Gastrointestinal Symptoms Rating Scale in Coeliac Disease Patients on Wheat Starch-based Gluten-free Diets

Background: A wheat starch-based gluten-free diet is widely adopted in the treatment of coeliac disease, even though the products contain trace amounts of gluten. The aim here was to establish whether such a diet sustains abdominal symptoms. Methods: The Gastrointestinal Symptom Rating Scale (GSRS) was applied to 58 coeliac disease patients on gluten-free diets and 110 non-coeliac controls. An estimate was made of daily dietary fibre and wheat starch-derived gluten. Psychological well-being was evaluated by a structured interview. Twenty-three coeliac patients consented to small-bowel biopsy. Results: The mean GSRS score in coeliac disease patients did not differ from that in control subjects. Poorer psychological well-being was associated with abdominal symptoms in coeliac patients, whereas the daily amount of wheat starch had no effect on GSRS score. Overall dietary compliance was good, and villous atrophy was found in only 2 out of 23 patients. The average fibre consumption, 13 g per day, was lower than recommended. Conclusions: Wheat starch-based gluten-free products are well-tolerated in coeliac disease patients, provided that their diets are otherwise strict.     

Wheat starch-containing gluten-free flour products in the treatment of coeliac disease and dermatitis herpetiformis. A long-term follow-up study

BACKGROUND: We investigated whether wheat starch-based gluten-free products are safe in the treatment of gluten intolerance. METHODS: The study involved 41 children and adults with coeliac disease and 11 adults with dermatitis herpetiformis adhering to a gluten-free diet for 8 years on average. Thirty-five newly diagnosed coeliac patients at diagnosis and 6 to 24 months after the start of a gluten-free diet and 27 non-coeliac patients with dyspepsia were investigated for comparison. Daily dietary gluten and wheat starch intake were calculated. Small-bowel mucosal villous architecture, CD3+, alphabeta+, and gammadelta+ intraepithelial lymphocytes, mucosal HLA-DR expression, and serum endomysial, reticulin, and gliadin antibodies were investigated. RESULTS: Forty of 52 long-term-treated patients adhered to a strict wheat starch-based diet and 6 to a strict naturally gluten-free diet; 6 patients had dietary lapses. In the 46 patients on a strict diet the villous architecture, enterocyte height, and density of alphabeta+ intraepithelial lymphocytes were similar to those in non-coeliac subjects and better than in short-term-treated coeliac patients. The density of gammadelta(+)cells was higher, but they seemed to decrease over time with the gluten-free diet. Wheat starch-based gluten-free flour products did not cause aberrant upregulation of mucosal HLA-DR. The mucosal integrity was not dependent on the daily intake of wheat starch in all patients on a strict diet, whereas two of the six patients with dietary lapses had villous atrophy and positive serology. CONCLUSION: Wheat starch-based gluten-free flour products were not harmful in the treatment of coeliac disease and dermatitis herpetiformis.     

Consumption of gluten-free products: should the threshold value for trace amounts of gluten be at 20, 100 or 200 p.p.m.?

OBJECTIVE: The threshold of gluten contamination in gluten-free products of both dietary and normal consumption is under debate. The objective of this study was to gather information on consumption of gluten-free products intended for dietary use of people under a gluten-free diet. This information is essential to ascertain the exposure of coeliac patients to gluten through their diet and deduce the maximum gluten content that these products should contain to guarantee a safe diet. METHODS: A diet diary of consumption of gluten-free products intended for dietary use was distributed to the coeliac societies of two typical Mediterranean countries (Italy and Spain) and two Northern countries (Norway and Germany). The diet diary included a self-weigh table of the selected food items and a 10-day consumption table. Results were reported in percentiles as distributions were clearly right skewed. RESULTS: The respondents included in the study accounted for 1359 in Italy, 273 in Spain, 226 in Norway and 56 in Germany. Gluten-free products intended for dietary use contributed significantly to the diet of coeliac patients in Italy, Germany and Norway and to a lesser degree in Spain. The most consumed gluten-free product in all countries was bread, and it was double consumed in the Northern countries (P<0.001). Mediterranean countries showed consumption of a wider variety of gluten-free foods and pasta was eaten to a large degree in Italy. CONCLUSIONS: The differences between Northern and Mediterranean countries were not in the total amount of gluten-free products but in the type of products consumed. The observed daily consumption of gluten-free products results in the exposure to rather large amounts of gluten, thus the limit of 200 p.p.m. should be revised. A limit of 20 p.p.m. for products naturally gluten-free and of 100 p.p.m. for products rendered gluten-free is proposed to guarantee a safe diet and to enable coeliac patients to make an informed choice. These limits should be revised as new data become available.     

