Pathogenesis of coeliac disease: implications for treatment

INTRODUCTION Coeliac disease(CD)is an enteropathy ,characterised by villous atrohy ,which occurs in genetically susceptible individuals .It affects mainly the proximal small intestine,and is caused by an intolerance to cereal storage proteins found in wheat ,barley and rye .     

Capsule endoscopy for patients with coeliac disease

Introduction: Coeliac disease is an autoimmune mediated condition in response to gluten. A combination of innate and adaptive immune responses results in villous shortening in the small bowel (SB) that can be morphologically picked up on capsule endoscopy. It is the only imaging modality that can provide mucosal views of the entire SB, while histology is generally limited to the proximal SB. Radiological modalities are not designed to pick up changes in villous morphology.

Areas covered: In this review, we provide a comprehensive analysis on the justified use of small bowel capsule endoscopy (SBCE) in the assessment of patients with coeliac disease; compare SBCE to histology, serology, and symptomatology; and provide an overview on automated quantitative analysis for the detection of coeliac disease. We also provide insight into future work on SBCE in relation to coeliac disease.

Expert commentary: SBCE has opened up new avenues for the diagnosis and monitoring of patients with coeliac disease. However, larger studies with new and established coeliac disease patients and with greater emphasis on morphological features on SBCE are required to better define the role of SBCE in the setting of coeliac disease.     

Endoscopic markers in adult coeliac disease

BACKGROUND: Various endoscopic markers have been described in coeliac disease, particularly in the second part of the duodenum, with minor attention generally being paid to the duodenal bulb. AIMS: To evaluate, prospectively, the presence of all endoscopic markers in the bulb and the second part of the duodenum on a large series of patients submitted to endoscopy for duodenal biopsy. PATIENTS AND METHODS. A total of 367 consecutive patients, submitted to endoscopy with duodenal biopsy for various indications, were considered. Biopsies were graded as normal, with partial villous atrophy (mild, moderate, severe) or with subtotal villous atrophy. Endoscopic markers and corresponding locations evaluated were: micronodular pattern [bulb and descending duodenum], mosaic appearance (bulb and descending duodenum), scalloped folds (descending duodenum), reduced or absent folds (descending duodenum). RESULTS: In 78 patients, a diagnosis of untreated coeliac disease was made. Endoscopic markers were seen in 73/78 patients, with only a single sign present (bulb or descending duodenum) in 12 patients. In the remaining 289 patients, normal histology and normal endoscopic findings were observed, except in two patients with reduced folds. Sensitivity, specificity, positive and negative predictive values and diagnostic accuracy regarding all endoscopic markers were 93.6%, 99.3%, 97.3%, 98.3% and 98.1%, respectively CONCLUSIONS: This study confirms the usefulness of endoscopic markers in detecting coeliac disease, underlining the importance of evaluating also abnormalities in the bulb and endoscopic single signs; although endoscopy may not detect all cases of coeliac disease, the recognition of endoscopic markers allows the selection for biopsy of unsuspected patients submitted to endoscopy for non-specific symptoms.     

Aplastic anaemia in association with coeliac disease: a series of three cases

We report a series of three patients in whom the diagnoses of aplastic anaemia (AA) and coeliac disease were made concurrently. Haematological manifestations of coeliac disease are well described but this is the first report to suggest an association with aplastic anaemia. 'Silent/atypical coeliac disease', in the absence of gastrointestinal symptoms, is increasingly recognised and patients may present with generalised symptoms, such as malaise and fatigue, which are easily attributable to AA. Immunosuppressive therapy for AA could modulate the course of celiac disease. We recommend clinicians should be vigilant for signs of coeliac disease in patients with AA.     

