Coeliac disease--has the time come for routine mass screening? In 2002--2010--2020?

It might be clinically relevant to have a very low threshold when screening for coeliac disease. The question is how low? In countries familiar with coeliac disease, the classic pattern of severe malabsorption and cachexia, as described in textbooks, has become rare. Coeliac disease is not born in the minds of doctors diagnosing dyspepsia and/or irritable bowel syndrome, or associated auto-immune diseases, such as thyroid, diabetes mellitus type I, Sj?gren's disease etc. The consequence is a delay in diagnosis, with secondary problems as long term autoimmune stimulation, osteoporosis and secondary malignancies. Enteropathy associated T-cell lymphomas are well known, but considering coeliac disease in T-cell lymphomas outside the gastrointestinal tract is not yet common sense. Large-scale screening studies on coeliac disease have been published and suggest a prevalence of coeliac disease in USA, Europe, Middle-East and Australia of about 1:200. Coeliac disease can be classified due to all these studies as an important health problem. However nation-wide screening programmes have not started yet, which are common for phenylketonuria and other metabolic defects. Probably they will be initiated as pilot-studies in national programmes within 10 years at the age of 2, and due to the bimodal distribution in CD with a later peak in the fourth decade, at 40 years. Additional data about cohorts of certain age groups are mandatory (f.i. 40 and/or 60 years), while initial discussions begin with national health authorities.     

Refractory coeliac disease: a window between coeliac disease and enteropathy associated T cell lymphoma

The treatment of coeliac disease (CD) is straightforward and simple: life-long adherence to a gluten-free diet. However, in a small subgroup of patients, the clinical and histological abnormalities persist or recur. This non-responsiveness leaves a poorly understood syndrome known as refractory coeliac disease (RCD). A specific definition of RCD is lacking in the literature. We speculate that RCD may appear in a subgroup of coeliacs with persisting histologic abnormalities. In all patients screened for RCD we look for DQ2 and DQ8. In non-DQ2/DQ8 patients we reconsider the diagnosis of CD and of auto-immune enteropathy. Most of the patients referred to us because of suspicion of RCD are affected by other diseases. Probably the commonest cause of non-responsiveness is continued gluten intake. Exocrine pancreas insufficiency, hyperthyroid disease, collagenous colitis are other common explanations. RCD and enteropathy-associated T cell lymphomas (EATL) can be distinguished by intra-epithelial lymphocyte phenotyping and TCR-gamma gene rearrangements. In RCD, an unexplained sustained stimulation of T cell cytotoxic activity is present. Immunosuppressive treatment might moderate this. Cyclosporine has been reported as a resounding success in case reports; however, our results were disappointing. We suggest azathioprine and steroids in RCD without aberrant T-lymphocytes in their mucosa. However, in RCD with aberrant T-lymphocytes we suggest chemotherapy. As the prognosis of EATLs is extremely poor the early detection of RCD with aberrant T cells is crucial.     

Refractory coeliac disease

A small proportion of coeliac disease (CD) patients fail to improve after a gluten-free diet (GFD) and may be considered as atypical regarding their outcome (refractory coeliac disease). The aim of this study is to diagnose and manage patients with CD who fail to improve after a GFD. Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict GFD and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy. Standardized treatment, however, has not been evaluated in such patients so far. In a subgroup of patients with RCD, an abnormal intraepithelial lymphocyte (IEL) population may be observed with the lack of surface expression of usual T-cell markers (CD3-CD8 and/or the T-cell receptor (TCR)) on IELs associated with T-cell clonality pattern suggest the presence of an early enteropathy-associated T-cell lymphoma (EATL) in a subgroup of patients with RCD. This hypothesis has been supported by studies, which revealed progression into overt intestinal T-cell lymphomas in a subgroup of RCD. Steroid treatment has been reported effective even in patients with underlying early EATL. However, long-term results are unsatisfactory in most of these patients with RCD and parenteral nutrition has to be applied in some of these cases. First results with more aggressive chemotherapies and use of cytokines are under way. Due to the difficulty of diagnostic and therapeutic regimens patients should be referred to tertiary centres for coeliac disease.     

Malignant complications of coeliac disease

Patients with coeliac disease (CD), particularly those who are undiagnosed or do not adhere to a strict gluten free diet (GFD), are prone to develop complications. Malignant complications are the most serious and should be suspected when expected responses to GFD are not achieved or sustained. Lymphomas, mostly T-cell type, and other malignant tumours, particularly carcinoma of the small bowel, less frequently of stomach and oesophagus, are associated with CD. Loss of response to a gluten free diet (refractory coeliac disease) and ulcerative jejunitis are two recently described complications of CD that may progress to an Enteropathy-Associated T-cell Lymphoma (EATL). Coeliac disease-related lymphoma most often appears at extra-nodal sites, essentially the small bowel, although one have to realise that T-cell lymphomas arising in sites outside the small bowel could be related to coeliac disease. Workup of an EATL must include immunehistology and if necessary T-cell flow cytometry and T-cell rearrangement. Adequate imaging with CT and PET-scanning is mandatory.     

