Histology of the terminal ileum in coeliac disease

Background: The histological lesion of gluten sensitivity primarily affects the proximal small bowel. The purpose of this study was to assess whether there were features of gluten‐sensitive enteropathy in biopsies taken from the terminal ileum during colonoscopy/ileoscopy. Specific and sensitive abnormalities might facilitate diagnosis of coeliac disease in patients undergoing colonoscopy as their initial procedure or help select those who should proceed to upper gastrointestinal endoscopy and duodenal biopsy. Methods: Terminal ileal biopsies, taken from 30 patients with duodenal villous atrophy consistent with coeliac disease and from 60 control patients with no evidence of coeliac or inflammatory bowel disease, were reviewed blindly and compared. Biopsies were assessed for the presence or absence of villous atrophy and crypt hyperplasia, and counts were made of intraepithelial lymphocytes (IELs). Results: One patient only, in the coeliac group, had partial villous atrophy with crypt hyperplasia in the terminal ileum. IEL counts were significantly higher (P?Conclusions: Coeliac disease may affect the entire small bowel. Increased IEL density in the terminal ileum is associated with duodenal VA and should prompt a search for coeliac disease by serology and duodenal biopsy. Conversely, a normal IEL count does not allow the exclusion of coeliac disease with confidence.     

Predisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis

OBJECTIVE: To assess the presence of both genetic and serological markers of coeliac disease in patients with microscopic colitis, and whether there was associated enteropathy. METHODS: HLA-DQ2, HLA-DQ8, serum immunoglobulin A-antiendomysial and immunoglobulin A-anti-tissue transglutaminase antibodies were investigated in 59 patients with microscopic colitis. Seventy healthy subjects acted as the control group. Endoscopic biopsies from the distal duodenum were obtained in DQ2-positive or DQ8-positive patients. Patients with histological changes compatible with gluten-sensitive enteropathy were started on a gluten-free diet. RESULTS: Seventeen of 70 (24.3%) healthy controls were DQ2-positive. Twelve of 25 (48%) patients with lymphocytic colitis (P = 0.027 versus controls), and 11 of 34 (32.3%) with collagenous colitis (P = 0.38 versus controls) were DQ2-positive. There were no differences in the frequency of DQ8-positivity. The coeliac serology was positive in one patient. Duodenal biopsies were performed in 23 DQ2-positive and/or DQ8-positive patients. None had villous atrophy (Marsh III lesion) (0%; 95% confidence interval, 0-6.1). A Marsh type I lesion was found in four patients. Three of these patients were put on a gluten-free diet with disappearance of diarrhoea. CONCLUSIONS: The results suggest that there is an association of lymphocytic colitis with HLA-DQ2 genes, which might be relevant in the pathogenesis of this disease. The association of microscopic colitis with Marsh type III coeliac disease seems to be rare, making it unnecessary to routinely screen for coeliac disease in microscopic colitis patients.     

Histology of the terminal ileum in coeliac disease

BACKGROUND: The histological lesion of gluten sensitivity primarily affects the proximal small bowel. The purpose of this study was to assess whether there were features of gluten-sensitive enteropathy in biopsies taken from the terminal ileum during colonoscopy/ileoscopy. Specific and sensitive abnormalities might facilitate diagnosis of coeliac disease in patients undergoing colonoscopy as their initial procedure or help select those who should proceed to upper gastrointestinal endoscopy and duodenal biopsy. METHODS: Terminal ileal biopsies, taken from 30 patients with duodenal villous atrophy consistent with coeliac disease and from 60 control patients with no evidence of coeliac or inflammatory bowel disease, were reviewed blindly and compared. Biopsies were assessed for the presence or absence of villous atrophy and crypt hyperplasia, and counts were made of intraepithelial lymphocytes (IELs). RESULTS: One patient only, in the coeliac group, had partial villous atrophy with crypt hyperplasia in the terminal ileum. IEL counts were significantly higher (P< 0.005) in the coeliac group than among controls (mean per 100 enterocytes 26 versus 10). An ileal IEL count > or =25 had a sensitivity for duodenal villous atrophy (VA) of 60% and specificity of 100%. CONCLUSIONS: Coeliac disease may affect the entire small bowel. Increased IEL density in the terminal ileum is associated with duodenal VA and should prompt a search for coeliac disease by serology and duodenal biopsy. Conversely, a normal IEL count does not allow the exclusion of coeliac disease with confidence.     