Evaluation of coeliac disease serological markers in Down syndrome patients

BACKGROUND: The increased incidence of coeliac disease in patients with Down syndrome makes screening of coeliac disease in this population advisable. AIM: Evaluation of efficiency of different serological markers to detect coeliac disease in Down syndrome patients. PATIENTS: A total of 56 Down syndrome patients (aged: 1-17 years) were included in study. METHODS: Patients were evaluated for both IgG and IgA anti-transglutaminase antibodies and for anti-gliadin IgA and IgG antibodies using either purified omega-gliadin, wheat ethanol extract or commercial gliadin. Patients who had at least one positive result were evaluated for antiendomysium antibodies using either monkey oesophagus or human umbilical cord by indirect immunofluorescence. Coeliac disease was diagnosed by typical histological changes on duodenal mucosa. RESULTS: Increased levels of at least one anti-gliadin IgA and IgG antibody marker were found in 27 out of 56 cases (26 for IgG and 9 for IgA). 11/56 were positive for IgG anti-transglutaminase antibodies and two of them were also positive for IgA anti-transglutaminase antibodies and anti-endomysium antibodies. These two patients were finally diagnosed as coeliacs. Gliadin antigenic fractions employed produced differences in the performance of the anti-gliadin IgA and IgG antibody test. The use of commercial gliadin or wheat ethanol extract showed low sensitivity in IgA anti-gliadin IgA and IgG antibody determination, whereas good sensitivity and specificity were observed with omega-gliadins. IgG anti-transglutaminase antibodies showed a high proportion of false positive results (9 out of 56), whereas anti-endomysium antibodies and IgA anti-transglutaminase antibodies presented an excellent correlation with presence of active coeliac disease. CONCLUSIONS: Two out of 56 Down syndrome patients were diagnosed as coeliacs, corresponding to an incidence of 3.6%. The use of omega-gliadin presented the best efficiency in anti-gliadin IgA and IgG antibody determination whereas IgA anti-transglutaminase antibodies and anti-endomysium antibody determination showed an absolute correlation with presence of active coeliac disease.     

Clinical features of coeliac disease

Aim of this review is to describe the extremely variable clinical presentation of coeliac disease. Moreover due to these varying manifestations, "coeliac literature" is characterised by a very rich terminology, which has not been unified, so far To help readers, not familiar with that terminology, we have given an explanation for the most common coeliac terms.     

Prevalence of coeliac disease in primary biliary cirrhosis and of antimitochondrial antibodies in adult coeliac disease patients in Italy

BACKGROUND: Although an association between primary biliary cirrhosis and coeliac disease has recently been reported in Northern Europe, there are still conflicting data concerning this issue. AIM: To evaluate both the prevalence of coeliac disease in a series of primary biliary cirrhosis patients and that of antimitochondrial antibodies in a series of adult biopsy proven coeliac disease patients from Northern Italy. PATIENTS AND METHODS: A total of 87 primary biliary cirrhosis patients (79 female, 8 male) were screened for both IgA-transglutaminase antibodies and antiendomysium antibodies and, in those with either IgA-transglutaminase antibodies or antiendomysium antibodies positivity, upper endoscopy with distal duodenum biopsy was offered. In those who refused upper endoscopy, the intestinal permeability test with lactulose/mannitol excretion was performed. RESULTS: Antiendomysium antibodies positivity was detected in 3 subjects (3.4%), all of whom had serum IgA-transglutaminase antibodies above the normal range, and fulfilled the diagnosis of coeliac disease. Of 21 other patients with serum IgA-transglutaminase antibodies above the normal range, 17 underwent upper endoscopy which revealed normal duodenum architecture. The remaining 4 patients underwent the lactulose/mannitol excretion test which was within the normal range. Sera from 108 adult coeliac disease patients were tested for antimitochondrial antibodies and positivity was found in 4 patients (3.7%): all had normal liver biochemistry tests, whereas 2 of them also presented thyroid disease. Antibodies directed to the 74-kDa polypeptide of antimitochondrial antibodies were found in 3 out of 4 antimitochondrial antibodies+ve patients. CONCLUSIONS: These results suggest an association between primary biliary cirrhosis and coeliac disease similar to that observed in the Northern European series. In conclusion, screening for coeliac disease with antiendomysium antibodies in primary biliary cirrhosis is justified, and screening for antimitochondrial antibodies is advisable in adult coeliac disease patients.     

Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study

Background—Selective immunoglobulin A (IgA)deficiency (SIgAD) is associated with coeliac disease (CD).
Aim—To make a retrospective study of theassociation of SIgAD with CD in Italy.
Methods—Hospital medical records of 2098 patientsconsecutively diagnosed as having CD were reviewed.
Results—Of 2098 patients with CD, 54 (2.6%) hadSIgAD, representing a 10-16-fold increase over that in the populationin general. This increase was not influenced by age or geographicalfactors. Patients with SIgAD had a higher incidence of silent forms(7/54, 13%), recurrent infections (16/54, 29.6%), and atopic diseases (7/54, 13%) than those without. The association with autoimmune andmalignant diseases and the outcome after eating a gluten free diet weresimilar in patients with or without SIgAD. In all patients with SIgAD,antibodies for IgA gliadin and endomysium were absent, but serum levelsof IgG anti-gliadin antibodies were high in almost all of them (51/54).
Conclusions—Serum IgA should be measured in orderto be able to interpret negative results for IgA anti-gliadinantibodies and anti-endomysial antibodies in patients being screenedfor CD. Since some patients with CD and SIgAD may be negative for IgGanti-gliadin antibodies, an intestinal biopsy should be performed inall suspected cases.

