Thomas Repas DO FACP CDE UW Hospital and Clinics Department of Medicine

1. Celiac Sprue: Review of a Multisystem Disease Thomas Repas DO FACP CDE UW Hospital and Clinics Department of Medicine Section of Endocrinology, Diabetes & Metabolism H4/568 CSC (5148), 600 Highland Avenue, Madison, WI 53792 Thursday November 17, 2005

2. Common Misconceptions • “Celiac is rare” • “Celiac is only a disease of children and young adults” • “Celiac only occurs in patients of European descent” • “All celiac patients have gastrointestinal symptoms” • “Serologic testing is unreliable” • “What does it matter if they have celiac or not?”

3. Objectives • History/Background • Prevalence • Pathophysiology • Clinical Manifestations • Associated Disorders • Diagnosis • Management

4. History of Celiac Disease

5. History of Celiac • Cereal grains were first domesticated from wild grasses in the Fertile Crescent about 10,000 years ago Simopoulos AP (ed): Evolutionary Aspects of Nutrition and Health. Diet, Exercise, Genetics and Chronic Disease. World Rev Nutr Diet. Basel, Karger, 1999, vol 84, pp 19–73

6. History of Celiac • Aretaeus from Cappadochia (now Turkey) in the 2nd century AD described a chronic malabsorptive condition • He named this disorder "koiliakos” which isGreek for "suffering in the bowels.” Booth, CC. History of celiac disease. BMJ 1989; 298:527.

7. History of Celiac • The second classical description was in 1888 in a report entitled "On the Coeliac Affection“ by Samuel Gee "to regulate the food is the main part of treatment ... The allowance of farinaceous foods must be small ... but if the patient can be cured at all, it must be by means of diet." S. Gee: “On the coeliac affection” Saint Bartholomew’s Hospital Reports, London, 1888, 24: 17-20

8. History of Celiac • During World War II, celiac children improved during the food shortages when bread was unavailable. • After the war, symptoms reoccurred when bread and cereals were reintroduced. • Dutch pediatrician Willem K Dicke recognized and confirmed this association between cereal grains and malabsorption. Dicke, WK. Simple dietary treatment for the syndrome of GheeHerter. Ned Tijdschr Geneeskd 1941; 85:1715. DICKE, WK, WEIJERS, HA, VAN DE, KAMER JH. Coeliac disease. II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr 1953; 42:34.

9. History of Celiac • The celiac lesion in the proximal small intestine was first described by Paulley in 1954. • It was learned that celiac disease and adult non-tropical sprue share many of the same features • These classic findings are: • mucosal inflammation • crypt hyperplasia • villous atrophy PAULLEY, JW. Observation on the aetiology of idiopathic steatorrhoea; jejunal and lymph-node biopsies. Br Med J 1954; 4900:1318 RUBIN, CE, BRANDBORG, LL, PHELPS, PC, TAYLOR, HC Jr. Studies of celiac disease. I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue. Gastroenterology 1960; 38:28

10. Prevalence of Celiac Disease

11. Prevalence of Celiac Disease • Historically, celiac was thought to be an uncommon disease • In the 1950s the prevalence of celiac disease among Europeans was thought to range between 1:4000 and 1:8000. • However, this diagnosis was based upon a presentation with classic symptoms of malabsorption

12. Prevalence of Celiac Disease • Celiac occurs primarily in whites of northern European ancestry • However, it has been reported in many other groups: • It has been reported in Indians, Arabs, Hispanics, Israeli Jews, Sudanese, and people of Cantonese extraction • Punjabis and Gujaratis from India who lived in England developed celiac 2.7 times as often as Europeans when on a gluten-rich diet Sher, KS, Fraser, RC, Wicks, AC, et al. High risk of coeliac disease in Punjabis. Epidemiological study in the South Asian and European populations of Leicestershire. Digestion 1993; 54:178.

13. Prevalence of Celiac Disease • In the 1970’s, celiac was recognized that celiac to be much more common than preciously thought.