Coeliac disease in Middle Eastern countries: a challenge for the evolutionary history of this complex disorder?

About 10,000 years ago domestication and farming of wheat and other cereals developed in the 'Fertile Crescent', an area including modern Turkey, Iraq and Iran. Agriculture then slowly spread from Middle East to Europe. Coeliac disease is the permanent intolerance to dietary gluten, the major protein component of wheat. It has been until relatively recently hypothesised that wheat consumption exerted a negative selective pressure on genes predisposing to coeliac disease, eventually leading to higher coeliac disease frequency in Northeastern Europe because of lack of exposure to cereals. This theory is at variance with recent studies showing that coeliac disease is as common in Middle Eastern countries as in Europe. High prevalence of coeliac disease has been found in Iran, in both the general population and at-risk groups, e.g. patients with irritable bowel syndrome or type 1 diabetes. Clinical manifestations of coeliac disease vary markedly with the age of the patient, the duration and the extent of disease. Clinical studies showed that presentation with non-specific symptoms or no symptoms is as common in the Middle East as in Europe. Wheat represented a major component of the Iranian diet for many centuries and it may be argued that the continuous and high level of exposure to wheat proteins has induced some degree of immune tolerance, leading to milder symptoms that may be misdiagnosed as irritable bowel syndrome or unexplained gastrointestinal disorders. The gluten-free diet represents a real challenge to both patients and clinicians in this area. This is particularly difficult in the absence of any supply for gluten-free diet in Middle Eastern countries.     

Effect of an oats-containing gluten-free diet on symptoms and quality of life in coeliac disease. A randomized study

BACKGROUND: Evidence suggests the acceptability of oats in a gluten-free diet in coeliac disease. We investigated the impact of an oats-containing diet on quality of life and gastrointestinal symptoms. METHODS: Thirty-nine coeliac disease patients on a gluten-free diet were randomized to take either 50 g of oats-containing gluten-free products daily or to continue without oats for 1 year. Quality of life was assessed using the Psychological General Well-Being questionnaire and gastrointestinal symptoms using the Gastrointestinal Symptom Rating Scale. Small-bowel mucosal villous architecture, CD3+, alphabeta+, gammadelta+ intraepithelial lymphocytes, serum endomysial and tissue transglutaminase antibodies were investigated. RESULTS: Twenty-three subjects were randomized to the oats-containing diet and 16 to the traditional gluten-free diet. All adhered strictly to their respective diet. Quality of life did not differ between the groups. In general, there were more gastrointestinal symptoms in the oats-consuming group. Patients taking oats suffered significantly more often from diarrhoea, but there was a simultaneous trend towards a more severe average constipation symptom score. The villous structure did not differ between the groups, but the density of intraepithelial lymphocytes was slightly but significantly higher in the oats group. The severity of symptoms was not dependent on the degree of inflammation. Antibody levels did not increase during the study period. CONCLUSION: The oats-containing gluten-free diet caused more intestinal symptoms than the traditional diet. Mucosal integrity was not disturbed, but more inflammation was evident in the oats group. Oats provide an alternative in the gluten-free diet, but coeliac patients should be aware of the possible increase in intestinal symptoms.     

