Figure .. Th e Celiac Iceberg

Symptomaticceliac disease Manifest

mucosal lesion

Normalmucosa

Silent celiacdisease

Latent celiac disease

Genetic susceptibility: - DQ2, DQ8Positive serology

Figure .. Interaction of Gluten with Environmental, Immune, and Genetic factors in Celiac Disease.Reprinted with permission from Green & Celier. (2007). New England Journal of Medicine, 357 (17), 1732.

1. Suspicion of celiac disease

2. Serologic tests:

3. Intestinal biopsy

4. Provisional diagnosis of celiac disease

5. Gluten-free diet

6. Definitive diagnosis of celiac disease

Clinical and/or histologic improvement

Characteristic histologic features of celiac disease

Probability of celiac diseaseLow probability

If high clinicalsuspicion

All negative

Anti-TG2 (or antiendomysical) antibodyTotal IgA Positive result for IgA anti-

TG2/endomysial antibody orIgA deficient and positive results for IgG anti-TG2/ endomysial or antigliadin antibody

Figure .. Proposed Algorithm for Evaluation of Patients in whom Celiac Disease is Suspected Reprinted with permission from Alaedini and Green. Annals of Internal Medicine, 142(4), 291

Figure .. Endoscopic Findings in Celiac Disease

Figure .. Histological Findings of Celiac Disease

Poorly responsive celiac disease

Exclusion of other causesof villous atrophy

Assessment of adherenceto gluten-free diet

Good adherence

EvaluationExclusion of bacterial overgrowth and pancreatic insufficiencyUpper gastrointestinal endoscopy or colonoscopy and biopsyIntraepithelial-lymphocyte pheno- type on duodenal biopsyEnteroscopy (push or push-pull)Abdominal radiology (small bowel studies and CT scan)Video-capsule endoscopy

AdenocarcinomaEnteropathy-associated

T-cell lymphomaRefractory celiac

disease

Normalintraepithelial-lymphocyte

phenotype (type 1)

Abnormal clonalintraepithelial-lymphocyte

phenotype (type 2)

Poor adherence

Dietary counselingReferral to support groupRegular follow-up by experienced dietitian

Figure .. An Assessment Plan for a Patient with Poorly Responsive Celiac Disease Copyright © 2007 Massachusetts Medical Society. All rights reserved.

REFERENCES

Abdo A , Meddings J , Swain M. ( 2004 ). Liver abnormalities in celiac disease . Clin Gastroenterol Hepatol , 2 , 107 – 112 .

Askling J , Linet M , Gridley G , Halstensen TS , Ekström K , Ekbom A. ( 2002 ). Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis . Gastroenterology , 123 , 1428 – 1435 .

Bingley PJ , Williams AJ , Norcross AJ , et al . ( 2004 ). Undiagnosed coeliac disease at age seven: population based prospective birth cohort study . BMJ , 328 , 322 – 323 .

Bonamico M , Mariani P , Th anasi E , et al . ( 2004 ). Patchy villous atrophy of the duode-num in childhood celiac disease . J Pediatr Gastroenterol Nutr , 38 , 204 – 207 .

Catassi C , Rätsch IM , Gandolfi L , et al . ( 1999 ). Why is coeliac disease endemic in the people of the Sahara? Lancet , 354 , 647 – 648 .

Cellier C , Patey N , Mauvieux L , et al . ( 1998 ). Abnormal intestinal intraepithelial lymphocytes in refractory sprue . Gastroenterology , 114 , 471 – 481 .

Cellier C , Delabesse E , Helmer C , et al . ( 2000 ). Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma . Lancet , 356 , 203 – 208 .

Chin RL , Sander HW , Brannagan TH , et al . ( 2003 ). Celiac Neuropathy . Neurology , 60 , 1581 – 85 .

Ciacci C , Cirillo M , Auriemma G , et al . ( 1996 ). Celiac disease and pregnancy outcome . Am J Gastroenterol , 91 , 718 – 722 .

