Gluten challenge test

The gluten challenge test is a medical test in which gluten-containing foods are consumed and (re-)occurrence of symptoms is observed afterwards to determine whether and how much a person reacts to these foods. The test may be performed in people with suspected gluten-related disorders in very specific occasions and under medical supervision, for example in people who had started a gluten-free diet without performing duodenal biopsy.[1][2][3]

Gluten challenge test
SynonymsGluten challenge
PurposeDiagnose gluten-related disorders

Gluten challenge is discouraged before the age of 5 years and during pubertal growth.[4]

Gluten challenge protocols have significant limitations because a symptomatic relapse generally precedes the onset of a serological and histological relapse, and therefore becomes unacceptable for most patients.[1][3][4][5]

History

Before serological and biopsy-based diagnosis of coeliac disease was available, a gluten challenge test was a prerequisite for diagnosis of coeliac disease.[6]

Today, with serological testing (determination of coeliac disease-specific antibodies in the blood) and duodenal biopsy with histological testing being available for diagnosing coeliac disease, patients with suspected coeliac disease are strongly advised to undergo both serological and biopsy testing before undertaking a gluten-free diet.[7] People who present minor damage of the small intestine often have negative blood antibodies titers and many patients with coeliac disease are missed when a duodenal biopsy is not performed.[8] Serologic tests have a high capacity to detect coeliac disease only in patients with total villous atrophy and have very low capacity to detect cases with partial villous atrophy or minor intestinal lesions with normal villi.[2] Currently, gluten challenge is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet.[2] Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet.[2] Gluten challenge is discouraged before the age of 5 years and during pubertal growth.[4] European guidelines suggest that in children and adolescents with symptoms which are compatible with coeliac disease, the diagnosis can be made without the need for an intestinal biopsy if anti-tTG antibodies titres are very high (10 times the upper limit of normal).[9]

A recently proposed criterion to non-coeliac gluten sensitivity diagnosis concludes that an improvement of gastrointestinal symptoms and extra-intestinal manifestations higher than 50% with a gluten-free diet (GFD), assessed through a rating scale, may confirm the clinical diagnosis of non-coeliac gluten sensitivity. Nevertheless, this rating scale, is not yet applied worldwide. To exclude a placebo effect, a double-blind placebo-controlled gluten challenge is a useful tool, although it is expensive and complicated in routine clinical ground, and therefore, is only performed in research studies.[1][10]

Testing

The test is also frequently used in clinical trials, for example for assessing the efficacy of novel drugs for patients with coeliac disease.[6]

Medical guidelines for performing a gluten challenge vary in terms of the recommended dose and duration of the test.

Preparation

In order to be able to assess the results of the gluten challenge, the patient needs to have been on a gluten-free diet beforehand, with symptoms having disappeared sufficiently for allowing for a subsequent re-appearance of symptoms under gluten challenge to be observed.

Procedure

It remains unclear what daily intake of gluten is adequate and how long the gluten challenge should last.[3] Some protocols recommend eating a maximum of 10 g of gluten per day for 6 weeks. Nevertheless, recent studies have shown that 2-week challenge of 3 g of gluten per day may induce histological and serological abnormalities in most adults with proven coeliac disease.[3][5] This newly proposed protocol has shown higher tolerability and compliance, and it has been calculated that its application in secondary-care gastrointestinal practice would identify celiac disease in 7% patients referred for suspected non-coeliac gluten sensitivity, while in the remaining 93% would confirm non-coeliac gluten sensitivity,[3] but is not yet universally adopted.[5] A double-blind placebo-controlled gluten challenge can be performed by means of capsules containing gluten powder (or wheat powder) or a placebo, respectively,[11] although it is expensive and complicated in routine clinical ground, and therefore, is only performed in research studies.[1][10]

There are indications that patients with non-coeliac gluten sensitivity show a reappearance of symptoms in far shorter time than is the case for coeliac disease: in non-coeliac gluten sensitivity, symptoms usually relapse in a few hours or days of gluten challenge.[12][13]

In cases of suspected coeliac disease, a gastrointestinal biopsy is performed at the end of the gluten challenge.[2] For an alternative diagnosis of non-coeliac gluten sensitivity, the reappearance of symptoms is assessed. However, there is no agreement so far as to how to perform a non-coeliac gluten sensitivity symptom evaluation after a gluten challenge.[11]

For people eating a gluten-free diet who are unable to perform an oral gluten challenge, an alternative to identify a possible celiac disease is an in vitro gliadin challenge of small bowel biopsies, but this test is available only at selected specialized tertiary-care centers.[5]

Variations

For determining whether certain foods such as oats can be tolerated by certain patients, a gradual challenge may be performed.[14]