Is Gluten a Cause of Gastrointestinal Symptoms in People Without Celiac Disease?

The avoidance of wheat- and gluten-containing products is a worldwide phenomenon. While celiac disease is a well-established entity, the evidence base for gluten as a trigger of symptoms in patients without celiac disease (so-called ‘non-celiac gluten sensitivity’ or NCGS) is limited. The problems lie in the complexity of wheat and the ability of its carbohydrate as well as protein components to trigger gastrointestinal symptoms, the potentially false assumption that response to a gluten-free diet equates to an effect of gluten withdrawal, and diagnostic criteria for coeliac disease. Recent randomized controlled re-challenge trials have suggested that gluten may worsen gastrointestinal symptoms, but failed to confirm patients with self-perceived NCGS have specific gluten sensitivity. Furthermore, mechanisms by which gluten triggers symptoms have yet to be identified. This review discusses the most recent scientific evidence and our current understanding of NCGS.     

Clinical response to gluten withdrawal is not an indicator of coeliac disease

Objective. Although the diagnosis of coeliac disease requires specific histological and serological findings, patients considered to be affected by coeliac disease only on the basis of clinical improvement after gluten withdrawal are commonly referred to our outpatient clinic. The objective of this study was to investigate whether the clinical response of gastrointestinal symptoms to gluten withdrawal and subsequent dietary re-introduction could be an indicator of the presence of coeliac disease. Material and methods. From December 1998 to January 2007, 180 patients on a gluten-free diet because of a diagnosis of coeliac disease not based on proper diagnostic criteria came to our out-patient clinic. In 112 of these patients, gluten was re-introduced into their diet. Subsequent duodenal biopsies and endomysial antibodies confirmed the diagnosis of coeliac disease in 51 of them. The relationship between improvement/worsening of symptoms and withdrawal/re-introduction of dietary gluten was analysed. Results. Gastrointestinal symptoms improved in 64.7% of coeliac patients and 75.0% of non-coeliac patients after gluten withdrawal (χ² test, p=NS). Gluten re-introduction was followed by clinical exacerbation in 71.4% of coeliac patients and 54.2% of non-coeliac patients (χ² test, p=NS). The positive predictive value for clinical improvement after gluten withdrawal was 36%; the positive predictive value for clinical exacerbation after gluten re-introduction was 28%. Conclusions. Clinical response to either withdrawal or re-introduction of dietary gluten has no role in the diagnosis of coeliac disease.     

Transition of care between paediatric and adult gastroenterology. Coeliac disease

Coeliac disease is a condition in which there is an abnormal mucosa in the small intestine. It improves with a gluten free diet, with avoidance of wheat, rye, barley and possibly oats. The history and epidemiology of this condition are discussed. Diagnosis is based on demonstrating that the characteristic histological abnormalities in the small intestine are dependent on gluten ingestion. Diagnostic pitfalls are discussed. The anti-endomysium and anti-tissue transglutaminase antibodies are specific and sensitive diagnostic tools. The wide variety of clinical symptoms and presentations are discussed including the associated condition of dermatitis herpetiformis. Failure to respond to a gluten-free diet can represent simple dietary problems, an alternative diagnosis or, occasionally, the development of a serious complication of coeliac disease such as ulcerative jejunitis or enteropathy-associated T cell lymphoma. Progress towards the characterization of the toxic epitopes within gluten that exacerbate coeliac disease and our current understanding of the genetics of the disorder are presented.     

Nuevas terapias en la enfermedad celiaca y sus complicaciones

The only accepted treatment for coeliac disease is strict adherence to a gluten-free diet. This type of diet may give rise to reduced patient quality of life with economic and social repercussions. For this reason, dietary transgressions are common and may elicit intestinal damage. Several treatments aimed at different pathogenic targets of coeliac disease have been developed in recent years: modification of gluten to produce non-immunogenic gluten, endoluminal therapies to degrade gluten in the intestinal lumen, increased gluten tolerance, modulation of intestinal permeability and regulation of the adaptive immune response. This review evaluates these coeliac disease treatment lines that are being researched and the treatments that aim to control disease complications like refractory coeliac disease.     