Collin P , Kaukinen K , Valimaki M , Salmi J. ( 2002 ). Endocrinological disorders and celiac disease . Endocr Rev , 23 , 464 – 483 .

Culliford A , Daly J , Diamond B , Rubin M , Green PH. ( 2005 ). Th e value of wireless capsule endoscopy in patients with complicated celiac disease . Gastrointest Endosc , 62 , 55 – 61 .

Dahele A , Ghosh S. ( 2001 ). Vitamin B12 defi ciency in untreated celiac disease . Am J Gastroenterol , 96 , 745 – 750 .

Daum S , Weiss D , Hummel M , et al . ( 2001 ). Frequency of clonal intraepithelial T lym-phocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue . Gut , 49 , 804 – 812 .

Dieterich W , Ehnis T , Bauer M , et al . ( 1997 ). Identifi cation of tissue transglutaminase as the autoantigen of celiac disease . Nat Med , 3 , 797 – 801 .

Farrell RJ , Kelly CP. ( 2002 ). Celiac Sprue . N Eng J Med , 346 , 180 – 188 . Fasano A , Berti I , Gerarduzzi T , et al . ( 2003 ). Prevalence of celiac disease in at-risk and

not-at-risk groups in the United States: a large multicenter study . Arch Intern Med , 163 , 286 – 292 .

Fine KD. ( 1996 ). Th e prevalence of occult gastrointestinal bleeding in celiac sprue . N Eng J Med , 334 , 1163 – 1167 .

Gasbarrini A , Sanz Torre E , Trivellini C , et al . ( 2000 ). Recurrent spontaneous abortion and intrauterine fetal growth retardation as symptoms of celiac disease . Lancet , 256 , 399 – 400 .

Gomez JC , Selvaggio GS , Viola M , et al . ( 2001 ). Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area . Am J Gastroenterol , 96 , 2700 – 2704 .

Greco L et al . ( 2002 ). Th e fi rst large population-based twin study of celiac disease . Gut , 50 , 624 – 628 .

Green PH , Shane E , Rotterdam H , et al . ( 2000 ). Signifi cance of unsuspected celiac disease detected at endoscopy . Gastroint Endosc , 51 , 60 – 65 .

Green PH , Stavropoulos SN , Panagi SG , et al . ( 2001 ). Characteristics of adult celiac disease in the USA : Results of a national survey . Am J Gastroenterol , 96 , 126 – 131 .

Green PH , Fleischauer AT , Bhagat G , Goyal R , Jabri B , Neugut AI. ( 2003 ). Risk of malignancy in patients with celiac disease . Am J Med , 115 , 191 – 195 .

Green PH , Jabri B ( 2003 ). Celiac disease . Lancet , 362 , 383 – 391 . Green PH , Rampertab SD. ( 2004 ). Small bowel carcinoma and coeliac disease . Gut , 53 , 774 . Green PH , Jabri B. ( 2006 ). Celiac Disease . Annu Rev Med 57 , 207 – 221 . Green PH , Cellier C. ( 2007 ). Celiac Disease . N Engl J Med 357 , 1731 – 1743 . Hadjivassiliou M , Gibson A , Davies-Jones GA , et al . ( 1996 ). Does cryptic gluten sensi-

tivity play a part in neurological illness? Lancet , 347 , 369 – 371 . Hovell CJ , Collett JA , Vautier G , et al . ( 2001 ). High prevalence of celiac disease in a

population-based study from Western Australia: a case for screening? Med J Aust , 175 , 247 – 250 .

Howdle PD , Jalal PK , Holmes GK , Houlston RS. ( 2003 ). Primary small-bowel malig-nancy in the UK and its association with celiac disease . QJM , 96 , 345 – 353 .

