When gluten is ingested and the body shows increased immunological responsiveness in someone who is genetically susceptible, cheap it is defined as gluten sensitive enteropathy or coeliac disease.   The prevalence of coeliac disease in Europe is about 1% in the adult population.[1], this [2], look [3],[4]

 NON-RESPONSIVE Coeliac Disease (NRCD)

When the subject does not respond to a gluten-free diet (GFD), or while still on GFD the subject has recurrence of symptoms or laboratory abnormalities, after 6-12 months adherence.  In 7-30% of cases symptomatic or histological improvement fails with a presumed GFD.  If no response to GFD has been seen after twelve moths, it can be defined as primary, and secondary despite adherence to GFD with symptom relapse after initial response.[5],[6]  It is important to be sure of the relevance of the initial diagnosis.  Serology, FHx, hyposplenism etc. has to be ruled out.  Biopsies have to be reviewed and could there be another reason of villous atrophy, look for HLA-DQ2/DQ8 tissue type.  Initial response to GFD is not enough to diagnose CD.

CAUSES – Non-Adherence to GFD  

The most common cause of NRCD is non-adherence to GFD (estimated adherence is 42-91%).[7],[8],[9]   Complete non-adherence is not so common and only about 5% according to the literature, with a range of 0-32%.  Gluten contamination happens either deliberately or inadvertently and a study by Abdulkarim et al[10] 25/49 subjects had persisting symptoms in spite of the intention on following GFD.  Persistent symptoms should be taken seriously and call for re-evaluation, even with histological improvements. Duodenal biopsies do not always reflect improvement as the distal small bowel heals faster than the proximal small bowel.[11],[12]   In some cases, very small amount of gluten can prevent mucosal healing and some subjects react to 10 mg per day and that can lead to mucosal abnormalities in the intestines.  Most individuals are unlikely to react to <10 mg per day.[13]  Serology is a marker of gluten exposure but not villous atrophy.  In some cases, subjects do react to oats.   An input from dietetic as well as to write food-diary is helpful to try to find the cause for NRCD.

 INITIAL Diagnosis

Coeliac disease cannot be diagnosed only on the cause of initial response to gluten as recent evidence show that symptoms can be induced in non-coeliac subjects.[14]  Histological evaluation has to be correct to be a diagnostic tool, family history can be supportive evidence and HLA genotyping as well, as the absence of HLA DQ2/HLA DQ8 underline unlikelihood of CD.[15],[16],[17]

OTHER Causes of Small Bowel Villous Atrophy

Diagnosing CD is by duodenal villous atrophy (DVA) but villous atrophy can be found in noncoeliac enteropathy (NCE) and misdiagnosing coeliac disease is not so uncommon according to Pallav et al[18].  The most common aetiologies for small bowel villous atrophy are the following; collagenous sprue, small bowel bacterial overgrowth, peptic duodenitis, non-specific immune mediated enteropathy, chohn´s disease, AIDS enteropathy, tropical sprue, common variable immunodeficiency (CVID) and adult autoimmune enteropathy.

OTHER Causes for Symptoms/Diarrhea  

Lactose malabsorbtion, irritable bowel syndrome (IBS), exocrine pancreatic insufficiency and small bowel bacterial overgrowth are all conditions that are associated with NRCD.10  Whipples disease, sphincter dysfunction and protein losing enterophaties as well as dietary allergy are also associated with NRCD.  One of the known direct cause of villous atrophy is exocrine pancreatic insufficiency in GFD adherent patients. Fructose/lactose intolerance can also occur because of the damage of the mucosal surface.  Microscopic colitis (MC) is easy to treat and there is strong evidence on association to CD.[19]  Small bacterial overgrowth and small bowel aspirates are known in CD, and IBS is common.

REFRACTORY Coeliac Disease (RCD)

RCD can be diagnosed when all other causes have been ruled out, for the ongoing symptoms.  RCD is a rare condition; subjects often have nutritional deficiencies and are underweight as a result of severe malabsorption.  Malabsroptive symptoms are persistent, diarrhea/steatorrhea is apparent and micronutrient loss e.g. zinc, copper, selenium etc.  Prevalence is from 8-18 % and according to Roshan et al[20] in a North American population, the cumulative incidence of RCD in CD diagnosed patients was 1.5%.  Weight loss was high, or 76.5% (unintentional).  Rubio-Tapia et al17 define RCD as the following:   “Refractory coeliac disease (RCD) is defined by persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a GFD for at least 6–12?months in the absence of other causes of non-responsive treated coeliac disease and overt malignancy.”