Wheat challenge in self-reported gluten sensitivity: a comparison of scoring methods

Background: The condition non-coeliac gluten sensitivity (NCGS) is clinically similar to coeliac disease, but lack objective diagnostic criteria. Symptom relief on gluten-free diet followed by gluten containing food challenge may confirm the condition in clinical settings.

Aim: To describe the results of an open bread challenge in patients with suspected NCGS, and to compare the results with recently suggested cut-offs for symptom change.

Material and methods: Fifty-six patients (12 males) self-instituted on gluten-free diet with negative coeliac disease diagnostics were examined for NCGS by an open bread challenge. Symptoms were reported by Gastrointestinal Symptom Rating Scale, IBS-version (GSRS-IBS) and visual analogue scale (VAS). Results were retrospectively compared to the Salerno and Monash cut-offs for symptom change.

Results: Forty-seven patients were diagnosed with NCGS. Total GSRS-IBS score and overall symptoms by VAS increased significantly in NCGS (p?<?.001), but not in non-NCGS patients (p?<?.12 and p?=?.08, respectively). Total GSRS-IBS challenge score and overall symptoms by VAS were significantly higher in NCGS than in non-NCGS patients (53 vs. 37, p?=?.004 and 76 vs. 39?mm, p?=?.02, respectively). Applying the Salerno and Monash cut-offs, 63 and 75% would be classified with NCGS, respectively. According to total GSRS–IBS absolute agreement was lowest between clinician’s diagnosis and Salerno cut-off (63%) and highest between Salerno and Monash cut-offs (88%).

Conclusion: Clinician diagnosed 85% with NCGS. The proportion of NCGS was lower according to the Salerno and Monash cut-offs. The Salerno cut-off should be the starting point for a common definition of symptom change.     

Quality of Life of Adult Coeliac Patients Treated for 10 Years

Background: For patients with coeliac disease, adherence to a gluten-free diet (GFD) is essential to restore the intestinal mucosa. It is less clear whether this ensures well-being of the patient. We have therefore assessed aspects of the quality of life of adult coeliac patients who had been on a GFD for 10 years. Methods: By means of the Short Form 36 Health Survey (SF-36), the subjective health status was measured in 89 adult coeliac patients (61% women) aged 35-74 years. Patients shown to be in histologic remission (n = 60) were evaluated by means of the Gastrointestinal Symptom Rating Scale (GSRS). Results: The coeliac patients scored significantly lower in the SF-36 than general population, notably within the General Health and Vitality domains. The low scoring was confined to the female patients, who also reported significantly more gastrointestinal symptoms in the GSRS than the male coeliacs. The functional status and perceived health of the coeliac patients appeared unrelated to their biopsy findings. Conclusions: After 10 years on a GFD adult coeliac patients fail to attain the same degree of subjective health as the general population. This is particularly true for female patients and suggests that factors beyond normalization of the intestinal mucosa are of importance for the perceived health status of coeliacs diagnosed in adult life.     

Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes

BACKGROUND: Environmental factors such as nutrition or exposure to infections play a substantial role in the pathogenesis of type 1 diabetes (T1D). We have previously shown that gluten-free, non-purified diet largely prevented diabetes in non-obese diabetic (NOD) mice. In this study we tested hypothesis that early introduction of gluten-enriched (gluten+) diet may increase diabetes incidence in NOD mice. METHODS: Standard, gluten-free, gluten+ modified Altromin diets and hydrolysed-casein-based Pregestimil diet were fed to NOD females and diabetes incidence was followed for 310 days. Insulitis score and numbers of gut mucosal lymphocytes were determined in non-diabetic animals. RESULTS: A significantly lower diabetes incidence (p < 0.0001) was observed in NOD mice fed gluten-free diet (5.9%, n = 34) and Pregestimil diet (10%, n = 30) compared to mice on the standard Altromin diet (60.6%, n = 33). Surprisingly, gluten+ diet also prevented diabetes incidence, even at the level found with the gluten-free diet (p < 0.0001, 5.9%, n = 34). The minority of mice, which developed diabetes on all the three diabetes-protective (gluten+, gluten-free, Pregestimil) diets, did that slightly later compared to those on the standard diet. Lower insulitis score compared to control mice was found in non-diabetic NOD mice on the gluten-free, and to a lesser extent also gluten+ and Pregestimil diets. No substantial differences in the number of CD3(+), TCR-gammadelta(+), and IgA(+) cells in the small intestine were documented. CONCLUSIONS: Gluten+ diet prevents diabetes in NOD mice at the level found with the non-purified gluten-free diet. Possible mechanisms of the enigmatic, dual effect of dietary gluten on the development of T1D are discussed.     

Cell-mediated immunity to gluten within the small intestinal mucosa in coeliac disease.

Jejunal biopsies from controls and coeliac patients were maintained in organ culture in the presence of gluten fraction III. The culture media were assayed for evidence of lymphokine activity in a migration inhibition test using normal peripheral blood leucocytes. Significant inhibition of migration was produced by media from untreated coeliac patients compared with controls (P less than 0.005) or treated coeliac patients (P less than 0.001), indicating the production of a leucocyte migration inhibition factor (LIF) by untreated coeliac mucosa in response to gluten fraction III. The degree of inhibition correlated with the preculture interepithelial lymphocyte count in the coeliac biopsies (P less than 0.02). In six coeliac patients studied when on a normal diet and on a gluten-free diet, LIF was produced while on a normal diet, but not while on a gluten-free diet. These results suggest that a local cell-mediated immune reaction to gluten is present in the mucosa of patients with untreated coeliac disease but that this is reversed by treatment with a gluten-free diet.     

The glycaemic index of a range of gluten-free foods.

AIMS: The number of people with both diabetes and coeliac disease is increasing. This study examined the effect of gluten-free, as opposed to gluten-replete carbohydrate containing foods, on post-prandial blood glucose concentrations. METHODS: The glycaemic index of six commonly used gluten-free carbohydrates are reported and compared with published figures for similar non-gluten-free products. RESULTS: The results indicate that the glycaemic index of gluten-free and gluten containing foods are similar. CONCLUSIONS: The inclusion of gluten-free foods in the diet of diabetic individuals with coeliac disease should not compromise glycaemic control.     

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.     

Effects of alendronate on bone mass in patients with primary biliary cirrhosis and osteoporosis: Preliminary results after one year

Detailed complement system studies were performed in 22 patients with adult coeliac disease. Activation products of C3 were observed in the fresh sera of all untreated patients, while only 4 had activation products of factor B of the alternate pathway. Levels of C4 and C3 were lower than normal mean, but only the depression of C4 reached a level of statistical significance. The amounts of circulating C3 activation products were significantly reduced when the patients were on a gluten-free diet. There is thus evidence that activation of the classical pathway of the complement system takes place in adult coeliac disease, and there is an association between gluten ingestion and the complement activity. We suggest that a possible mechanism of tissue injury in this disease is activation of complement factors by a humoral immune reaction to dietary gluten in the intestinal wall.     

Coeliac Disease: Histopathological Findings in the Small Intestinal Mucosa Studied by a Peroral Biopsy Technique

Villous atrophy, changes in the surface epithelium, mucosal thickening, and glandular hypertrophy were a feature of all the mucosal biopsies from the small intestine obtained from eight coeliac children. No histological differences were observed between the children previously treated with intermittent gluten-free diets and the untreated children. Serial biopsy studies were carried out on one coeliac child before and after treatment with a gluten-free diet over a period of two years. On the whole they confirmed the irreversible nature of the observed histopathological changes but minor improvements could not be excluded. Mucosal abnormalities in coeliac disease are the same as in adult idiopathic steatorrhoea, where they are observed in patients with or without a response to a gluten-free diet. It is concluded that the elimination of gluten from the diet has little if any influence on the histopathological abnormalities observed in coeliac disease.     