Karpati S. ( 2004 ). Dermatitis herpetiformis: close to unraveling a disease . J Dermatol Sci , 34 , 83 – 90 .

Kaukinen K , Halme L , Collin P , et al . ( 2002 ). Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure . Gastroenterol , 122 , 881 – 888 .

Lee SK , Lo W , Memeo L , Rotterdam H , Green PH ( 2003 ) . Duodenal histology in patients with celiac disease aft er treatment with a gluten-free diet . Gastrointest Endosc , 57 , 187 – 191 .

Lee SK , Green PH ( 2005 ). Endoscopy in celiac disease . Curr Opin Gastroenterol , 21 , 589 – 594 .

Lenhardt A , Plebani A , Marchetti F , et al . ( 2004 ). Role of human-tissue transglutaminase IgG and anti-gliadin IgG antibodies in the diagnosis of coeliac disease in patients with selective immunoglobulin A defi ciency . Dig Liver Dis , 36 , 730 – 734 .

Logan RF. ( 1996 ). Screening for celiac disease: Has the time come for mass screening? Acta Paediatra Suppl , 412 , 15 – 19 .

Louka AS , Sollid LM ( 2003 ). HLA in celiac disease: unraveling the complex genetics of a complex disorder . Tissue Antigens 61 , 105 – 117 .

Mäki M , Mustalahti K , Kokkonen J , et al . ( 2003 ). Prevalence of celiac disease among children in Finland . N Engl J Med , 348 , 2517 – 2524 .

Meyer D , Stavropoulos S , Diamond B , et al ( 2001 ). Osteoporosis in a North American adult population with celiac disease . Am J Gastroenterol 96 : 112 – 119 .

Norris JM , Barriga K , Hoff enberg EJ et al . ( 2005 ). Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease . JAMA , 293 , 2343 – 2351 .

Oxentenko AS , Grisolano SW , Murray JA , et al . ( 2002 ). Th e insensitivity of endoscopic markers in celiac disease . Am J Gastroenterol , 97 , 933 – 938 .

Patey-Mariaud De Serre N , Cellier C , Jabri B , et al . ( 2000 ). Distinction between celiac disease and refractory sprue: a simple immunohistochemical method . Histopathology , 37 , 70 – 77 .

Peräaho M , Kaukinen K , Mustalahti K , et al . ( 2004 ). Eff ect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease: a randomized study . Scand J Gastroenterol , 39 , 27 – 31 .

Persson LA , Ivarsson A , Hernell O. ( 2002 ). Breastfeeding protects against celiac dis-ease in childhood: epidemiological evidence . Adv Exp Med Biol , 503 , 115 – 123 .

Rampertab SD , Forde KA , Green PH. ( 2003 ). Small bowel neoplasia in coeliac disease . Gut , 52 , 1211 – 1214 .

Rampertab SD , Pooran N , Brar P , Singh P , Green PH. ( 2006 ). Trends in the presenta-tion of celiac disease . Am J Med , 119 ( 4 ) , e9 – e14 .

Ravelli A , Bolognini S , Gambarotti M , Villanacci V. ( 2005 ). Variability of histologic lesions in relation to biopsy site in glutensensitive enteropathy . Am J Gastroenterol , 100 , 177 – 185 .

Reunala TL. ( 2001 ). Dermatitis herpetiformis . Clin Dermatol , 19 , 728 – 736 . Rostom A , Dubé C , Cranney A , et al . ( 2005 ). Th e diagnostic accuracy of serologic tests

for celiac disease: a systematic review . Gastroenterology , 128 , Suppl 1 , S38 – 46 . Rostom A , Murray JA , Kagnoff MF. ( 2006 ). American Gastroenterological Association

(AGA) Institute technical review on the diagnosis and management of celiac disease . Gastroenterology , 131 , 1981 – 2002 .