Gluten challenge in borderline gluten-sensitive enteropathy

OBJECTIVES: In patients with signs and symptoms of malabsorption, suggestive of gluten-sensitive enteropathy, small intestinal biopsies sometimes only reveal infiltration of lymphocytes into the mucosal epithelium. This infiltrative lesion (Marsh I) is not a definite proof for gluten-sensitive enteropathy. However, in the present study, we aimed to show that a subgroup of these patients could ultimately be identified as being gluten sensitive. METHODS: A total of 38 patients with a Marsh I lesion were subjected to a gluten challenge comprising 30 g of gluten added daily to a normal gluten-containing diet for 8 wk. Before and after the challenge, small intestinal biopsies were taken, and symptoms and signs of malabsorption were scored. RESULTS: In 12 patients we demonstrated a significant change in mucosal histopathology, i.e., subtotal villous atrophy (Marsh IIIB, n = 1), partial villous atrophy (Marsh 3A, n = 6) or infiltrative-crypthyperplastic lesions (Marsh II, n = 5). In the other 26 patients, the small intestinal mucosa remained unchanged. After initiation of a gluten-free diet, follow-up small intestinal biopsies in 12 patients who initially had progressive mucosal pathology after gluten challenge showed normalization of mucosal pathology in seven cases, regression to a Marsh I lesion in four, and to a Marsh II lesion in one. Symptom relief was seen in all 12 patients. Ten of 26 patients without histological response to the gluten challenge were motivated to adhere to a gluten-free diet. Follow-up biopsies revealed unchanged Marsh I lesions in eight patients and normalization (Marsh 0) in two patients. Three patients had follow-up biopsies while on a normal diet. All had unchanged Marsh I lesions. CONCLUSIONS: In the present study we demonstrated that a gluten challenge might be useful in identifying patients as being sensitive to gluten if initial small intestinal biopsies reveal only minor abnormalities.     

Spectrum of gluten-sensitive enteropathy in first-degree relatives of patients with coeliac disease: clinical relevance of lymphocytic enteritis

BACKGROUND: Limited data on a short series of patients suggest that lymphocytic enteritis (classically considered as latent coeliac disease) may produce symptoms of malabsorption, although the true prevalence of this situation is unknown. Serological markers of coeliac disease are of little diagnostic value in identifying these patients. AIMS: To evaluate the usefulness of human leucocyte antigen-DQ2 genotyping followed by duodenal biopsy for the detection of gluten-sensitive enteropathy in first-degree relatives of patients with coeliac disease and to assess the clinical relevance of lymphocytic enteritis diagnosed with this screening strategy. PATIENTS AND METHODS: 221 first-degree relatives of 82 DQ2+ patients with coeliac disease were consecutively included. Duodenal biopsy (for histological examination and tissue transglutaminase antibody assay in culture supernatant) was carried out on all DQ2+ relatives. Clinical features, biochemical parameters and bone mineral density were recorded. RESULTS: 130 relatives (58.8%) were DQ2+, showing the following histological stages: 64 (49.2%) Marsh 0; 32 (24.6%) Marsh I; 1 (0.8%) Marsh II; 13 (10.0%) Marsh III; 15.4% refused the biopsy. 49 relatives showed gluten sensitive enteropathy, 46 with histological abnormalities and 3 with Marsh 0 but positive tissue transglutaminase antibody in culture supernatant. Only 17 of 221 relatives had positive serological markers. Differences in the diagnostic yield between the proposed strategy and serology were significant (22.2% v 7.2%, p<0.001). Relatives with Marsh I and Marsh II-III were more often symptomatic (56.3% and 53.8%, respectively) than relatives with normal mucosa (21.1%; p = 0.002). Marsh I relatives had more severe abdominal pain (p = 0.006), severe distension (p = 0.047) and anaemia (p = 0.038) than those with Marsh 0. The prevalence of abnormal bone mineral density was similar in relatives with Marsh I (37%) and Marsh III (44.4%). CONCLUSIONS: The high number of symptomatic patients with lymphocytic enteritis (Marsh I) supports the need for a strategy based on human leucocyte antigen-DQ2 genotyping followed by duodenal biopsy in relatives of patients with coeliac disease and modifies the current concept that villous atrophy is required to prescribe a gluten-free diet.     

Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet.