Keywords:coeliac disease; IgA deficiency

     

Shared genetics in coeliac disease and other immune-mediated diseases

Identifying disease-associated variants can improve the predictive models of disease risk and provide mechanistic insights into disease development. Coeliac disease (CD) is the only autoimmune trait with a known environmental trigger, which makes it an excellent model for studying the complexity of genetic and environmental factors in the development of autoimmunity. In this review, we will focus on the genetic loci that have recently been associated with CD and that contain genes involved in innate and adaptive immunity. Some of these loci are shared with other immune-mediated diseases, suggesting an overlap of the genetic mechanisms involved in the development of such diseases. Some therapies, e.g. tumour necrosis factor inhibitors or a gluten-free diet, are already proving effective for more than one autoimmune disease. Follow-up of individuals with a high genetic risk of CD and other autoimmune diseases could help to elucidate the role of environmental factors (such as infectious agents or alterations in the microbiome) and prevent disease development.     

Increased red cell distribution width and coeliac disease

BACKGROUND/AIMS: Despite availability of sensitive screening tests, coeliac disease is still underdiagnosed. To determine which haematochemical abnormalities might be more predictive of this condition, we reviewed the clinical records of our series of adult patients affected by coeliac disease. METHODS: Six haematochemical parameters (haemoglobin, red cell distribution width, serum levels of iron, albumin, calcium and potassium) were evaluated in 126 consecutive adult untreated coeliac patients diagnosed since 1990. RESULTS: Elevated red cell distribution width was the most frequent haematochemical abnormality, being present in 57.9% of our patients (Chi square analysis, p<0.01 versus other laboratory changes). CONCLUSION: The increase of red cell distribution width was more common than iron-deficiency anaemia, a well-known indicator of coeliac disease. Elevated red cell distribution width can thus be considered a new predictor of coeliac disease and in the presence of this a search should be made for antiendomysial antibodies.     

The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences

Background—Coexistent primary biliary cirrhosis(PBC) and coeliac disease has been recorded but the association has notbeen systematically studied.
Aims—To determine relative prevalences of PBC andcoeliac disease in a defined population over a 12 year period.
Patients and methods—All patients with PBCor coeliac disease in a stable population of 250 000 in South Waleswere identified from a clinical register and laboratory records.
Results—Sixty seven patients with PBC and 143 patients with coeliac disease have been diagnosed and followed over amedian of 86 (4-135) months; point prevalences in 1996 were 20 per100 000 for PBC and 54 per 100 000 for coeliac disease. PBC inpatients with coeliac disease was sought by investigating abnormalliver function tests. Ten (7%) had persistent abnormalities and three had PBC. Coeliac disease in patients with PBC was sought byinvestigating malabsorption, haematinic deficiency, positiveantigliadin antibody, or coeliac disease family history. Elevenpatients underwent duodenal biopsy revealing one further coeliacdisease case. Four patients (three women) have both conditions giving apoint prevalence for patients with both conditions of 1.6 per 100 000(95% confidence limits 0.44 to 4.1 per 100 000). Prevalence of PBC inpatients with coeliac disease was 3% and of coeliac disease inpatients with PBC was 6%.
Conclusion—A 12 year study of a stable 250 000population revealed a relative prevalence of PBC in 3% of 143 patientswith coeliac disease and of coeliac disease in 6% of 67 patients with PBC. PBC and coeliac disease are therefore associated. Screening forPBC in patients with coeliac disease using antimitochondrial antibodytesting and screening for coeliac disease in patients with PBC withantigliadin antibody testing or duodenal biopsy are recommended.