14. Prevalence of Celiac Disease • In one study, 17,201 Italian school children (aged 6 to 15 years) were recruited from several regions of Italy and represented 69 percent of the eligible population. • Screening was performed with anti-gliadin and anti-endomysial antibodies • Diagnosis was confirmed with small intestines mucosal biopsy Catassi, C, Fabiani, E, Ratsch, IM, et al. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl 1996; 412:29

15. Prevalence of Celiac Disease In this study • The prevalence of biopsy proven celiac was 1:184 • The ratio of undiagnosed to diagnosed celiac disease was a remarkable 7:1 • Most children had minor but significant nonspecific symptoms Catassi, C, Fabiani, E, Ratsch, IM, et al. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl 1996; 412:29

16. Prevalence of Celiac Disease • Many studies have also shown high prevalence • 1:152 in the Belfast MONICA project evaluating 1,823 participants 1 • 1:256 was noted in a screening study of 1866 Swedish blood donors 2 • 1:99 in a study of 3654 Finnish students 3 • 1:96 in a study of 3188 Italian school children 4 1. Johnston, SD, Watson, RG, McMillan, SA, et al. Preliminary results from follow-up of a large-scale population survey of antibodies to gliadin, reticulin and endomysium. Acta Paediatr Suppl 1996; 412:61. 2. Grodzinsky, E. Screening for coeliac disease in apparently healthy blood donors. Acta Paediatr Suppl 1996; 412:36. 3. Maki, M, Mustalahti, K, Kokkonen, J, Kulmala, P. Prevalence of Celiac disease among children in Finland. N Engl J Med 2003; 348:2517. 4. Tommasini, A, Not, T, Kiren, V, et al. Mass screening for coeliac disease using antihuman transglutaminase antibody assay. Arch Dis Child 2004; 89:512

17. Prevalence of Celiac Disease • The prevalence of celiac in the US is similar to Europe • One large multi-center US study of 13145 subjects consisted of the following: • 4508 first-degree relatives of patients with celiac disease • 1275 second-degree relatives • 3236 symptomatic patients • 4126 not-at-risk individuals Fasano, A, Berti, I, Gerarduzzi, T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study. Arch Intern Med 2003; 163:286

18. Prevalence of Celiac Disease • In this study, the prevalence of celiac disease was as follows: • 1:22 in first-degree relatives • 1:39 in second-degree relatives • 1:56 in symptomatic patients • 1:133 in the not-at-risk groups Fasano, A, Berti, I, Gerarduzzi, T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study. Arch Intern Med 2003; 163:286

19. Pathophysiology of Celiac Disease

20. Pathophysiologyof Celiac Disease • Celiac disease as an immune disorder that is triggered by an environmental agent (the gliadin component of gluten) in genetically predisposed individuals Kagnoff, MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am 1992; 21:405. Schuppan, D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119:234.

21. Pathophysiologyof Celiac Disease Grain protein exists in four general storage forms which are categorized by their solubility characteristics: • Prolamins (soluble in ethanol) • Glutenins (partially soluble in dilute acid or alkali solutions) • Globulins (soluble in 10 percent NaCl) • Minor albumins (soluble in water) Glutens specifically are the prolamins and the glutenins Bernardin, JE, Saunders, RH, Kasarda, DD. Absence of carbohydrate in coeliac toxic A-gliadin. Cereal Chem 1976; 53:612. Freedman, AR, Galfre, G, Gal, E, et al. Western immunoblotting of cereal proteins with monoclonal antibodies to wheat gliadin to investigate coeliac disease. Int Arch Allergy Appl Immunol 1988; 85:346. Troncone, R, Auricchio, S, De Vincenzi, M, et al. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Pediatr Gastroenterol Nutr 1987; 6:346. Vader, LW, Stepniak, DT, Bunnik, EM, et al. Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology 2003; 125:1105

22. Taxonomy of Grains Gliadins Secalins Hordeins Avenins Zeins KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

23. Pathophysiologyof Celiac Disease • The pathophysiology of gliadin toxicity in celiac patients is poorly understood • One hypothesis is that similarities between gliadin proteins and certain enteral pathogens may result in the immunologic response to antigens in gluten. Kagnoff, MF, Paterson, NY, Kumar, PJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987; 28:995

