Celiac Disease: Myths and Reality

1. Celiac Disease: Myths and Reality John Zubialde, MD Professor of Family and Preventive Medicine University Of Oklahoma College of Medicine

2. Objectives: Participants will: • Understand etiology of Celiac Disease • Understand the spectrum of disease manifestation • Be able to appropriately test for the disease • Be able to appropriately treat and monitor patients with the disease • Be able to identify and monitor for associated conditions

3. History and Pathogenesis First described by Aretaeus of Cappadocia in 100 AD Cause unknown until WW2 when Dutch Pediatrician Willem Dicke described the association of relapsing diarrhea in children with consumption of bread and cereals and its resolution with their removal. Wheat, barley, and rye noted to be primary offending agents. In 1954 the pathogenic lesion of small bowel including mucosal inflammation, crypt hyperplasia and villous atrophy was described in children with malabsorption In 1980’s this “disease of childhood” recognized as being the same disease as “Nontropical Sprue” in adults. (Gluten Sensitive Enteropathy or Nontropical Sprue) 1990’s on -we now understand it as an autoimmune disease with clear genetic associations and a typical antibody signature. It has links to other autoimmune diseases. Ramifications of non-treatment are only now being understood.

4. Pathogenesis • Genetic Association • In genetically predisposed individuals, it is an immune disorder triggered by an environmental agent (alpha gliadin component of gluten) which is only partially degraded by tissue transglutaminase. HLA DQ2 and or DQ8 gene loci. Only 36% of disease is HLA component dependant – so other associated genetic foci must also be in play. • Associated Autoantibodies • IgAautoantibodies to endomesium (smooth muscle connective tissue) and more specifically to tissue transglutaminase which functions to deamidate gliadin peptides. • IgGautoantibodies to deamidated gluten peptides (eg gliadin)

5. Pathogenesis • Incompletely understood • Gliadin Reactive T Cells • Incomplete degradation of gliadin peptides by tissue transglutaminase- stimulation of T cells with associated T Cell activity on targeted intestinal and other tissues • Innate Immunity: Response by macrophages, monocytes and dendritidic cells • Humoral- Leukocyte associated activity • Gliadin receptors on intestinal epithelial cells that transport gliadin peptides to the lamina propria for T cell activation.

6. Reality or Myth? Celiac disease is relatively rare in our population “Classic” Celiac disease with its associated diarrhea and malabsorption is the most common presentation Cultural prevalence changes with diets

7. Epidemiology Highest known prevalence: Whites of Northern European Ancestry Reported prevalence in 1950’s- 1:4000 to 1:8000 based on classic presentation of malabsorption Epidemiological studies based on biopsy 1:300 – 1:500 Epidemiological studies based on genetics and auto-antibodies 1:100-1:250 At risk groups: 1:22 first degree relatives, 1:39 second degree relatives High prevalence- suggests that “silent celiacs” are much higher percentage than “classics” Increasing prevalence with age and exposure to high wheat “western diets” in transplants from other cultures. Small absolute increase in Mortality compared with general population Small increase in digestive tract cancers

8. Reality or Myth? Celiac disease is exclusively a disease of the gastrointestinal tract.

9. Types: Five Current Classifications • Classic Disease: • Severe GI symptoms: Malabsorption with steatorrhea, weight loss, vitamin and nutrient deficiency that resolves on a gluten free diet within weeks to months • Severity of symptoms does not fully correlate with histological changes seen on biopsy (villous atrophy) • Decreasing severity of villous atrophy from proximal to distal small bowel • Atypical Disease: • Antibody Positive: with and without villous atrophy • Mild to Moderate GI complaints • Other associated conditions • unexplained iron deficiency anemia • dental enamel defects • unexplained arthritis and myalgias • unexplained transaminase elevations • infertility (both male and female) • unexplained neuropathies, headaches (migraine), ataxias, or epilepsy • neuropsychiatric including general sx of fatigue, slow mentation, and depression/dysthymia • metabolic bone disease and osteopenia/osteoporosis (vitamin D deficiency) • Antibody Negative: Irritable Bowel Disease that responds to gluten free diet

10. Types (continued) • Asymptomatic or “silent” disease: • Have villous atrophy and auto-antibody evidence • No GI symptoms • No associated conditions • Latent Disease: • “Disease in remission” Clinical improvements and loss of clinical and histological findings after gluten free diet is implemented. Symptomatic disease may seemingly remit even after later returning to a glutinous diet. • Potential Disease: • Positive antibody testing • No GI symptoms • No villous atrophy and or associated symptoms.