Keywords:primary biliary cirrhosis; coeliac disease; prevalence

     

Adult coeliac disease: prevalence and clinical significance

BACKGROUND AND AIMS: Although coeliac disease is a common condition, the role of population screening is not clear. The aim of this study was to determine the prevalence and clinical significance of coeliac disease in the adult population of Christchurch, New Zealand. METHODS: A total of 1064 adults randomly selected from the 1996 Christchurch electoral rolls were enlisted. The subjects were screened for coeliac disease using the anti-endomysial antibody test (EMA), and all those with positive tests were reviewed and underwent a small bowel biopsy. RESULTS: Twelve of the 1064 persons tested (1.1%) were EMA positive and all had small bowel biopsy histology consistent with coeliac disease. Two of the 12 subjects were previously known to be EMA positive although neither had a small bowel biopsy. One additional subject with known and treated coeliac disease was also enrolled but was EMA negative. Thus, the overall prevalence of coeliac disease was 13 of 1064 subjects (1.2%, or 1:82), 10 of whom were newly diagnosed (0.9%, or 1:106) and three were previously known or suspected to have coeliac disease (0.3%, or 1:355). The prevalence in both sexes was similar. Nine of the 12 EMA-positive coeliac disease subjects identified by the use of screening reported symptoms, of which tiredness and lethargy were the most common. The subjects were of normal stature, although females tended to be lean. None of the subjects were anaemic, but four were iron deficient and four folate deficient. Five of the 12 had sustained bone fractures. Bone mineral density was reduced in males but not in females. CONCLUSIONS: The prevalence of coeliac disease in the adult population of Christchurch, New Zealand, is 1.2%. Unrecognized coeliac disease which was detected by population screening was three-fold more common than proven or suspected coeliac disease. Population screening may identify subjects who could benefit from treatment.     

Short report: No-biopsy pathway following the interim BSG guidance reliably diagnoses adult coeliac disease

Recent interim guidance from the British Society of Gastroenterology, aligned to historical paediatric practice, advises a no-biopsy protocol (NBP) for adults with high anti-tissue transglutaminase (tTG-IgA) titres and other clinical factors. A 7-year retrospective review identified 433 patients with positive tTG-IgA. Of these 433, 98 (23%) fulfilled the high titre criteria for an NBP which may have reduced endoscopic burden on the service. A high titre versus low titre translated in a 95% versus 75% histological confirmation of coeliac disease (p<0.01). The addition of anti-endomysial antibody analyses impacted minimally on these predictive rates. Our data support an NBP approach for selected patients. Of concern, however, was the finding that a third of patients with positive titres were not referred for a biopsy despite national guidance at the time advocating it. A clear message needs to be transmitted that the NBP is only for those with high titre, as opposed to any tTG-IgA positivity.     

Skeletal scintigraphy in coeliac disease

A patient with undiagnosed, long-standing coeliac disease had multiple hot spots on skeletal scintigraphy, similar to those observed in malignant disease metastatic to the skeleton. A gluten-free diet corrected the pathological laboratory values, and a repeat skeletal scintigram 15 months after the first one was normal. It is important to identify the secondary hyperparathyroidism of coeliac disease as a cause of multiple hot spots in skeletal scintigraphy--the finding resembles malignancy, but is due to a benign, curable condition.     

Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective

The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work‐up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence‐based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results.     

Case control study on health-related quality of life in adult coeliac disease

AIMS: To evaluate whether health-related quality of life in adult coeliac disease is related to: 1) adhesion to gluten-free diet; 2) manifestation of clinical features; and 3) associated diseases. PATIENTS AND METHODS: A total of 68 coeliac patients (54 female and 14 male) aged between 18 and 74 years, on gluten-free diet for at least two years were studied. The subjective health status was measured by means of the Short Form 36 Health Survey. A series of 136 subjects, matched according to sex, age and ethnic group, were evaluated as control group. RESULTS: Patients obtained worse scores with respect to healthy controls at all domains of Short Form 36 Health Survey (p<0.05); compliers showed better results than non-compliers. The lowest scores were obtained in patients with more than six symptoms, mostly in non-compliers, the highest in compliers with less than six symptoms. Patients with two or more associated diseases presented significantly worse scores than patients with only one associated disease. CONCLUSIONS: The importance of gluten-free diet in clinical management of coeliac disease is confirmed by results of the present study; moreover, the results seem to indicate that a complex interplay of factors should be taken into account in evaluating health-related quality of life in adult coeliac disease. Accordingly, our data show that health-related quality of life of coeliac patients is impaired not only by poor compliance but also by different negative factors such as severity of illness (in terms of number of symptoms) at diagnosis and comorbidity.     