On the pathogenesis and clinical course of mesenteric lymph node cavitation and hyposplenism in coeliac disease

BACKGROUND: Coeliac disease is a disorder characterised by malabsorption related to abnormal small bowel structure and intolerance to gluten. There are several reports of an increased risk for malignancy in coeliac disease and its relation to gluten-free, reduced gluten, or normal diet. While a normal diet is associated with an excess of cancer of the mouth, pharynx, oesophagus, and also of lymphoma, treatment with a gluten-free diet restores the cancer risk back to normal. PATIENT: In the present study, we report on a 63-year-old female patient with a history of coeliac disease for twenty years who presented with persistent diarrhoea, weight loss, and an abdominal mass. RESULTS: The gastroenterological work-up revealed small bowel mucosal atrophy, absence of functional splenic tissue, and evidence for an involution of a mesenteric lymph node, termed cavitation. DISCUSSION: This triad has been previously described to represent a rare disease entity related to coeliac disease. We report a two-year follow-up and a review of the literature on the pathogenesis, prognosis, and therapeutical implications of this disease entity.     

Psychoneurotic symptoms and alexithymia in coeliac disease

Objective. Depression, psychological problems and the impairment of quality of life are reported to occur in untreated coeliac disease. Alexithymia (“no words for feelings”) is associated with various gastrointestinal disorders. The aim of this study was to evaluate whether patients with coeliac disease suffer from psychoneurotic symptoms or alexithymia, and whether a gluten-free diet has an impact on the symptoms. Material and methods. The Crown-Crisp Experiential Index (CCEI) and its six subscales were applied to measure neurotic psychopathology, and the 20-item version of the Toronto Alexithymia Scale (TAS-20) and its 3-factor scales to measure alexithymia. The testing was carried out in 20 consecutive adult patients with biopsy-proven coeliac disease before and after one year of treatment on a gluten-free diet. The data were compared with those obtained earlier in non-coeliac Finnish subjects. Results. Somatic anxiety was higher in coeliac disease patients before the introduction of the gluten-free diet than after adhering to the diet. Otherwise, the diet had no significant impact on the CCEI scores. The patients were not suffering from alexithymia, but the TAS-20 score improved significantly during the follow-up. The scores did not differ from those published in the Finnish population. Conclusions. Psychological problems were not common in adult coeliac disease patients. Gluten-free diet had only a minor influence on the symptoms. Common knowledge about coeliac disease and the readily available gluten-free products may have had an impact on these results.     

Non-dietary therapeutic clinical trials in coeliac disease

Coeliac disease is a permanent immunological intolerance to gluten proteins in genetically predisposed individuals. The only management is life-long strict adherence to a gluten-free diet. Unfortunately, compliance with gluten-free diet is very difficult in practice due to the widespread presence of gluten in Western diets. For this reason, about 50% of coeliacs following a gluten-free diet continue to suffer from symptoms and present with autoantibodies and/or villous atrophy while on a gluten-free diet. It is therefore important to explore new therapies to improve the management of coeliac disease. To date, five experimental therapies have been tested in randomized and controlled clinical trials. Larazotide acetate reduces the para-cellular passage of gluten to the lamina propria by preventing the opening of intercellular tight junctions. The endopeptidases ALV003 and AN-PEP break down gluten to produce less or non-toxic peptide fragments. A therapeutic vaccine is being tested with the aim of developing gluten tolerance. Finally, infection with the nematode Necator americanus and treatment with the CCR9 antagonist Traficet-EN have also been reported.While substantial progress has been made in the last few years, it is important to remember that all these investigational therapies are in research stage and are generally being considered as “adjunctive” therapies to the gluten-free diet and not as substitutes of the gluten-free diet at this point in time.