24. Pathophysiologyof Celiac Disease • Kagnoff et al suggested that the alpha fraction of gliadin demonstrated an amino acid region that was homologous to the 54KDa E1b protein coat of adenovirus 12 • The authors postulated that exposure to this virus in a susceptible person may be potentially be involved in the pathogenesis of celiac disease Kagnoff, MF, Paterson, NY, Kumar, PJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987; 28:995

25. Pathophysiologyof Celiac Disease • Other studies, however, have failed to show an association with the presence of celiac sprue and serum antibody titers to the adenovirus 12 protein Nilsen, EM, Lundin, KE, Krajci, P, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 1995; 37:766

26. Pathophysiologyof Celiac Disease • The current hypotheses: • Gliadin-sensitive T cells in genetically predisposed individuals recognize gluten-derived peptide epitopes and develop an inflammatory response which produces mucosal damage Nilsen, EM, Lundin, KE, Krajci, P, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 1995; 37:766

27. Pathophysiologyof Celiac Disease • Genetic factors play an important role- there is significantly increased risk of celiac among family members • A close association with the HLA-DQ2 and/or DQ8 gene locus has been recognized • HLA-DQ2 is found in 98 percent of celiac patients from Northern Europe. • However, ~25% of “normal” individuals in this population will also demonstrate HLA-DQ2 Kagnoff, MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am 1992; 21:4 Schuppan, D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119:234. Petronzelli, F, Bonamico, M, Ferrante, P, et al. Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet 1997; 61:307 Houlston, RS, Ford, D. Genetics of coeliac disease. QJM 1996; 89:737. Houlston, RS, Tomlinson, IP, Ford, D, et al. Linkage analysis of candidate regions for coeliac disease genes. Hum Mol Genet 1997; 6:1335

28. Current Model for Pathogenesis of Celiac Disease KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

29. Pathophysiologyof Celiac Disease • HLA class II molecules are expressed on the surface of antigen-presenting cells • They can bind to and subsequently present “foreign” peptides to populations of CD4 T cells that recognize the DQ2- or DQ8-peptide complex KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

30. Role of Tissue Transglutaminase • Tissue transglutaminase can deamidate glutamine, converting glutamine to negatively charged glutamic acid • This renders these peptides better binders to the disease relevant DQ2 or DQ8 molecules • Once bound to DQ2 or DQ8, the DQ-“gluten” peptide complexes activate DQ2 or DQ8 restricted T cells KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

31. Gluten peptide binding in the peptide binding groove of a DQ2 heterodimer • Gluten peptides form left-handed polyproline II helixes that are a preferred conformation for binding in the peptide-binding groove of HLA class II molecules. • Pockets at several positions have a preference for negatively charged residues such as those formed in gluten peptides upon deamidation KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

32. Activation of DQ-restricted T cells in Celiac Disease KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

33. Celiac Disease: Clinical Manifestations

34. Celiac Disease: Clinical Manifestations in Children The classical presentation is in children after weaning and introduction of cereals into the diet: • Failure to thrive • Apathy • Pallor • Anorexia • Muscle wasting with generalized hypotonia • Abdominal bloating and distention • Soft, bulky, clay-colored, offensive stools

35. Celiac Disease: Clinical Manifestations • As our understanding of celiac improved and serologic testing has become available, subclinical forms of the disease have been recognized

36. Celiac Disease: Clinical Manifestations in Children Catassi, C, et al Acta Paediatr 1996; 412(suppl):29.

37. Celiac Disease: Clinical Manifestations in Adults In a study of 1138 people with biopsy–proven celiac disease: • Majority of individuals were diagnosed in their 4th to 6th decades. • Women predominated (2.9:1)- the female predominance was less marked in the elderly. • Diarrhea was the main presenting symptom occurring in 85%. • 36% had a previous diagnosis of irritable bowel syndrome. • Symptoms were present a mean of 11 years before diagnosis. Green PHR, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 2001;96:126–131.

38. Celiac Disease: Clinical Manifestations in Adults In a population-based study from Minnesota, Murray et al noted a 10-fold increase in the incidence of celiac disease from 1950 to 2001. • The clinical severity of the disease decreased, with fewer people with diarrhea and weight loss at presentation. • Only 54% had diarrhea at diagnosis, 34% abdominal pain and 30% bloating. • Obesity was present in 27%. Murray JA, et al. Trends in the incidence and clinical features of celiac disease in a North American community, 1950-2001. Clin Gastroenterol Hepatol 2003;1:19–27.

