One hundred and twelve patients were referred to our center and underwent assessment for NRCD. The mean age of this group was 48.5 years (range 19-72 years) and 69% were female; CD had been diagnosed at a mean age of 31 years. The commonest presenting symptoms were diarrhea (65%), lethargy (43%), abdominal pain (27%) and weight loss (23%). The demographic details and clinical symptoms are shown in Table . The results are summarised in Figure
Demographics and distribution of symptoms in 112 patients referred to our institution with continued symptoms on a gluten-free diet (%)
Flow chart showing the investigation and diagnoses of the patient cohort. RCD: Responsive celiac disease; SBBO: Small bowel bacterial overgrowth; EATL: Enteropathy-associated T cell lymphoma.
Twelve out of the 112 patients had been wrongly diagnosed with CD. Due to the doubt over the diagnosis, these 12 patients underwent gluten challenge and repeat biopsy which was normal in all cases. Additionally, anti-endomysial antibody (EMA) tests were all negative, although four patients had anti-gliadin antibodies detected. In four cases, initial duodenal biopsy had not been performed previously and diagnosis had been made based on dramatic reduction in symptoms with initial wheat exclusion. In the remaining eight, we were able to examine the original histology in five patients. Four of these were sufficiently normal to exclude CD in tandem with the subsequent negative gluten challenge. One patient did have villous atrophy on their original biopsy, which was felt to have been due to bacterial overgrowth, which had subsequently improved with antibiotic treatment. We were not able to examine previous specimens from three patients but the negative gluten challenge was deemed sufficient to exclude a diagnosis of CD. In total, six out of 12 patients had been previously shown to have supportive positive serology for CD in other institutions (mainly anti-gliadin antibody). Seven patients were diagnosed with irritable bowel syndrome; three with primary SBBO; and one each with anorexia nervosa and IgE-mediated wheat allergy. These individuals were subsequently removed from the analysis.
Forty-five of the remaining 100 patients were found to be ingesting sufficient gluten to cause their symptoms. Of these, 24 were discovered to be consuming gluten accidentally, and 21 admitted poor compliance with aspects of their prescribed diet. In total, 37 (23/24 accidental group and 14/21 poor compliance group) patients underwent repeat duodenal biopsy in order to establish this information. Of these specimens, 33/37 were abnormal (Marsh IIIa-c) which assisted in correlating the continued ingestion with the persisting histological abnormalities.
The majority (28/37) proceeded to have a further duodenal sample taken that showed comparative improvement in all but one case. In this case, further gluten ingestion was admitted on further questioning. In summary, all 45 patients in this group reported symptomatic improvement on a strict GFD, with 27/45 having demonstrable histological improvement.
Eleven patients were treated successfully for microscopic colitis. Diagnosis was made based on the presence of diarrhea and typical colonic histological features. All of these patients underwent simultaneous small bowel biopsy which was abnormal in 7/11 (64%) cases, mainly with an isolated intra-epithelial lymphocytosis. No alternative cause was established on enquiry or testing. These individuals were treated with a combination of mesalazine, loperamide, prednisolone and azathioprine (1-2.5 mg/kg). Five out of 11 required azathioprine for resolution of symptoms. Three patients suffered a relapse of diarrhea within 2 years; again treated successfully with oral steroids. When abnormal, patients had comparative improvement in their duodenal histology following resolution of symptoms. We performed a total of 75 colonoscopies in NRCD patients with diarrhea and found significant lymphocytic infiltration in 15. This included four patients defined as having RCD who did not show histological or clinical improvement with immunosuppressive treatment.
Nine patients were successfully diagnosed and treated for bacterial overgrowth with sustained resolution of symptoms. There have been two relapses both in the same patient within 2 years; responding on each occasion to further courses of antibiotic treatment (metronidazole and ciprofloxacin). Interestingly, one patient was found to have combined variable immunodeficiency as an underlying cause for bacterial overgrowth and was referred for immunoglobulin infusions as part of further management.
Ten patients had normal investigations (all had duodenal biopsy and colonoscopy). This group was reassured and treated symptomatically for irritable bowel syndrome. At review after 2 years, 5/10 had continued functional symptoms with no new positive investigations. One patient had been diagnosed empirically with lactose intolerance. The remaining four patients were symptom free.
Lactose intolerance was diagnosed in six individuals; all of whom had dramatic symptomatic resolution when a lactose-free diet was commenced. All of these patients had primary NRCD.
We identified seven patients with coexisting inflammatory bowel disease (IBD); all of whom were suffering from ulcerative colitis. The predominant pattern was proctitis in five patients, and two had sigmoid colitis. Six responded to 5-ASA therapies, and one required azathioprine to control their IBD. All remained well and no surgical intervention has been required at 2 years follow-up.
After initial assessment and duodenal biopsy, 20 patients were considered to have a high suspicion of RCD. All of these patients had weight loss and diarrhea and a history of positive correlative celiac serology. After exhaustive investigation and assessment according to the United European Gastroenterology Week guidelines[11
] (median duration 5 mo), a firm diagnosis of RCD was made in 9/20 patients; all of whom had a raised IEL count (> 20 per 100 enterocytes). Furthermore, all had marked villous atrophy (Marsh IIIa-c). None of this group was found to have a positive anti-enterocyte antibody. An alternative and remediable explanation for symptoms was identified in 11 patients (seven continued gluten ingestion; three with bacterial overgrowth; and one with microscopic colitis). RCD may be divided into those without aberrant T cells (type I) and those with aberrant T cells or ulcerative jejunitis (type II)[11
]. Of the nine refractory patients, seven had type II RCD with positive clonality by γ TCR PCR. Three had ulcerative jejunitis; four were found to have or developed an enteropathy-associated intestinal lymphoma, two of whom have subsequently died, one from proven EATL and the other from suspected EATL (a post-mortem was refused by the relatives); both survived less than 1 year from diagnosis. The other two patients remain alive; one is on immunosuppressive medication and the other has been successfully treated with surgery. The remaining patients have continued to have symptoms over the follow-up period of 2 years (median 33 mo).
Of the two patients with type I RCD, one has died but we have no information available as to the precise cause of death, and the other patient has continued to have symptoms over the follow-up period of 2 years. In summary 3/9 (33%) patients diagnosed with RCD in our study have died.
Other diagnoses that were established are listed in Table . A diagnosis was only included if the symptoms were clearly attributable and symptomatic improvement occurred with appropriate treatment. Ten patients had more than one diagnosis established during the study period (median 33 mo). This was largely as a result of ongoing investigation for additional symptoms during the study period.
Summary of established diagnosis in 100 patients referred to our center with non-responsive celiac disease
Further assessment of patients’ symptoms was conducted 2 years after their initial evaluation. Overall, four patients had died, with one from an unrelated cause. The vast majority (78%) reported being symptom-free at 2 years. A total of eight patients reported continued symptoms, with four describing them as moderate or severe. Those with continued symptoms included four diagnosed with RCD, two with irritable bowel syndrome and two with microscopic colitis. Ten patients could not be contacted.
In the 100 patients with NRCD, 73% had detectable anti-tissue transglutaminase (tTG) antibodies at varying titers. There was no statistical correlation between presence of antibodies, antibody titer and the established cause of NRCD. However, it was noted that 9/20 patients with RCD had positive celiac serological tests.