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Why Celiac Disease is So Easy to Miss

Clinician Reviews. 2014 September;24(9):508-513

References

1. Sanders L. Hurt all over. New York Times Sunday Magazine. November 11, 2011:MM22.

2. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107:1538-1544.

3. Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med. 2012;367:2419-2426.

4. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357: 1731-1743.

5. 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;163:286-292.

6. Mustalahti K, Catassi C, Reunanen A, et al; Coeliac EU Cluster, Project Epidemiology. The prevalence of celiac disease in Europe: results of centralized, international mass screening project. Ann Med. 2010;42:587-595.

7. Farrel R, Kelly C. Celiac disease and refractory celiac disease. In: Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 9th ed. Philadelphia, PA: Saunders; 2010: 1797-1820.

8. Gujral N, Freeman HJ, Thomson Ab. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. 2012;18:6036-6059.

9. Sleisenger MH. Diseases of malabsorption. In: Beeson PB, McDermott W. Cecil-Loeb Textbook of Medicine. 13th ed. Philadelphia, PA: WB Saunders Company; 1971:1285-1291.

10. Reilly NR, Green PH. Epidemiology and clinical presentations of celiac disease. Sem Immunopathol. 2012;34:473-478.

11. Kagnoff MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am. 1992;21:405-425.

12. Riddle MS, Murray JA, Porter CK. The incidence and risk of celiac disease in a healthy US adult population. Am J Gastroenterol. 2012;107:1248-1255.

13. Rampertab SD, Pooran N, Brar P, et al. Trends in the presentation of celiac disease. Am J Med. 2006;119:355.e9-355.e14.

14. Pietzak M. Celiac disease, wheat allergy, and gluten sensitivity: when gluten free is not a fad. JPEN J Parenter Enteral Nutr. 2012;36(1 suppl):68S-75S.

15. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10:13.

16. Rubio-Tapia A, Hill ID, Kelly CP, et al; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management celiac disease. Am J Gastroenterol. 2013;108:656-676.

17. Hill ID, Dirks MH, Liptak GS, et al; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guidelines for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroentertol Nutr. 2005;40:1-19.

18. Husby S, Koletsko S, Korponay-Szabó IR, et al; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastoenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology and Nutrition Guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54:136-160.

19. Catassi C, Fasano A. Celiac disease diagnosis: simple rules are better than complicated algorithms. Am J Med. 2010;123:691-693.

20. US Food and Drug Administration. Foods labeled gluten-free must now meet FDA's definition. Available at: http://www.fda. gov/Food/NewsEvents/ConstituentUpdates/ucm407867.htm. Accessed August 13, 2014.

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22. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293:2343-2351. 

23. Pozo-Rubio T, Olivares M, Nova E, et al. Immune development and intestinal microbiota in celiac disease. Clin Dev Immunol. 2012;2012:654143

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For patients  who are consuming a diet that includes gluten and have symptoms that suggest CD, the ACG guidelines recommend initial testing for IgA tissue transglutaminase (tTG) antibodies. Because symptoms may be intermittent, a patient may delay seeking care until he or she develops secondary manifestations, which often are debilitating and overshadow the GI complaints. Chronic complications of untreated CD include lymphoma and adenocarcinomas of the jejunum, recurrent miscarriages, neurologic disorders, osteoporosis, and hyposplenism.^3,4,8

Since CD can manifest with widely varying symptoms, some researchers believe the disease should be classified into 3 categories based on presentation: classic CD, which presents with diarrhea, weight loss, malabsorption, and vitamin deficiency; atypical CD, which presents with minimal GI symptoms but can include anemia, neurologic symptoms, arthritis, or infertility; and asymptomatic CD, which typically displays no symptoms but usually is identified on incidental screening.^3,8,16Non-celiac gluten sensitivity is a distinct condition in which the body reacts adversely to gluten; it is not an autoimmune disease with an inflammatory response.

Order serologic testing  for at-risk patients 

Because CD remains underdiagnosed,¹⁶ taking a thorough family history and dietary history and making sure to at least consider CD as a part of a differential diagnosis is important. Although population-based screening has been proposed, its benefits and cost-effectiveness remain unproven. As a result, serologic testing of at-risk groups—individuals with conditions known to be associated with CD—remains the current standard.³ The TABLE lists groups for whom serologic testing for CD is indicated.^16,17

In addition, the American College of Gastroenterology (ACG) and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) provide guidance on the diagnosis and treatment of adults and children with CD. (An ACG diagnostic algorithm is available at http://www.nature.com/ajg/journal/v108/n5/pdf/ajg201379a.pdf.)

Adults. For patients who are consuming a diet that includes gluten and have symptoms that suggest CD, the ACG guidelines recommend initial testing for IgA tissue transglutaminase (tTG) antibodies.¹⁶ The IgA tTG has a sensitivity and specificity >95%.¹⁶ An alternative test, the IgA endomysial (IgA EMA) test, has similar sensitivity but is time-consuming and its accuracy depends on the experience and skill of the laboratory technician. A negative result for either test has a high negative predictive value for CD.^3,16

IgA deficiency is much more common in patients with CD than in the general population and can result in a false negative test for tTG and EMA. Therefore, consider taking a baseline IgA measurement first. If the patient has an IgA deficiency, the test you’ll use next will change: The preferred test for CD is either immunoglobulin G (IgG) tTG or IgG deamidated gliadin peptides (DGP).^3,16

If a patient is already gluten-free... To rule out CD in patients who are already consuming a gluten-free diet, order HLA-DQ2 and HLA-DQ8 testing because these markers have a specificity >99%; if the HLA test is negative, the disease is excluded.^8,16

Children. NASPGHAN recommends taking a baseline IgA measurement in children at risk for CD and then testing for IgA tTG antibodies, but not until patients are 3 years old and have been on a diet that includes gluten for at least 1 year.¹⁷ Repeat testing at a later date it is recommended for those with negative results because some evidence suggests that in certain patients, later serologic testing will be positive. Alternatively, you may offer HLA testing. If the HLA test is negative, CD can be excluded >99% of the time.

Diagnosis usually is confirmed  by intestinal biopsy

 Positive results on serologic testing should be confirmed with a biopsy of the small bowel; findings characteristic of CD include an increased number of intraepithelial lymphocytes (>25 per 100 enterocytes), elongation of the crypts, and partial to total villous atrophy.⁴ Final confirmation of CD is resolution of symptoms by consuming a gluten-free diet.^3,8

Alternate approaches to confirming the diagnosis. Although intestinal biopsy has long been considered the gold standard for diagnosis of CD, this may change. In 2012, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition proposed that the biopsy may not be necessary in children with the following 3 characteristics: classic intestinal symptoms of CD, IgA tTG levels >10 times higher than normal, and a positive HLA-DQ2.¹⁸

Catassi and Fasano¹⁹ have proposed shifting from relying on algorithms and intestinal biopsy to a quantitative approach. They suggest using the “4 out of 5” rule, meaning the diagnosis of CD can be confirmed if at least 4 of the following 5 criteria are satisfied: typical CD symptoms, a positive IgA tTG, a positive HLA-DQ2 or -DQ8, celiac enteropathy on small bowel biopsy, and response to a gluten-free diet.¹⁹