Gut endocrine cell population in coeliac disease estimated by immunocytochemistry using a monoclonal antibody to chromogranin.

Abnormalities of gut endocrine responses, as well as changes in the number of different endocrine cell types, have been reported convincingly in coeliac patients. Nevertheless, no estimation of total numbers of gut endocrine cells has yet been made in well defined groups of coeliacs. In this study, we have visualised all endocrine cell types in jejunal biopsies from coeliac patients with active and quiescent disease as well as in controls, using a monoclonal antibody to chromogranin. This protein was purified originally from bovine adrenal medulla and is known to be a reliable marker for all endocrine cells of the gut. The following groups were considered: (a) nine coeliacs with active illness, (b) 10 coeliacs under gluten-free diet, (c) eight coeliacs receiving gluten challenge, (d) five non-coeliacs (controls). Histological (haematoxylin and eosin) and immunocytochemical (peroxidase anti-peroxidase) stains were applied to 3 micron paraffin sections. Quantitative estimation of endocrine cell density was made using four different methods in order to evaluate the results fully (number of cells/mm2, number of cells/visual field, number of cells/8 crypts-villi, number of cells/unit of length of muscularis mucosae). In patient groups (a) and (c), coeliacs with active disease and coeliacs on gluten challenge diet respectively, a significantly higher number of endocrine cells was observed in comparison with normal controls (group d). In group (b) patients, coeliacs on gluten-free diet, no significant changes in the number of endocrine cells were observed in comparison with controls. Our results show that a significant increase in endocrine cell density exists in coeliacs with active illness (groups a and c), in comparison with controls. This condition is resolved in coeliacs receiving a gluten-free diet (group b).     

Anti-ganglioside antibodies in coeliac disease with neurological disorders

BACKGROUND: Anti-ganglioside antibodies have been described in sera of coeliac patients with peripheral neuropathy and cerebellar ataxia. AIMS: To investigate the correlation between anti-ganglioside antibodies and neurological involvement in coeliac disease before and after gluten-free diet. PATIENTS AND METHODS: Twenty-two untreated coeliac patients with neurological dysfunction and 30 untreated coeliacs without neurological dysfunction, 20 patients with neurological disorders, 50 autoimmune disease and 20 blood donors were tested for anti-GM1, anti-GD1b and anti-GQ1b IgG and IgM antibodies by enzyme-linked immunosorbent assay. RESULTS: IgG antibodies to at least one of the three antigens tested were positive in 64% of coeliac patients with neurological symptoms compared to 30% of coeliacs without neurological dysfunction (P=0.02), 50% of patients with neurological disorders (P=ns), 20% with autoimmune diseases (P=0.003) and none of blood donors (P=0.0001). A strict gluten-free diet determined anti-ganglioside antibody disappearance in about half of coeliacs. CONCLUSIONS: A significant correlation between anti-ganglioside antibodies and neurological disorders in patients with an underlying coeliac disease has been found. Anti-ganglioside antibodies may represent a new immunological marker to identify neurological impairment in patients with coeliac disease.     

IgA antigliadin antibodies and persistence of jejunal lesions in adult coeliac disease

In 46 adult patients with coeliac disease, 41 (89%) of whom were positive for IgA and/or IgG antigliadin antibodies (AGA) when untreated, we investigated after a gluten-free diet the relationship between the persistence of AGA, the persistence of jejunal lesions, and the duration and compliance with the diet. IgG AGA were positive in 21 coeliac patients (46%) after variable periods of gluten-free diet and were associated with IgA positivity only in 4 cases (9%). Both IgA and IgG AGA positivity appeared to be more related to the lack of improvement of the jejunal lesions than to the strictness and duration of gluten withdrawal. Nine coeliacs showed no improvement of jejunal lesions after the gluten-free diet. Of these 9, 4 showed persistent IgA AGA, while the remaining 5 resulted IgAAGA-negative as before when untreated. Though intestinal biopsy remains the best means of determining the positive effect of gluten withdrawal, the persistence of IgA AGA in treated coeliacs is always predictive of the persistence of severe jejunal lesions. The persistence of IgG AGA, on the contrary, should be regarded as an immunological memory.     