11. Associated Conditions Dermatitis Herpetiformis Type 1 Diabetes Mellitus Selective IGA deficiency- makes diagnosis more complicated Down Syndrome Unexplained Liver Disease- unexplained enzyme elevations GERD with associated motility issues Eosinophilicesophagitis Atrophic Glossitis: “burning tongue” Inflammatory and Irritable Bowel Disease Reproductive: Increased miscarriage, infertility, and IUGR babies. Myocarditis and idiopathic dilated cardiomyopathy Pancreatitis Autoimmune thyroid disease

12. Reality or Myth? Screening for Celiac Disease should be a regular part of health screening.

13. Diagnosis • Who should be tested? • GI sx • Chronic or recurring diarrhea • Malabsorption and weight loss • Abdominal bloating, immotility, and chronic irritable bowel • Other associated sx/findings • Unexplained Iron, B12, folate deficiency • Persistent elevation of serum aminotransferases • Recurrent apthousstomatitis, dental enamel hypoplasia, sore tongue • Idiopathic onset of periferal neuropathy, migraines, and irritable bowel. • Men with idiopathic infertility • Women with infertility, recurrent fetal losses, idiopathic low birthweight infants • High risk • 1st and second degree relatives of celiacs • Dermatitis Hepetiformis • Type 1 diabetes • Other autoimmune diseases • Autism (?) • Turner, Downs, and Williams syndromes

14. Testing • Serologic studies should be done on a glutenous diet – age 5 and over • Serum IgA • IgA tissue transglutaminase (sn 98 sp 100) • IgAendomesial antibody (sn 98 sp 98) • Antigliadin antibody -no longer used- low sensitivity and specificity (sn 80 sp 95) • IgG to Deamidated Gliadin Peptide (DGP) • The only reliable test in IgA deficient individuals • Strong assn with other food antibodies (casein, ovalbumin,lactoglobulin) • Small Bowel Biopsy – Gold Standard • Recommendation for those with positive serologic testing – under debate • Duodenal bulb and 2nd and 3rd portion of the duodenum • Genetic • HLA DQ2 and DQ8

15. Reality or Myth? All antibody positive patients should be treated

16. Treatment • All Individuals with Biopsy proven disease • All Individuals with Atypical Disease: Antibody presence and symptoms/findings- even minor • Individuals with antibody presence, no sx, no villous atrophy- debatable • Individuals with Atypical Disease variant: Irritable Bowel –antibody negative- Well worth a try- but this is a hard diet in western culture. • DIET, DIET, DIET • Gluten Free Diet – Wheat, Rye, and Barley –Definitely • Read labels carefully- many stabilizers and additives contain gluten (malt extracts etc) (eg Soy sauce) • Avoid dairy if pt is in symptomatic phase • Oats – more complex- Oats contain a related gluten and this may be “dose dependant” • American Oat supply is frequently cross contaminated with wheat – know your oat supplier/manufacturer

17. Treatment • Micronutrient deficiencies should be treated • Iron • Folic acid, • Vitamin D • B12 • Be careful of bone mass in children and adults • Vaccination • Pneumococcal vaccination recommended, especially in IgA deficiency.

18. Take Home • Celiac Disease- Knowledge about this disease is evolving rapidly • It is an autoimmune disease • Better characterized as “Gluten Sensitive Enteropathy” (Gluten + Genetics+ Environment) • It is a “Spectrum of Disease” that is complex and associated with multiple presentations and tissue targets based on a multitude of genetic and environmental factors.