Numbers of T cell receptor (TcR) gamma delta+ and alpha beta+ intestinal lymphocytes were studied in 34 coeliac patients in respect of their diet and the grade of villous atrophy. Particular attention was given to a group of 21 patients with coeliac disease according to ESPGAN criteria who were on a well tolerated long term normal diet and in nine of whom the mucosa had returned to normal or nearly normal. A significant increase in TcR gamma delta+ cells was observed in the gut epithelium of coeliac patients compared with age matched controls, and this did not correlate with either the presence of gluten in the diet or with the grade of villous atrophy. Thus, numbers of TcR gamma delta+ intraepithelial lymphocytes (IEL) were considerably above the normal range in four of seven patients on a gluten free diet and in four of nine patients who had recovered a normal or nearly normal mucosa in spite of a normal diet. In contrast, numbers of intestinal TcR alpha beta+ cells varied with the stage of the disease. Their number was high in the epithelium of patients with active coeliac disease (n = 18) but significantly less in patients whose mucosa had returned to normal or nearly normal either after gluten free diet (n = 7) or in spite of a normal diet (n = 9). Immunohistochemical markers of intestinal mononuclear cell activation detected in active coeliac disease were either weakly expressed or absent in the latter patients. It is suggested that TcR alpha beta+ but not TcR gamma delta+ IEL are sensitised to gliadin in coeliac disease, and that only the former cells play a direct part in the pathogenesis of the villous atrophy. The normal counts of TcR alpha beta+ IEL and the absence of detectable mononuclear activation in the biopsy specimens of a few patients who have recovered clinical and histological tolerance to gluten sustains this hypothesis and also suggests that immunological tolerance to gluten may be acquired in a subgroup of coeliac patients. Hte appreciable increase in TcR gamma delta+ IEL observed in some of the latter patients, however, is similar to that observed in latent coeliac disease urging for their careful and prolonged follow up until the role of TcR gamma delta+ IEL in the pathogenesis of coeliac disease is elucidated.     

No harm from five year ingestion of oats in coeliac disease

BACKGROUND: Six to 12 months of ingestion of moderate amounts of oats does not have a harmful effect in adult patients with coeliac disease. As the safety of long term intake of oats in coeliac patients is not known, we continued our previous 6-12 month study for five years. AIM: To assess the safety of long term ingestion of oats in the diet of coeliac patients. PATIENTS: In our previous study, the effects of a gluten free diet and a gluten free diet including oats were compared in a randomised trial involving 92 adult patients with coeliac disease (45 in the oats group, 47 in the control group). After the initial phase of 6-12 months, patients in the oats group were allowed to eat oats freely in conjunction with an otherwise gluten free diet. After five years, 35 patients in the original oats group (23 still on an oats diet) and 28 in the control group on a conventional gluten free diet were examined. METHODS: Clinical and nutritional assessment, duodenal biopsies for conventional histopathology and histomorphometry, and measurement of antiendomysial, antireticulin, and antigliadin antibodies. RESULTS: There were no significant differences between controls and those patients consuming oats with respect to duodenal villous architecture, inflammatory cell infiltration of the duodenal mucosa, or antibody titres after five years of follow up. In both groups histological and histomorphometric indexes improved equally with time. CONCLUSIONS: This study provides the first evidence of the long term safety of oats as part of a coeliac diet in adult patients with coeliac disease. It also appears that the majority of coeliac patients prefer oats in their diet.     

Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease

BACKGROUND AND AIM: Both the clinical presentation and the degree of mucosal damage in coeliac disease vary greatly. In view of conflicting information as to whether the mode of presentation correlates with the degree of villous atrophy, we reviewed a large cohort of patients with coeliac disease. PATIENTS AND METHODS: We correlated mode of presentation (classical, diarrhoea predominant or atypical/silent) with histology of duodenal biopsies and examined their trends over time. RESULTS: The cohort consisted of 499 adults, mean age 44.1 years, 68% females. The majority had silent coeliac disease (56%) and total villous atrophy (65%). There was no correlation of mode of presentation with the degree of villous atrophy (p=0.25). Sixty-eight percent of females and 58% of males had a severe villous atrophy (p=0.052). There was a significant trend over time for a greater proportion of patients presenting as atypical/silent coeliac disease and having partial villous atrophy, though the majority still had total villous atrophy. CONCLUSIONS: Among our patients the degree of villous atrophy in duodenal biopsies did not correlate with the mode of presentation, indicating that factors other than the degree of villous atrophy must account for diarrhoea in coeliac disease.     