Human intestinal mucosal mast cells: expanded population in untreated coeliac disease.

Previous retrospective studies of intestinal mucosal mast cells in coeliac disease have given divergent results, and we have recently reported that inappropriate methodology could account for these discrepancies. In this prospective study, mucosal mast cell counts were performed in Carnoy fixed, peroral jejunal biopsy specimens from patients with coeliac disease, both untreated and treated with a gluten-free diet; and from controls (mainly irritable bowel syndrome). Mean mucosal mast cell count in 27 control subjects was 146/mm2, SD 29. Significantly higher values were obtained in untreated coeliac disease (mean 243, SD 41, p less than 0.001) returning to the normal range in coeliacs treated with a gluten-free diet with normal jejunal biopsy morphology. In seven patients mucosal mast cell counts were performed in multiple jejunal biopsies, and these showed that mucosal mast cell distribution was not patchy. There was no evidence of degranulation of intestinal mucosal mast cells under the conditions of routine biopsy (overnight fast). An increase in mucosal mast cells in untreated coeliac disease may be one explanation for the high number of IgE positive stained cells in the intestinal mucosa that has been reported by some authors.     

Effect of gluten-free diet on splenic hypofunction of adult coeliac disease.

Splenic function has been serially measured by counting pitted red cells in 15 coeliac patients, before and during a gluten-free diet. The basal percentage values of pitted cells decreased significantly during treatment but no correlation was observed between the duration of the gluten-free diet and the percentage of recovery of splenic function over basal values. Out of six coeliacs with pitted cell values consistent with splenic hypofunction, three showed a total recovery after gluten withdrawal. Our data suggest that, contrary to recent reports, hyposplenism in adult coeliac disease is improved by a gluten-free diet, and that environmental factors may be important in determining and maintaining this complication.     

Cell-mediated immunity, malnutrition and plasma zinc levels in adult coeliac disease

The aim of this study was to clarify the relationships between cell-mediated immunity, nutritional status and plasma zinc levels in adult coeliac disease. Compared with healthy volunteers and treated coeliac patients, cell-mediated immunity, assessed by skin tests, was significantly depressed in untreated coeliac disease. As far as plasma zinc is concerned, it was confirmed that levels are significantly low in untreated patients and that they increase significantly after gluten-free diet, although this is not sufficient to return the plasma zinc levels to within the control range in 39% of the treated patients. Malnutrition, assessed by anthropometric criteria, was present in the majority of the untreated coeliacs and improved significantly after removal of gluten from the diet. In untreated coeliac patients, however, skin tests did not correlate with either plasma zinc levels or nutritional status, suggesting that in untreated coeliac disease depressed cell-mediated immunity is probably secondary to other immunological abnormalities     

The serum IgA class anti-tissue transglutaminase antibodies in the diagnosis and follow up of coeliac disease. Results of an international multi-centre study. International Working Group on Eu-tTG.

OBJECTIVES: So far the reliability of the anti-tissue transglutaminase (anti-tTG) test for the diagnosis of coeliac disease has mostly been evaluated using slightly different enzyme-linked immunosorbent assays (ELISAs) in selected and usually small groups of patients. The aims of this study were: (1) to evaluate the reliability of the IgA anti-tTG antibodies for the diagnosis of coeliac disease; and (2) to define the sensitivity and specificity of a commercially available kit for the anti-tTG antibodies' quantitative determination. DESIGN: Each centre in this international multi-centre study collected sera from three groups of subjects: coeliac disease patients at the onset of (1) or on a gluten-free diet for at least 12 months (2); disease and healthy controls (3). METHODS: The anti-tTG antibodies were determined in duplicate using an ELISA-based commercially available kit (Eu-tTG Eurospital, Trieste, Italy). RESULTS: The following overall cases and controls have been enrolled: (1) 399 subjects with active coeliac disease; (2) 351 treated coeliac disease cases; (3) 432 controls. The centralized re-testing was performed on: (1) group a: 176 patients with active coeliac disease (mean anti-tTG, 21 arbitrary units [AU]); (2) group b: 172 treated coeliac disease cases (mean anti-tTG, 5 AU); (3) group c: 206 controls (mean anti-tTG, 3 AU). In active coeliacs, the anti-tTG antibodies showed a significant progressive decrease with age, while in controls an opposite trend was found. In active coeliac disease patients, the anti-tTG antibodies were significantly higher in coeliacs with a grade III enteropathy than in those showing a grade II lesion. In treated coeliacs, the mean anti-tTG values were significantly lower in patients strictly adhering to a gluten-free diet than in those reporting dietary transgressions. The sensitivity and the specificity of the Eu-tTG assay were 90% and 96%, respectively. CONCLUSION: The results of this study show that the commercially available test for the anti-tTG antibodies' determination is a reproducible and valuable tool for the diagnosis and follow up of coeliac disease.     