39. Spectrum of Celiac Disease Marked GI symptoms Few if any GI symptoms Fatigue Depression, irritability Menstrual irregularity Weakness Infertility Growth Disturbance Neurologic Complaints Diarrhea Bulky, Pale, Foul stools Abdominal Distension, Bloating Abdominal cramps Weight loss Loss of or increased appetite KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

40. Classification of Celiac Disease • Classical celiac disease • Celiac disease with atypical symptoms • Silent celiac disease • Latent celiac disease NATIONAL INSTITUTES OF HEALTH, CONSENSUS DEVELOPMENT CONFERENCE STATEMENT: Celiac Disease. June 28–30, 2004

41. Celiac Disease: Associated Disorders

42. Celiac Disease: Associated Disorders • Dermatitis Herpetiformis • Iron deficiency anemia • Osteoporosis, Osteomalacia and Vitamin D deficiency • Malignancies • Type 1 diabetes • Other autoimmune endocrine disorders • Neuropsychologic Features • Others (Downs syndrome, IgA deficiency, rheumatologic disorders)

43. Celiac Disease: Dermatitis Herpetiformis • Symmetric vesicles, crusts and erosions distributed over the extensor areas of the elbows, knees, buttocks, shoulders and scalp, with a tendency to grouping of individual lesions. PRUESSNER, HT. Detecting Celiac Disease in Your Patients. 1998 by the American Academy of Family Physicians University of Texas Medical School at Houston

44. Celiac Disease: Dermatitis Herpetiformis • It has been reported that up to 10 percent of individuals with celiac will also have dermatitis herpetiformis American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526. Guidetti, CS, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders,Gut 2001;49:502–505

45. Celiac Disease: Other Skin Disorders • Acquired icthyosis • Cutaneous amyloid • Cutaneous vasculitis • Eczema • Epidermal necrolysis • Nodular prurigo • Pityriasis rubra pilara • Pustular dermatitis American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526.

46. Celiac Disease: Iron Deficiency Anemia • In a study of 227 patients with biopsy–proven celiac disease- iron-deficiency anemia was the mode of presentation in 8%1 • In a Mayo Clinic study, celiac disease was identified as the cause of iron deficiency in 15% of those undergoing endoscopic assessment for iron deficiency.2 • In a prospective study of adults, mean age in their 50s, Karnum et al found 2.8% to have celiac disease.3 1. Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac disease. Dig Dis Sci 2003;48:395–398. 2. Oxentenko AS, et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002;97:933–938. 3. Karnam US, et al. Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study. South Med J 2004;97:30–34.

47. Celiac Disease: Osteoporosis • 840 individuals were evaluated by serologic screening for celiac disease at the Washington University Bone Clinic • 266 with osteoporosis • 574 without osteoporosis • Individuals with positive serologic test were offered endoscopic intestinal biopsy • The prevalence of biopsy-proven celiac disease was • 3.4% in individuals with osteoporosis • 0.2% in individuals without osteoporosis Stenson WF et al. Increased Prevalence of Celiac Disease and Need for Routine Screening Among Patients With Osteoporosis ARCH INTERN MED/VOL 165, FEB 28, 2005

48. Celiac Disease: Osteoporosis Stenson WF et al. Increased Prevalence of Celiac Disease and Need for Routine Screening Among Patients With Osteoporosis ARCH INTERN MED/VOL 165, FEB 28, 2005

49. Celiac Disease: Osteoporosis P=0.02 Treatment of the patients with celiac disease with a gluten-free diet for 1 year resulted in improvement in T scores. Stenson WF et al. Increased Prevalence of Celiac Disease and Need for Routine Screening Among Patients With Osteoporosis ARCH INTERN MED/VOL 165, FEB 28, 2005

50. Celiac Disease: Vitamin D Deficiency • 255 women with osteoporosis • 53 women tested positive for tTG ab • Prevalence of serological disease 9.4% Nuti, R et al. Prevalence of undiagnosed coeliac syndrome in osteoporotic women. Journal of Internal Medicine 2001; 250: 361±366