References
  1. Volta U, Caio G, De Giorgio R, Henriksen C, Skodje G, Lundin KE (Jun 2015). "Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat-related disorders". Best Pract Res Clin Gastroenterol. 29 (3): 477–91. doi:10.1016/j.bpg.2015.04.006. PMID 26060112.
  2. Rostom A, Murray JA, Kagnoff MF (Dec 2006). "American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease". Gastroenterology (Review). 131 (6): 1981–2002. doi:10.1053/j.gastro.2006.10.004. PMID 17087937.
  3. Elli L, Branchi F, Tomba C, Villalta D, Norsa L, Ferretti F, Roncoroni L, Bardella MT (Jun 2015). "Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity". World J Gastroenterol (Review). 21 (23): 7110–9. doi:10.3748/wjg.v21.i23.7110. PMC 4476872. PMID 26109797.
  4. Ontiveros N, Hardy MY, Cabrera-Chavez F (2015). "Assessing of Celiac Disease and Nonceliac Gluten Sensitivity". Gastroenterology Research and Practice (Review). 2015: 1–13. doi:10.1155/2015/723954. PMC 4429206. PMID 26064097.
  5. Aziz I, Hadjivassiliou M, Sanders DS (Sep 2015). "The spectrum of noncoeliac gluten sensitivity". Nat Rev Gastroenterol Hepatol (Review). 12 (9): 516–26. doi:10.1038/nrgastro.2015.107. PMID 26122473. S2CID 2867448.
  6. Denise Faustman (13 March 2014). The Value of BCG and TNF in Autoimmunity. Elsevier Science. p. 130. ISBN 978-0-12-800461-6.
  7. Green PH, Lebwohl B, Greywoode R (May 2015). "Celiac disease". J Allergy Clin Immunol (Review). 135 (5): 1099–106. doi:10.1016/j.jaci.2015.01.044. PMID 25956012. S2CID 21552589.
  8. van der Windt DA, Jellema P, Mulder CJ, Kneepkens CM, van der Horst HE (2010). "Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review". JAMA. 303 (17): 1738–46. doi:10.1001/jama.2010.549. PMID 20442390. Most studies used similar histological criteria for diagnosing celiac disease (Marsh grade ≥III), but the level of damage may vary across populations. Only 4 studies presented the proportion of patients in whom only partial villous atrophy was found (Marsh grade of IIIA), which ranged from 4% to 100%. The presence of positive serum antibodies has been shown to correlate with the degree of villous atrophy, and patients with celiac disease who have less severe histological damage may have seronegative findings. This could be important, especially in primary care, in which levels of mucosal damage may be lower, and consequently, more patients with celiac disease may be missed.
  9. Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (Jan 2012). "European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease" (PDF). J Pediatr Gastroenterol Nutr (Practice Guideline). 54 (1): 136–60. doi:10.1097/MPG.0b013e31821a23d0. PMID 22197856. S2CID 15029283. Archived from the original (PDF) on 2016-04-03. Retrieved 2016-03-29.{{cite journal}}: CS1 maint: uses authors parameter (link)
  10. Vriezinga SL, Schweizer JJ, Koning F, Mearin ML (Sep 2015). "Coeliac disease and gluten-related disorders in childhood". Nature Reviews. Gastroenterology & Hepatology (Review). 12 (9): 527–36. doi:10.1038/nrgastro.2015.98. PMID 26100369. S2CID 2023530.
  11. Lundin KEA, Alaedini A, Non-celiac Gluten Sensitivity. In: Benjamin Lebwohl; Peter H. R. Green (1 November 2012). Celiac Disease, An Issue of Gastrointestinal Endoscopy Clinics. Elsevier Health Sciences. ISBN 978-1-4557-4735-1.
  12. Volta, Umberto; Caio, Giacomo; Tovoli, Francesco; De Giorgio, Roberto (2013). "Non-celiac gluten sensitivity: an emerging syndrome with many unsettled issues". Italian Journal of Medicine. 8 (4): 225. doi:10.4081/itjm.2013.461. ISSN 1877-9352.
  13. Caio, Giacomo; Volta, Umberto; Tovoli, Francesco; De Giorgio, Roberto (2014). "Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity". BMC Gastroenterology. 14 (1): 26. doi:10.1186/1471-230X-14-26. ISSN 1471-230X. PMC 3926852. PMID 24524388.
  14. H. A. Harfi; F. B. Stapleton; William Oh; H. Nazer; R. J. Whitley (10 January 2012). Textbook of Clinical Pediatrics. Springer Science & Business Media. p. 1899. ISBN 978-3-642-02202-9.
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