HLA-B8 and cell-mediated immunity to gluten.

The leucocyte migration inhibition (LMI) test was used as an indicator of cell mediated immunity to gluten fraction III in 30 healthy controls and 58 patients with adult coeliac disease and the results related to HLA status and duration of treatment with a gluten-free diet. HLA-B8 controls showed significantly lower leucocyte migration indices, indicating greater immune response, than non-HLA B8 controls. Untreated coeliacs showed no difference from HLA-B8 controls. There was no difference between results from HLA-B8 and non-HLA-B8 coeliacs. Leucocyte migration was even lower in coeliacs early in treatment but rose after treatment for over one year. These results may reflect an immune response gene for gluten in linkage disequilibrium with HLA-B8. The increased immune response to gluten as measured in this test cannot be the sole factor in aetiology of coeliac disease. Furthermore, it is necessary to re-evaluate earlier results of cell-mediated immunity in coeliac disease with reference to HLA status of the controls.     

The jejunal cellular infiltrate in coeliac disease complicated by lymphoma

Lymphocytes and plasma cells in the lamina propria and lymphocyte in the epithelium have been quantitated in jejunal biopsies from 18 patients with coeliac disease who developed lymphoma. In six patients two or more serial biopsies were available for study. Counts were compared with those obtained in 15 healthy controls and 30 other coeliacs, 15 of whom have been on a gluten-free diet for more than 12 months.Results showed that although the lymphoma patients have abnormal counts compared with controls, they differed from untreated coeliacs in that they had lower plasma cell and higher lymphocyte counts in the lamina propria and lower lymphocyte counts in the epithelium. Such changes tended to be present for up to five years before the diagnosis of lymphoma was made. The results suggest that the immunological status of coeliac patients with lymphoma differs from that of other coeliacs and it could represent a primary abnormality and also be relevant to the development of lymphoma.     

Coeliac disease and malignancy

The development of malignancy, particularly lymphoma, is the most serious complication to affect patients with coeliac disease. Although the association has been known for about 40 years, there are still gaps in our understanding. The prevalence of lymphoma and why only some coeliac patients develop this are not clear but environmental and genetic factors must be at work. Based on data from a large coeliac clinic in Derby, about 55 lymphomas per year would arise in the coeliac population of the United Kingdom, of which half would affect the small bowel. Whether patients with coeliac disease who have atypical or no symptoms at diagnosis, are at the same risk as those who are diagnosed as a result of classical symptoms as was more the case in the past, is not known. Some patients, however do have coeliac disease and lymphoma diagnosed at the same presentation. This consideration has implications for initiating screening programmes to detect coeliac disease and thus offer patients a gluten-free diet early that would help to reduce the risk of lymphoma from developing. In this context, case-finding rather than blanket population screening is to be recommended on present evidence. Research into the role of intraepithelial lymphocytes in the genesis of lymphoma has indicated that non-responsive coeliac disease (refractory sprue) and ulcerative jejunoileitis (ulcerative jejunitis) are part of the lymphoma spectrum. The diagnosis of lymphoma can be difficult and the prognosis, in general, is poor, although with modern chemotherapeutic regimes and surgery in selected cases, long-term survival is possible. The best option is to try and prevent lymphoma from arising by advising all patients to adhere to a strict gluten-free diet. Malignant complications of coeliac disease are uncommon but will continue to challenge clinicians and clinical scientists. Unravelling the mechanisms that contribute to the development of lymphoma and other tumours in coeliac disease may well contribute to a wider understanding of oncogenesis.     

Paediatric aspects of coeliac disease: old challenges and new ones…

The concept of coeliac disease has expanded from a gastrointestinal disease with malabsorption to a systemic immunological disease with a genetic basis. Epidemiological studies indicate that environmental factors, like the infant feeding pattern, affect the clinical presentation while population-screening studies indicate that the prevalence, at least in Caucasian populations, is similar. Secondary complications, like malignancies, osteopenia - osteoporosis, gynaecological and obstetrical problems and autoimmune diseases, are common. The risk is reduced or prevented by treatment with a gluten-free diet. The basis for such a secondary prevention is: 1. early case-finding by a) knowledge about different presentations of the disease and factors affecting that, b) generous serological testing in patients with vague symptoms, c) screening of risk groups, and, 2. support for children and adolescents with coeliac disease to comply with the gluten-free diet.     