Sategna-Guidetti C , Pulitano R , Grosso S , Ferfoglia G. ( 1993 ). Serum IgA antiendomy-sium antibody titers as a marker of intestinal involvement and diet compliance in adult celiac sprue . J Clin Gastroenterol , 17 , 123 – 127 .

Sedlack RE , Smyrk TC , Czaja AJ , et al . ( 2002 ). Celiac disease-associated autoimmune cholangitis . Am J Gastroenterol , 97 , 3196 – 3198 .

Shah VH , Rotterdam H , Kotler DP , Fasano A , Green PH. ( 2000 ). All that scallops is not celiac disease . Gastrointestinal Endoscopy , 5 ( 16 ), 717 – 720 .

Shahbazkhani B , Malekzadeh R , Sotoudeh M , et al . ( 2003 ). High prevalence of celiac disease in apparently healthy Iranian blood donors . Eur J Gastroenterol Hepatol , 15 , 475 – 478 .

Siegel M , Bethune MT , Gass J , et al . ( 2006 ). Rational design of combination enzyme therapy for celiac sprue . Chem Biol , 13 , 649 – 658 .

Smedby KE , Akerman M , Hildebrand H , Glimelius B , Ekbom A , Askling J. ( 2005 ). Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma . Gut , 54 , 54 – 59 .

Sollid LM , Lie BA. ( 2005 ). Celiac disease genetics: current concepts and practical applications . Clin Gastroenterol Hepatol , 3 , 843 – 851 .

Sood A , Midha V , Sood N , Malhotra V. ( 2003 ). Adult celiac disease in northern India . Indian J Gastroenterol , 22 , 124 – 126 .

Stepniak D , Spaenij-Dekking L , Mitea C , et al . ( 2006 ). Highly effi cient gluten degrada-tion with a newly identifi ed prolyl endoprotease: implications for celiac disease . Am J Physiol Gastrointest Liver Physiol , 291 , G621 – 629 .

Tata LJ , Card TR , Logan RF , et al . ( 2005 ). Fertility and pregnancy-related events in women with celiac disease: a population based cohort study . Gastroenterol , 128 , 849 – 855 .

Tatar G , Elsurer R , Simsek H , et al . ( 2004 ). Screening of tissue transglutaminase antibody in healthy blood donors for celiac disease screening in the Turkish popu-lation . Dig Dis Sci , 49 , 1479 – 1484 .

Th ompson T. ( 2003 ). Oats and the gluten-free diet . J Am Diet Assoc , 103 , 376 – 379 . Tommasini A , Not T , Kiren V , et al . ( 2004 ). Mass screening for coeliac disease using

antihuman transglutaminase antibody assay . Arch Dis Child 89 , 512 – 515 . Trier JS. ( 1991 ). Celiac sprue . N Engl J Med , 325 , 1709 – 1719 . Tursi A , Brandimarte G , Giorgetti GM. ( 2003 ). Prevalence of antitissue transglutami-

nase antibodies in diff erent degrees of intestinal damage in celiac disease . J Clin Gastroenterol , 36 , 219 – 221 .

Vader LW , Stepniak DT , Bunnik EM et al . ( 2003 ). Characterization of cereal toxicity for celiac disease patients based on protein homology in grains . Gastroenterol , 125 , 1105 – 1113 .

Vahedi K , Mascart F , Mary JY , et al . ( 2003 ). Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease . Am J Gastroenterol , 98 , 1079 – 1087 .

Valdimarsson T , Lofman O , Toss G , et al . ( 1996 ). Reversal of osteopenia with diet in adult celiac disease . Gut , 38 , 322 – 327 .

Volta U , Rodrigo L , Granite A , et al . ( 2002 ). Celiac disease in autoimmune cholestatic liver disorders . Am J Gastroenterol , 97 , 2609 – 2613 .

West J , Logan RF , Hill PG , et al . ( 2003 ). Seroprevalence, correlates, and characteristics of undetected coeliac disease in England . Gut , 52 , 960 – 965 .