individuals for enhanced by the use of several reference individuals for each of the studied individuals.each of the studied individuals.

• The large population provided high statistical power and The large population provided high statistical power and allowed for sub analysis.allowed for sub analysis.

Table 2Table 2

ConclusionConclusion• Increased risk of diabetes was seen (300 cases) 2-3 fold Increased risk of diabetes was seen (300 cases) 2-3 fold

greater than reference individualsgreater than reference individuals• Could be attributed to various factors such as environmental Could be attributed to various factors such as environmental

or genetic susceptibility.or genetic susceptibility.• Gluten is a necessary trigger for celiac disease so feeding Gluten is a necessary trigger for celiac disease so feeding

pattern may have been a factor.pattern may have been a factor.• Daisy and BABY DIAB studies found a four to fivefold increase Daisy and BABY DIAB studies found a four to fivefold increase

risk in children exposed to gluten before age of 4 months.risk in children exposed to gluten before age of 4 months.• Risk estimates were substantially lower than prior findings of Risk estimates were substantially lower than prior findings of

diabetes diagnosis followed by celiac diseasediabetes diagnosis followed by celiac disease• An explanation could be that those with more severe An explanation could be that those with more severe

autoimmune disease have an earlier symptomatic onset of autoimmune disease have an earlier symptomatic onset of type 1 diabetes.type 1 diabetes.

• An alternative explanation is that the inflammation associated An alternative explanation is that the inflammation associated with celiac disease remained for a period after diagnosis.with celiac disease remained for a period after diagnosis.

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

ConclusionConclusion• The association could be a result of shared HLA characteristics The association could be a result of shared HLA characteristics

or an interaction between food introduction and genetic or an interaction between food introduction and genetic susceptibility.susceptibility.

• Approximately 1/3Approximately 1/3rdrd of celiac patients are positive for HLA-DQ2 of celiac patients are positive for HLA-DQ2 and this is a positive risk factor for type 1 diabetes so the and this is a positive risk factor for type 1 diabetes so the increased risk could be attributed entirely to HLA characteristics.increased risk could be attributed entirely to HLA characteristics.

• False negative celiac disease is unlikely since <1% of reference False negative celiac disease is unlikely since <1% of reference population should be affected by celiac disease.population should be affected by celiac disease.

• All children in Sweden are hospitalized upon diagnosis of type 1 All children in Sweden are hospitalized upon diagnosis of type 1 diabetes so sensitivity to diabetes should be high in this study.diabetes so sensitivity to diabetes should be high in this study.

• In conclusion, the cohort study found a 2-3fold risk increase of In conclusion, the cohort study found a 2-3fold risk increase of type 1 diabetes before age of 20. Shared nutritional factors and type 1 diabetes before age of 20. Shared nutritional factors and common HLA profiles may explain the significance.common HLA profiles may explain the significance.

• The risk increase for type 1 diabetes is low considering that 95% The risk increase for type 1 diabetes is low considering that 95% of individuals with celiac disease are HLA-DQ2 positive.of individuals with celiac disease are HLA-DQ2 positive.

Experiment CritiqueExperiment Critique• Family history of subjects not taken into accountFamily history of subjects not taken into account

• Many subjects taken from decades ago and the Many subjects taken from decades ago and the diagnosis of type 1 diabetes may have been diagnosis of type 1 diabetes may have been inconsistent with rates from the last few yearsinconsistent with rates from the last few years

• Study isolated to a set of hospital records in Study isolated to a set of hospital records in Sweden, primarily Caucasian and middle class.Sweden, primarily Caucasian and middle class.

• Subjects were anonymous so there was no telling Subjects were anonymous so there was no telling what these subjects diet consisted of.what these subjects diet consisted of.

• Also the prevalence of celiac disease within the Also the prevalence of celiac disease within the subjects siblings and parents could not be noted.subjects siblings and parents could not be noted.

Further ExperimentationFurther Experimentation

• Use more current records to account for Use more current records to account for present day type 1 diabetes diagnosis, present day type 1 diabetes diagnosis, compare rate of increased susceptibility compare rate of increased susceptibility from this study to a current onefrom this study to a current one

• Focus on other geographical or Focus on other geographical or demographical areasdemographical areas

• Take more detailed records of subjects to Take more detailed records of subjects to determine secondary variables that could determine secondary variables that could account for different resultsaccount for different results

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