1. Celiac Disease and Autoimmune Disorders Fitting the Pieces Together Dr. S. Natsheh, MD FRCPC May 26, 2007

2. Outline Review Autoimmune Disease and Basic Immunology Explore the relationship between ATD, T1DM and celiac disease –Genetics, Prevalence –Does gluten exposure –induce autoantibody production? –increase the risk of autoimmune disorders? –improve control of other diseases? Impact on screening for CD

3. Objectives Define autoimmune disease Understand basic immunology physiology in autoimmune disorders Explain the link between celiac disease, thyroid disease, and type 1 diabetes –as autoimmune disorders –impact on disease control and prevention

4. Disclaimer I am not an endocrinologist I am not an immunologist

5. What is an Autoimmune Disease? Disease created by an overactive immune system Breakdown of body’s for self –Results in our own immune system attacking parts of our own body

6. Basic Immunology The immune system is complex Protects body from infection, disease, and foreign substances –Distinguishing self from non-self Defective immune system: –Recurrent infections –May be fatal

7. Immune System Innate Constant Unchanging Adaptive Specific Memory

8. Basic Immunology-Adaptive Lymphocytes: –B-cells Produce antibodies Able to directly recognize foreign antigens Most require T-cells to become activated to secrete antibodies –T-cells Eliminate foreign antigens (viruses, fungi, protozoa) Require presentation of epitopes on antigen presenting cells via HLA proteins Coordinate the Adaptive Immune Response Mature by passing through thymus and lymphoid tissue and learn to recognize self =

9. Lymphokines B B B Y Y Y

10. Human Leukocyte Antigen System (HLA) Two Classes: –I On all nucleated cells Activate killer T-cells –II On Antigen Presenting Cells (APC), B-cells and activated T-cells DP, DQ, DR Activate helper T-cells: alert B-cells to produce antibodies Vary between individuals The structure determines which proteins are presented to immune cells –Thus, if and which autoimmune disorder to which a person may be susceptible

11. HLA presenting cells T-CellsB-Cells Immunoglobulins

12. Autoimmunity – WHY? Multifactorial: –Molecular mimicry –Foreign T-cell epitopes –Genetic makeup –Failure to deactivate in the thymus Defect in programmed cell death Defect in self-antigen presenting cells

14. Autoimmune Diseases Thyroiditis Celiac Disease Diabetes Grave’s Disease Lupus MS RA Addison’s Disease Ankylosing Spondylitis Autoimmnue Hepatitis Aplastic Anemia IBD Guillain-Barre Myesthenia Gravis Pemphigus Primary Biliary Cirrhosis Sjogren’s Syndrome Arteritis Wegener’s Granulomatosis

15. Celiac Disease- An Autoimmune Disorder? Strong association with other autoimmune disorders HLA link –DQ2 and DQ8 –DR3 and DR4 CD4 T-cells – local inflammatory response Autoantibodies Genetics –Regions on chromosomes 5, 11, 15, & 19 More common in females

16. Celiac Disease and Autoimmune Disorders –R–Rheumatoid Arthritis –A–Autoimmune Liver Disease –S–Sjögren’s Syndrome –I–IgA Nephropathy –A–Addison’s Disease –A–Alopecia –P–Psoriasis –T–Thyroid Disease –T–Type 1 Diabetes

17. Thyroid Disease Small gland located in the front of the neck. Produces thyroid hormones – T3 and T4 The hormones control the body’s metabolism Thyroid Stimulating Hormone (TSH) is produced by the pituitary to stimulate the production and release of T4

18. Normal Thyroid Function

19. Thyroid Disease Underactive thyroid –Hypothyroidism Hashimoto’s Thyroiditis Overactive thyroid –Hyperthyroidism Grave’s Disease

20. Hypothyroidism Underproduction of thyroid hormones to maintain body’s metabolism Multiple causes: –Autoimmune –Drugs –Surgery –Damage to gland –Insufficient iodine Treatment: –Hormone replacement

21. Autoimmune Hypothyroidism Antibodies: –Thyroglobulin –Thyroperoxidase

22. Hypothyroidism Symptoms ►Tired►Weight Gain►Menstrual Irregularities ►Depression►Dry Hair►High Blood Pressure ►Cold Sensitivity►Tough Skin►Infertility ►Muscle Cramps►Constipation►Slow Heart Rate ►Brittle Nails►Enlarged Thyroid

23. AHT - Prevalence HT → CD HT2-7% CD → HT CD8-13% General population: HT: 0.55% CD: 0.33%

24. Hypothyroidism Antibodies: –Antithyroglobulin –Antithyroperoxidase CDATD DQ2 DQ8 DR3 DR4 DQ2

25. Hyperthyroidism Overproduction of thyroid hormone Treatment: –Medications to decrease thyroid hormone production –Destroy part of the thyroid gland

26. Hyperthyroidism Thyroid-Stimulating Hormone Receptor Antibody (TSAb) TSAb

27. Hyperthyroidism ►Heat Intolerance ►Racing Heart Beat ►Irritability ►Weight Loss►Diarrhea►Osteoporosis ►Warm smooth skin ►Change in Periods ►Insomnia ►Pigmentation of the Skin ►Tremors►Fine Brittle Hair ►Hives►Muscle Weakness

28. AGD - Prevalence GD → CD GD0-5% CD → GD CD1-2% General population: GD: 2.7% CD: 0.33%

29. Hyperthyroidism Antibodies: –Thyrotropin Receptor Antibodies CDGrave’s Disease DR3 DQ2 DR4 DQ8 DR3

30. Insulin-Dependent Diabetes An association between diabetes and celiac disease has been observed since the late 1960’s. The majority of patients are asymptomatic from a celiac disease perspective.