Coeliac disease: more than villous atrophy

A continuing flow of new scientific developments concerning coeliac disease in the last decade asks for the formulation of a new concept of pathophysiology and clinical approach of the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6. Immunological research has led to the concept of a T-cell driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies, and in addition the understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs and the disease may present with less severe symptoms of malabsorption while screening studies suggest an overall prevalence of up to 1 in 200-300. In the present paper (an update on histopathology) we specifically describe the work of our group in Arnhem, concerning the identification and validation of the spectrum of intestinal histopathology in gluten sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypthyperplasia (Marsh II lesion), and villous atrophy, subdivided in partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of "refractory coeliacs", including the identification of (pre-) malignant aberrant T-cells in the intestinal mucosa of these patients. The new data on immunogenetics, epidemiology, histo-pathology and patient characteristics point to a significant change of views on coeliac disease.     

Coeliac disease diagnosed by means of duodenoscopy and endoscopic duodenal biopsy

Nineteen patients with suspected coeliac disease were examined by duodenoscopy and biopsy. In all patients a histopathology consistent with coeliac disease was demonstrated in endoscopic biopsies of the duodenal mucosa. On close-up view villous atrophy was seen in vivo. Fourteen patients were re-examined on a gluten-free diet. In 13 patients a restitution of the duodenal mucosa was shown. Duodenoscopy combined with biopsy seems to be a reliable method for the assessment of the mucosal change in coeliac disease.     

Chronic non-specific ulcerative duodenojejunoileitis: report of four cases.

Four patients with chronic non-specific ulcerative duodenojejunoileitis (CNSUDJI) are reported. The clinical picture included abdominal pain, fever, and a malabsorption syndrome. Main rediological findings were diffuse narrowing of the jejunal loops with total effacement of the mucosal folds. Multiple peroral biopsies of the small intestine showed various degrees of mucosal abnormalities from total villous atrophy to normal villi, but ulcerations were diagnosed only by operative full thickness biopsies or resection of the small bowel. The ulcerative process was associated with well-documented coeliac disease in two patients: in one of them it occurred as a fatal complication involving also the colon, three years after the start of a gluten free diet, while the disease was in full clinical and histological remission. In the other case, coeliac disease was revealed by obstructive symptoms due to stenosing ulcerations; five months after surgical resection of the stenosis, institution of a gluten free diet induced a dramatic improvement. In the two other patients ulcerations were not associated with coeliac disease: one of them had a patchy villous atrophy and resisted a gluten free diet and total parenteral nutrition; she was improved by and dependent upon steroids but finally died. The last patient had normal villous height; ulcerations were located exclusively along the mesenteric border of the small bowel; he had a low-grade protracted evolution resisting any form of therapy and developed a peripheral neuropathy of unknown aetiology. On the basis of our cases and of a review of the literature the discussion focuses on the difficulty in diagnosing CNSUDJI, its relationship with coeliac disease, and its management and prognosis.     

Effect of a gluten-free diet on growth and small-bowel histology in children with celiac disease in India

BACKGROUND AND AIM: Follow-up studies on growth and histological recovery of children with celiac disease (CD) while on a gluten-free diet (GFD) are lacking from Asia. We therefore assessed the effects of this diet. METHODS: Forty-two children with CD were enrolled. Weight and height were expressed as weight for height (WfH) and height standard deviation scores (HSDS), respectively. Twenty-five children had repeated duodenal biopsies after 1-2 years and 14 had a third biopsy after 3-7 years of GFD. Compliance was checked by regular interview and IgA antiendomysial antibody estimation (EMA). RESULTS: At diagnosis (n = 25), mean HSDS was -3.3 +/- 1.6 with 76% having a HSDS of <-2; 60% were undernourished (WfH mean 81.6 +/- 5.7). Over a mean follow up of 3.7 years, HSDS improved to -1.3 +/- 1.7 and 84% cases achieved normal nutrition. Mean height velocity was 13.9 cm during first year and 5.6 cm in subsequent years. Small-bowel biopsies at diagnosis showed subtotal villous atrophy (Marsh IIIb) in 18 (72%) and partial villous atrophy (Marsh IIIa) in seven (28%) patients. Repeat biopsy at 1-2 years showed shift from subtotal to partial villous atrophy in 94% (n = 17/18) and normalization in one patient. In patients with Marsh IIIa improvement of partial villous atrophy was observed in all. Immunoglobulin A endomysial antibody was negative in 81%. Repeat biopsies at 5 years of GFD showed improvement to Marsh I-II, but none normalized. CONCLUSION: The majority of children with CD show normalization of nutrition and growth after GFD. Small-bowel histology improves markedly but does not normalize even after 5 years of GFD.     