RCD can be subdivided as primary or secondaryPrimary – strict adherence to GFD but persisting symptoms.  Secondary – recurrence of symptoms after apparent response to GFD for at least one year.  Further division can be made, type 1 (polyclonal expansion of IESs and villous atrophy) or type 2 (includes ulcerative jejunitis, colonal expansion of aberrant IESs) RCD, depending on intraepithelial T-cell populations phenotypic appearance.  Subjects diagnosed with type 2 RCD do have poorer response to treatment and are therefore more prone to develop lymphoma and have about 50% chance of 5-year survival compared to 90-100% in those with type 1 RCD diagnosis.  Mortality can be traced to malabsorption and progression to enteropahy associated T-cell lymphoma (EATL).[21],[22],[23]  Investigation in RCD is to rule out malignancy, think about CT or PET-CT, small bowel imaging and double-balloon enteroscopy (DBE), OGD – histology for IEL population analysis.[24]


Coeliac disease affects about 1% of the European population.  Non-Responsive coeliac disease affects 7-30% of CD diagnosed subjects and the most common cause is non-adherence to GFD.  If the initial diagnosis is true, it is important to investigate what is the underlying cause of histological changes as persisting symptoms.  In some cases, 8-18%, refractory coeliac disease can be diagnosed and if presented as type 2 there are high chances of lymphoma and survival chances are 5 years in 50% of the cases.

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

2 Mooney PD, Evans KE, Singh S, Sanders DS. Treatment failure in coeliac disease: a practical guide to investigation and treatment of non-responsive and refractory coeliac disease. J Gastrointestin Liver Dis 2012;21(2):197-203.

3 Mustalahti K, Catassi C, Reunanen A, Fabiani E, Heier M, McMillan S, et al. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project. Ann Med 2010;42(8):587-595(9).

4 Nehra V, Marietta E, Murray J. Celiac disease. Elsevier 2005;407-417.

5 Leffler DA, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Etiologies and predictors of diagnostics in nonresponsive celiac disease. Clin Gastroenterol Hepatol 2007;5(4):445-50.

6 Fasano A, Catassi C. Celiac disease. N Engl J Med 2012;367:2419-26.

7 O´Leary C, Wieneke P, Healy M, et al. Celiac disease and the transformation from childhood to adulthood: a 28-year follow-up. Am J Gastroenterol 2004;99:2437-2441.

8 Hall NJ, Rubin G, Charnock A. Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment Pharmacol Ther 2009;30:315-330.

9 Leffler DA, Edwards-George J, Dennis M, et al. Factors that influence adherence to a gluten-free diet in adults with celiac disease. Dig Dis Sci 2008;53:1573-1581

10 Abdulkarim AS, Burgart LF, See J, Murray JA. Etiology of nonresponsive celiac disease: results of a systematic approach. AM J Gastroenterol 2002;97(8):2016-21

11 Grefte JM, Bouman JG, Grond J, Jansen W, Kleibeuker JH. Slow and incomplete histological and funtional recovery in adult gluten sensitive enteropathy. J Clin Pathol 1988,41:886-891.

12 Kaukinen K, Peraaho M, Lindfors K, partanen J, Woolley N, Pikkarainen P, et al. Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease. Aliment Pharm Therap 2007;25(10):1237-1245.

13 Akobeng AK, Thomas AG. Systematic review: tolerable amount of gluten for people with coeliac disease. Aliment Pharm Therap 2008;27(11):1044-1052.

14 Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol 2011;106(3):508-14.

15 Evans KE, Sanders DS. Joint BAPEN and British Society of Gastroenterology Symposium on ‘coeliac disease: basics and controversies’. Coeliac disease: optimising the management of patients with persisting symptoms? Proc Nutr Soc 2009,68(3):242-8.

16 Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol 2008;103:190-195.

17 Rubio-Tapia Alberto, Murray JA. Classification and management of refractory coeliac disease. Gut 2010;59:547-557.

18 Pallav K, Leffler DA, Tariq S, Kabbani T, Hansen J, Peer A, et al. Noncoeliac enteropathy: the differential diagnosis of villous atrophy in contemporary clinical practice. Aliment Pharmacol Ther 2012;35:380-90.

19 Williams JJ, Kaplan GG, Makhija S, Urbanski SJ, Dupre M, et al. Microscopic colitis-defining incidence rates and risk factors: a population-based study. Clin Gastroenterol Hepatol 2008;6(1):35-40.

20 Roshan B, Leffler DA, Jamma S, Dennis M, Sheth S, Falchuk K, et al. The incidence and clinical spectrum of refractory celiac disease in a north american referral center. Am J Gastroenterol 2011;106(5):923-8.

21 Al-Toma A, Verbeek WHM, Hadithi M, Blomberg BME, Mulder CJJ. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut 2007;56:1373-8.

 22 Rubio-Tapia A, Kelly DG, Sahr BD, Dogan A, Wu TT, Murray JA. Clinical staging and survival in refractory celiac disease: a single center experience. Gastroenterology 2009,136(1):99-107.

23 Malamut G, Afchain P, Verkarre V, et al. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 2009,136:81-90.

24 Tennyson CA, Semrad CE. Small bowel imaging in celiac disease, in Lebwohl B, Green PHR editors. Celiac disease, an issue of gastrointestinal endoscopy clinics. Washington, NY, USA:Department of Medicine, Columbia University Medical Center;2012.

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