31. Insulin-Dependent Diabetes AKA: Type 1 Diabetes Inadequate insulin secretion by the pancreas –Due to destruction of the β-cells of Langerhans islets Usually autoimmune destruction May be idiopathic

34. Antibodies: –Islet cell antibodies –Insulin auto- antibodies –Glutamic acid decarboxylase –Thyrosine phosphate CDT1DM DR3/4 DQ 2/8 DR3/4 DQ 2/8

35. T1DM T1DM → CD T1DM1-10% CD → T1DM CD3-10% General population: T1DM: 0.33% CD: 0.33%

36. Diabetes Does celiac disease affect control of diabetes? –Controversial

37. GFD and Diabetes control Patients may have hypoglycemia, thought to be due to malabsorption Most studies showed improved anthropometric data. Studies limited by dietary compliance and length of follow-up

38. YESNO Sigurs et al, 1993 Holmes, 2001 Saadah, 2004 Prázný et al, 2005 Amin et al, 2002 Cronin et al, 1997 Salvilahti et al, 1985 Acerini et al, 1998 Simmons et al, 2006 Hansen et al, 2006 Does subclinical disease confound this data? Dietary compliance?

39. Latent DM T1.5DM Clinical presentation as T2DM Autoantibodies Case report of 8yo female –Initial management on oral hypoglycemic agents –Later developed DKA, autoantibodies for T1DM, CD, and HD

40. Does Gluten Induce the production of Autoantibodies?

41. Toscano et al, 2000 44 CD 25 GFD 5 ( 20%) 19 GCD 10 (52.6%) At Least 1 Autoantibody Controls - 0

42. Ventura et al, 2000 Ab Control Celiac Patients 0 mo 6mo12mo24mo EMA090000 ICA16500 GAD03000 IAA02000 TPO4131062

43. Bonamico et al, 1997 42 CD patients 23 3 (13%) 19 9 (47.4%) GFD GCD Antibodies

44. WHY does Gluten affect additional antibody production? TTG has a role in the regulation of cell death Uncontrolled cell death in other organs Fertile Field theory –Infection-induced generalized autoimmune response Neoepitope formation

45. WHY? Gliadin unmasks the action of self- antigens –Normally hidden in the GI mucosa –Share epitopes with endocrine proteins Malabsorption of key nutrients induces the formation of autoantibodies –Iodine

46. BUT… antibodies ≠ disease So…. Does Gluten exposure increase the risk of Other Autoimmune Disorders?

47. Does Gluten Exposure Increase Risk of Autoimmune Disorders? Controversial May be difference between adult patients and pediatric patients Depends on definition of Autoimmune Disease

48. Pediatrics Ventura et al, 1999 –Compared CD vs healthy controls vs IBD patients –Stratified by age –Results: Autoimmune disorders more common in CD and IBD groups multiple autoimmune disorders in the CD group not IBD Older age of diagnosis, more likely to develop another autoimmune disorder

49. Pediatrics Ventura et al: –In the patients < 2yo: Gluten exposure through challenge resulted in an increased incidence of autoimmune disorders –8.2% vs 3.3% Length of gluten challenge was proportionate to the risk of other autoimmune disorders

50. Pediatrics Length of Gluten Challenge Percentage of Patients with Autoimmune Disease < 12 months3.65% 13-36 months9.1% > 36 months26.3%

51. Adults Number of studies None have replicated these results.

52. No evidence that GFD prevents progression to clinical T1DM

53. Does GFD Improve Pre-existing Endocrine Diseases? Improved control of ATD –Likely better absorption of replacement hormones –Not autoimmune disease Malnutrition –Affects CNS functioning –Not autoimmune disease

54. Other Points of Interest: The younger the age of onset of T1DM, the more likely one is to develop CD The older the age of diagnosis of CD, the more likely one is to develop another autoimmune disorder Individuals with CD and ATD or T1DM are more likely to have additional autoimmune disorders

55. Should we routinely screen for Celiac Disease in asymptomatic patients?

56. NO - screening Long-term outcome of treatment in this group is unknown –We do not know if there is any benefit Large burden for a child and family with 2 diagnoses We do not know optimal time to screen

57. Yes - screening Treatment of CD is beneficial May improve control May prevent development of other autoimmune disorders Organ dysfunction impacts control of other diseases Reduced chance of long-term side-effects –Osteoporosos –Cancer…

58. Conclusions Strong association of Celiac Disease and other autoimmune disorders –Thyroid Disease –Type 1 DM Gluten Free Diet may be –Protective –Preventative Screening is controversial Available research is difficult to consolidate

62. What is the Thyroid?

64. Close window Figure 1 Nature Immunology 2, 781 - 784 (2001) doi:10.1038/ni0901-781 Close window Lessons from animal models for human autoimmune diseases Veena Taneja & Chella S. David Figure 1. The basic parameters of autoimmunity are the same. In the thymus, a self-peptide with high binding affinity for HLA molecules leads to negative selection of T cells. In contrast, a self-peptide with low binding affinity can lead to positive selection of T cells, some of which could be potentially autoreactive. Some of the HLA molecules are able to positively select more autoreactive T cells and may predispose an individual to autoimmunity. Viral or bacterial antigens that mimic self-antigens are presented in the context of HLA molecules and can activate these autoreactive T cells in the periphery, thus triggering an autoimmune response. The response may be directed to an organ that overexpresses costimulatory molecules or cytokines and expresses an antigen that matches the specificity of autoreactive T cells. This in turn leads to inflammation, expansion of B cells, pathogenesis and destruction of the organ. Close window ©2007 Nature Publishing Group | Privacy policy Close window ©2007 Nature Publishing GroupPrivacy policy

68. Hypothyroidism