The occurrence of terminal ileal histological abnormalities in patients with coeliac disease

INTRODUCTION: Coeliac disease causes histological changes throughout the small bowel, but is often a proximal lesion. We wanted to assess whether terminal ileal histological abnormalities occurred more commonly in patients with coeliac disease and if specific assessment of intraepithelial lymphocytes increases the recognition of undiagnosed coeliac disease. METHODS: Terminal ileal biopsies were prospectively examined over a 3-year period (April 2001-May 2004). Patients were included if they were found to have a synchronous duodenal biopsy that gave a new diagnosis of coeliac disease (n=20). Terminal ileal biopsies taken at colonoscopy during the same period were also examined from four groups of patients: coeliac disease established on a gluten-free diet but with persisting symptoms (n=25), inflammatory bowel disease (n=47), chronic diarrhoea (n=44) and polyp surveillance (n=47). All biopsies were graded according to the Marsh criteria and an intraepithelial lymphocytes count per 100 enterocytes was obtained. RESULTS: There was only one patient from all five groups who had villous atrophy of the terminal ileal. This patient had a new diagnosis of coeliac disease. The mean intraepithelial lymphocytes count in the coeliac disease group was 23.7 intraepithelial lymphocytes/100 enterocytes. This was significantly higher than the control groups: coeliac disease on a gluten-free diet=17.5 (p<0.012), inflammatory bowel disease=12.3 (p<0.0001), diarrhoea=12.6 (p<0.0001) and polyp=13.7 (p<0.0002). Validating terminal ileal villous intraepithelial lymphocytes counts as a test for coeliac disease using an intraepithelial lymphocytes/100 enterocytes of >25 gives a sensitivity of 45% and a specificity of 97.8%. CONCLUSION: Routinely quantifying terminal ileal intraepithelial lymphocytes may be of limited clinical value. However, subjective recognition of raised intraepithelial lymphocytes on a terminal ileal biopsy should alert the clinician to the possibility of coeliac disease.     

Reintroduction of gluten in adults and children with treated coeliac disease.

Twenty-eight patients, thought to have coeliac disease and on gluten free diets, were put on a normal diet to confirm their diagnoses. Nineteen had been diagnosed in adult life (ACD) and nine in childhood (CCD). Patients were assessed on jejunal, morphological, and symptomatic parameters. Eighteen patients with ACD relapsed within seven weeks. Nine patients with CCD relapsed at variable times but five took longer than seven weeks, the longest period beint 10 months. Seven patients had no symptoms despite morphological deterioration during challenge and one patient, with ACD, did not relapse and was HLA B8 negative. This patient with ACD had subtotal villous atrophy on two jejunal biopsies and later showed morphological improvement on a gluten free diet. There was no correlation between the relapse time and time spent on a gluten free diet.     

Endoscopic resection of giant gastrointestinal stromal tumor at the esophagogastric junction: a case report

Background

There is an unmet need for novel treatments, such as drugs or vaccines, adjunctive to or replacing a burdensome life-long gluten-free diet for coeliac disease. The gold standard for successful treatment is a healed small intestinal mucosa, and therefore, the outcome measures in proof-of-concept studies should be based on evaluation of small intestine biopsies. We here evaluated morphometric, immunohistochemical and messenger RNA (mRNA) expression changes in coeliac disease patients challenged with gluten using PAXgene fixed paraffin-embedded biopsies.

Methods

Fifteen coeliac disease patients were challenged with 4 g of gluten per day for 10 weeks and 24 non-coeliac patients served as disease controls. A wide array of histological and immunohistochemical staining and mRNA-based gene expression tests (RT-qPCR and RNAseq) were carried out.