Celiac disease: clinical and subclinical forms

Coeliac disease is an intolerance to gluten that classically produces a chronic diarrhoea with a picture of malabsorption and a total villous atrophy. These elements regress completely in a sequential way under a prolonged strict gluten-free diet. The progress registered in the understanding of this affection depends on the individualization of the atypical forms (delayed isolated stature, constipation...) of asymptomatic forms thanks to the study of specific antibodies (anti-gliadin, anti-endomysium, and more recently anti-transglutaminase). The auto-immune nature of coeliac disease is well established. The diagnostic criteria are simplified allowing the commencement of a gluten-free diet which must be perfectly detailed. Finally, allergy to wheat flour merits individualization in the framework of coeliac disease (cf. article).     

Coeliac proctitis

An increased association of ulcerative colitis and coeliac disease has been reported, as have the results of several small-bowel biopsy studies in ulcerative colitis. Forty-two patients from a population of 438 patients with coeliac disease had rectal biopsies. Fourteen of these showed inflammation of various degrees of severity, including three compatible with a diagnosis of ulcerative colitis. The presenting complaint in 34 of these patients was diarrhoea or steatorrhoea. Twenty-seven patients had coeliac disease diagnosed at the same time or after their rectal biopsy. The other 15 were previously diagnosed coeliacs. Twelve of the 14 patients with abnormal rectal biopsy specimens were known to have subtotal/total villous atrophy at the time of rectal biopsy. Proctitis as seen in these coeliac patients had no unique features to differentiate it from proctitis caused by other disorders. The diarrhoea/steatorrhoea stopped in all patients on commencement of a gluten-free diet, except in those with ulcerative colitis. Proctitis is common in patients with coeliac disease presenting with diarrhoea/steatorrhoea. This study supports the finding of an increased association of coeliac disease and ulcerative colitis and is, to our knowledge, the first rectal biopsy study of a coeliac population.     

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.     

Coeliac disease and Type 1 diabetes mellitus - the case for screening.

AIM: To review the relationship between coeliac disease and Type 1 diabetes mellitus with emphasis on prevalence of coeliac disease, presentation and implications for screening. METHODS: Papers collected over many years by the author have been included in the review and a literature search employing Medline was undertaken to August 2000. Search words used were coeliac disease and diabetes mellitus. RESULTS: Twenty papers exploring the prevalence of coeliac disease by serological screening of Type 1 diabetes in children, eight in adults and two including both groups were found. An additional 48 papers are included and relate to serological screening tests for coeliac disease, expressions and complications of coeliac disease, the value of GFD and the genetics of the two conditions. Unless formal screening studies are undertaken coeliac disease will not be diagnosed because patients are asymptomatic, have atypical symptoms or even in those with symptoms the diagnosis is overlooked. Based on small bowel biopsy, diagnosis the prevalence of coeliac disease in Type 1 diabetes in children is 1:6 to 1:103 and in adults 1:16 to 1:76. Patients may improve following the start of a gluten-free diet (GFD) in terms of symptoms, growth in children, serum antibody levels, haematological and biochemical indices, morphology of the small intestinal mucosa and control of diabetes. CONCLUSION: Coeliac disease commonly occurs in Type 1 diabetes. It is recommended that screening for coeliac disease should be part of the routine investigation and offered to all patients because of the high prevalence and the potential benefits of treatment with a GFD. This includes control of symptoms, stabilization of diabetes and prevention of complications associated with coeliac disease. The cost per patient diagnosed with coeliac disease from the existing population with Type 1 diabetes would be pound860 and for those newly arising pound950.     

Hyposplenism, adult coeliac disease, and autoimmunity.

Functional hyposplenism is associated with a variety of disorders including coeliac disease. The aims of this study were to estimate the need for a small intestinal biopsy in the investigation of hyposplenism, and to assess the relationship of autoimmunity to hyposplenism and coeliac disease. During one year, the features of hyposplenism were found in blood films of 27 patients who had not had a splenectomy. Ten patients were already known to have coeliac disease. Intestinal biopsy was performed in another 13 patients; coeliac disease was diagnosed in six. Of the 23 patients biopsied, coeliac disease was present in 16 (70%). Autoantibodies were detected in significantly more patients with hyposplenism than in healthy controls (P less than 0.05), and in significantly more coeliacs with hyposplenism than coeliacs with normal blood films (P less than 0.01). The increased incidence of autoantibodies in coeliacs with hyposplenism compared with other coeliacs was not associated with a difference in the incidence of HLA-B8. Small bowel biopsy should be carried out in the investigation of unexplained hyposplenism. There may be a link between hyposplenism and the autoimmune manifestations of coeliac disease.