Abdominal CT findings may suggest coeliac disease

BACKGROUND: Coeliac disease is the most common gastrointestinal immunological disorder in the western countries. Many adult patients present non-specific symptoms and signs of malabsorption such as chronic diarrhoea, anaemia, weight loss and abdominal distention. In non-specific and doubtful conditions, computed tomography is often the first medical examination performed. In a clinical practice, a critical review of computed tomography signs is therefore mandatory. AIMS: To evaluate the abdominal computed tomography findings, which are useful to suggest the presence of coeliac disease in adult patients. PATIENTS AND METHODS: The computed tomography studies of 28 coeliac patients were reviewed, looking for any intestinal and extraintestinal abnormality. The computed tomography findings evaluated were: abnormalities of intestinal fold pattern, bowel dilatation, fluid and air excess, duodenal abnormalities, intestinal intussusception, bowel wall thickening, lymphadenopathy, ascites, intestinal stenosis, mesenteric vascular changes. The abdominal computed tomography of a group of 30 normal subjects was also analysed. RESULTS: Intestinal fold pattern abnormalities were seen in 23/28 patients. Intestinal dilatation was seen in 21/28. Fluid excess in 18/28 and lymphadenopathy was seen in 12/28 patients; engorgement of mesenteric vessels in 7/28. Bowel wall thickening was observed in 6/28 patients and transient intussusception was observed in 6/28 patients. Increased air content within the bowel in 4/28 and ascites in 2/28 patients. Bowel dilatation together with fluid excess was observed in 18/28 patients. None of the above mentioned abnormalities abnormalities were seen in normal subjects. CONCLUSIONS: Data of the present study show that several abdominal computed tomography findings may be seen in coeliac adult patients; these findings should be taken into consideration with a high in level of suspicion by radiologists, to avoid diagnostic delay and unnecessary diagnostic and therapeutic procedures.     

Intestinal transglutaminase 2 specific antibody deposits in non-responsive coeliac disease

Background and aims

The diagnosis of coeliac disease is problematic in individuals not responding to a gluten-free diet. Small-bowel villous atrophy occurs in other enteropathies and non-responsive patients are often seronegative. We investigated whether small-bowel mucosal transglutaminase-2 specific autoantibody deposits distinguish non-responsive coeliac disease from other enteropathies.

Methods

Small-bowel mucosal autoantibody deposits were determined in 27 non-responsive, 28 responsive coeliac patients and 10 controls with other enteropathies. Of the non-responsive coeliac patients six were adhering poorly and 21 strictly to the diet; six of the 21 had enteropathy-associated lymphoma, five refractory coeliac disease and 10 otherwise persistent villous atrophy. The presence of mucosal autoantibody deposits was compared to serology, villous morphology, densities of intraepithelial lymphocytes (IELs) and markers of refractory coeliac disease.

Results

Twenty out of 21 well-adhering, all six poorly adhering non-responsive and all 28 untreated responsive coeliac patients had small-bowel mucosal autoantibody deposits present, while controls with other enteropathies were negative. Small-bowel mucosal autoantibody deposits were more accurate in detecting coeliac disease than serology or IEL densities. Refractory coeliac markers revealed only cases with the most severe condition.

Conclusions

Small-bowel mucosal autoantibody deposits differentiate coeliac disease from other enteropathies, enabling the design of appropriate therapeutic strategies.     

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.     

Genetic dissection between silent and clinically diagnosed symptomatic forms of coeliac disease in multiplex families

Background. Coeliac disease has a large variation in clinical outcome. In addition to the classical disease with malabsorption, many individuals have a silent form, in which subjective symptoms are missing but autoantibodies and mucosa lesions are identical to the symptomatic disease.

Aim. To investigate whether differences in HLA DR-DQ genes explain the variation in outcome.

Materials and methods. HLA DQ alleles were determined in 28 multiplex families with sibling pairs in which one had the symptomatic disease but the other had the silent form.

Results. No differences in the distribution of HLA DR-DQ haplotypes could be observed. The clinically diagnosed coeliac disease seemed to have earlier onset than silent coeliac disease.

Conclusions. Results indicate that the major genetic susceptibility locus, HLA DO, does not determine the exact clinical outcome of coeliac disease.