Results

Digital quantitative villous height: crypt depth ratio (VH: CrD) measurements revealed significant duodenal mucosal deterioration in all coeliac disease patients on gluten challenge. In contrast, the Marsh-Oberhuber class worsened in only 80% of coeliac patients. Measuring the intraepithelial CD3⁺ T-lymphocyte and lamina propria CD138⁺ plasma cell densities simultaneously proved to be a meaningful new measure of inflammation. Stainings for γδ T cells and IgA deposits, where previously frozen samples have been needed, were successful in PAXgene fixed paraffin-embedded samples. Messenger RNA extraction from the same paraffin-embedded biopsy block was successful and allowed large-scale qRT-PCR and RNAseq analyses for gene expression. Molecular morphometry, using the mRNA expression ratio of villous epithelium-specific gene APOA4 to crypt proliferation gene Ki67, showed a similar significant distinction between paired baseline and post-gluten challenge biopsies as quantitative histomorphometry.

Conclusion

Rigorous digitally measured histologic and molecular markers suitable for gluten challenge studies can be obtained from a single paraffin-embedded biopsy specimen. Molecular morphometry seems to be a promising new tool that can be used in situations where assessing duodenal mucosal health is of paramount importance. In addition, the diagnostically valuable IgA deposits were now stained in paraffin-embedded specimens making them more accessible in routine clinics.

     

Continuous Infusion of Cholecystokinin Leads to Down-Regulation of the Cholecystokinin-A Receptor in the Rat Pancreas

Background: Coeliac disease may present with dyspepsia or reflux. There are characteristic duodenal appearances associated with villous atrophy (mosaic pattern mucosa and loss, reduction in number or scalloping of duodenal folds) which may prompt small-bowel biopsy during routine upper gastrointestinal endoscopy. These appearances were sought in patients referred by their general practitioners for open-access endoscopy (OAE), to determine the prevalence and significance of coeliac disease as a cause of symptoms. Methods: Five hundred consecutive patients undergoing OAE by one consultant gastroenterologist were studied. Forceps biopsy specimens from the distal duodenum were taken if appearances were suggestive. If villous atrophy was confirmed, the response of symptoms to dietary gluten exclusion was assessed. Results: Ten patients had suggestive endoscopic appearances, of whom eight had villous atrophy, giving a prevalence of coeliac disease of 1.6% (1:63). All eight had mosaic pattern mucosa, with three also having reduction of duodenal folds, and four having scalloped folds. All had serum endomysial antibodies (EmA). Apart from diarrhoea, described by one patient, there were no symptoms of `typical' coeliac disease at diagnosis: three patients were overweight. After dietary gluten exclusion all reported symptomatic improvement, with disappearance of EmA in five patients to date. Conclusions: There is a high prevalence of coeliac disease among patients undergoing OAE, which is relevant to their clinical symptoms and which can be identified by careful endoscopic inspection of the duodenum.     

Persistent Mucosal Abnormalities in Coeliac Disease Are Not Related to the Ingestion of Trace Amounts of Gluten

Background: It is expected that in patients with coeliac disease the small-bowel mucosal mucosa will return to normal if they adhere to a gluten-free diet (GFD). However, in many this is not the case. This study aims to determine whether this persistent villous atrophy (VA) could be due to continued ingestion of the trace amounts of gluten in `gluten-free' foods, as defined by the WHO/FAO Codex Alimentarius. Methods: Duodenal biopsy specimens from 89 adults with long-standing coeliac disease were examined, and the findings correlated with their form of gluten-free diet. Results: In 51 subjects the duodenal specimen was normal, whereas in 38 there was villous atrophy (partial, 28; subtotal, 8; total, 2). There was no relationship between the presence or absence of VA and ingestion of either a GFD as defined by the Codex Alimentarius (Codex-GFD; 39 patients) or a GFD that contained no detectable gluten (NDG diet; 50 patients). Intraepithelial lymphocyte counts were higher, and lactase levels lower, in subjects with an abnormal biopsy specimen than in those in whom it was normal. However, within each of these biopsy groups there was no difference in these variables between patients on a Codex-GFD and those on an NDG-GFD. IgA antigliadin antibody was detected in 4 of 29 patients on a Codex-GFD and in 3 of 13 on a NDG-GFD (NS). Conclusion: The persistent mucosal abnormalities seen in patients with coeliac disease on a GFD are not due to the ingestion of trace amounts of gluten. The consequences of these abnormalities have yet to be determined.     

Persistent mucosal abnormalities in coeliac disease are not related to the ingestion of trace amounts of gluten.

BACKGROUND: It is expected that in patients with coeliac disease the small-bowel mucosal mucosa will return to normal if they adhere to a gluten-free diet (GFD). However, in many this is not the case. This study aims to determine whether this persistent villous atrophy (VA) could be due to continued ingestion of the trace amounts of gluten in 'gluten-free' foods, as defined by the WHO/FAO Codex Alimentarius. METHODS: Duodenal biopsy specimens from 89 adults with long-standing coeliac disease were examined, and the findings correlated with their form of gluten-free diet. RESULTS: In 51 subjects the duodenal specimen was normal, whereas in 38 there was villous atrophy (partial, 28; subtotal, 8; total, 2). There was no relationship between the presence or absence of VA and ingestion of either a GFD as defined by the Codex Alimentarius (Codex-GFD; 39 patients) or a GFD that contained no detectable gluten (NDG diet: 50 patients). Intraepithelial lymphocyte counts were higher, and lactase levels lower, in subjects with an abnormal biopsy specimen than in those in whom it was normal. However, within each of these biopsy groups there was no difference in these variables between patients on a Codex-GFD and those on an NDG-GFD. IgA antigliadin antibody was detected in 4 of 29 patients on a Codex-GFD and in 3 of 13 on a NDG-GFD (NS). CONCLUSION: The persistent mucosal abnormalities seen in patients with coeliac disease on a GFD are not due to the ingestion of trace amounts of gluten. The consequences of these abnormalities have yet to be determined.     

Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: a prospective and randomized clinical study

OBJECTIVE: In coeliac disease, autoantibodies directed against transglutaminase 2 are produced in small-bowel mucosa, and they have been found to be deposited extracellularly. The aim of this study was to investigate whether such mucosal IgA deposits are important in the diagnostic work-up of early-stage coeliac disease without small-bowel mucosal villous atrophy. MATERIAL AND METHODS: Forty-one adults suspected of coeliac disease owing to increased density of mucosal gamma(delta)+ intraepithelial lymphocytes but normal villous morphology were randomized to gluten challenge or a gluten-free diet for 6 months. Clinically and histologically verified gluten dependency was compared with existence of small-bowel mucosal transglutaminase 2-specific extracellular IgA deposits and (coeliac disease-type) HLA DQ2 and DQ8; 34 non-coeliac subjects and 18 patients with classical coeliac disease served as controls. RESULTS: Of the 41 patients, 5 in the challenge group and 6 in the gluten-free diet group were clinically gluten sensitive; all 11 had HLA DQ2 or DQ8. Ten of these 11 patients showed transglutaminase 2-targeted mucosal IgA deposits, which were dependent on gluten consumption. Minimal IgA deposits were seen in only 3 out of 30 patients with suspected coeliac disease without any clinically detected gluten dependency. The deposits were found in all classical coeliac patients and in none of the non-coeliac control subjects. CONCLUSIONS: Clinically pertinent coeliac disease exists despite normal small-bowel mucosal villous architecture. Mucosal transglutaminase 2-specific IgA deposits can be utilized in detecting such patients with genetic gluten intolerance.     

Capsule endoscopy: An alternative to duodenal biopsy for the recognition of villous atrophy in coeliac disease?

BACKGROUND: Villous atrophy present on a duodenal biopsy remains the 'gold standard' diagnostic test for coeliac disease. However, endoscopic biopsy may cause morbidity and discomfort. Our aim was to evaluate wireless capsule endoscopy as an alternative test for the recognition of villous atrophy. METHOD: Twenty-one patients with a positive endomysial antibody referred for endoscopy and duodenal biopsy were also offered a wireless capsule endoscopy to evaluate their small bowel. Concurrently, other patients (n=23) referred for a wireless capsule endoscopy acted as controls. Wireless capsule endoscopy reports were assessed for the presence of villous atrophy by one blinded investigator. RESULTS: Twenty endomysial antibody positive patients subsequently had villous atrophy on duodenal biopsy. The controls all had normal duodenal biopsies (with a negative endomysial antibody) and no evidence of villous atrophy noted on their wireless capsule endoscopy. Of the 20 endomysial antibody positive patients with confirmed villous atrophy on biopsy, 17 had villous atrophy also detected by wireless capsule endoscopy. The sensitivity, specificity, positive and negative predictive values for wireless capsule endoscopy recognising villous atrophy were 85%, 100%, 100%, 88.9%, respectively. CONCLUSION: Wireless capsule endoscopy may be an option to recognise villous atrophy in patients with a positive endomysial antibody who are unwilling, or unable to have a gastroscopy. However, a negative test should be followed by a biopsy if coeliac disease is to be excluded.