Small bowel adenocarcinoma copy number profiles are more closely related to colorectal than to gastric cancers.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer and consequently, the options for clinical trials are limited. As they are treated according to either a colorectal or a gastric cancer regimen and the molecular biology of a tumor is a pivotal determinant for therapy response, chromosomal copy number aberrations were compared with the colorectal and gastric adenocarcinomas. MATERIALS AND METHODS: A total of 85 microsatellite stable (MSS) adenocarcinomas from the stomach, colorectum and small bowel were selected from existing array comparative genomic hybridization (aCGH) datasets. We compared the aCGH profiles of the three tumor sites by supervised analysis and hierarchical clustering. RESULTS: Hierarchical clustering revealed substantial overlap of 27 SBA copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas. DNA copy number aberrations located at chromosomes 1p36.3-p34.3, 4p15.3-q35.2, 9p24.3-p11.1, 13q13.2-q31.3 and 17p13.3-p13.2 were the strongest features discriminating SBAs and colorectal adenocarcinomas from gastric adenocarcinomas. CONCLUSIONS: We show that MSS SBAs are more similar to colorectal than to gastric cancer, based on the 27 genome-wide DNA copy number profiles that are currently available. These molecular similarities provide added support for treatment of MSS small bowel cancers according to colorectal cancer regimens.

Evidence of high sugar intake, and low fibre and mineral intake, in the gluten-free diet.

BACKGROUND: The only therapy for coeliac disease (CD) is a long-term gluten-free diet (GFD). Little is known about the detailed composition of such a diet. AIM: To clarify the nutritional composition of a GFD and to compare it with a non-GFD diet in representative non-CD populations. METHODS: A total of 139 consecutive patients with CD were invited to fill in a prospective validated 5-day food diary, of whom data from 93 were analysed. Results were compared with data from the National Diet and Nutrition Survey of Adults and the UK Women's Cohort Study (UKWCS). RESULTS: Individuals consuming a strict GFD generally had similar intakes of energy and nutrients to those of comparison populations, but a higher proportion of carbohydrate intake was obtained from nonmilk extrinsic sugars and intakes of nonstarch polysaccharides were low. Compared with the UKWCS sample, female patients adhering to a GFD had lower intakes of magnesium, iron, zinc, manganese, selenium and folate. In male patients, intakes of magnesium and selenium were particularly low. CONCLUSIONS: This study reinforces the need for clinicians to recognize that avoidance of gluten cannot be the sole focus of a gluten-free diet. Maintenance of adequate intakes of essential nutrients and in particular complex carbohydrates must also be the goal for patients.

Long-term histological follow-up of people with coeliac disease in a UK teaching hospital.

BACKGROUND: Coeliac disease is a relatively common condition which is usually managed by placing patients on a gluten free diet. Follow up biopsies to confirm histological recovery are controversial with a considerable variation in practice observed. AIM: To determine the length of time to histopathological recovery in a group of coeliac disease patients and its associations with clinicopathological data. DESIGN AND METHODS: All patients attending a specialist coeliac disease clinic prior to March 2009 were entered onto a database which recorded various clinicopathological data. The histopathology reports for all duodenal biopsies were reviewed and each biopsy was given a histopathological disease score based on a modified Marsh grade. RESULTS: Two hundred and eighty-four patients underwent index and at least one subsequent biopsy. Two-hundred and twenty-seven (80%) showed histopathological improvement and 100 (35%) returned to normal (median recovery time 1.9 years, inter-quartile range 1.0-4.8 years). Patients with less severe disease at diagnosis were more likely to show a better response (r = 0.281, P < 0.0001). Older patients demonstrated a shorter time to histopathological recovery (r = -0.200, P = 0.001). Compliance with a gluten free diet was correlated with the best biopsy score (r = -0.134, P = 0.040) and degree of histological recovery (r = 0.161, P = 0.014). CONCLUSION: Current guidelines for the timing of repeat biopsy after commencing a gluten free diet are unclear, although 4-6 months has been recommended. This study shows that time to histological recovery is longer than traditionally thought and may need to take into account the patient's age at diagnosis, the initial disease score and the level of compliance with a gluten free diet.

Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.

OBJECTIVE: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). RESULTS: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. CONCLUSIONS: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

Advances in celiac disease.

PURPOSE OF REVIEW: This article aims to summarize recent critical research in celiac disease. RECENT FINDINGS: The crucial epitopes that confer toxicity to gliadin and related prolamins continue to be defined, as do methods of assessing their toxicity. New approaches to making the gluten-free diet more palatable are being studied. SUMMARY: The position of proline residues is critical to the toxicity of cereal proteins to patients with celiac disease. Other genetic factors, apart from HLA status, remain elusive. Exciting advances in altering the toxicity of cereal proteins are being made.

Systemic cytomegalovirus infection complicating ulcerative colitis: a case report and review of the literature.

Cytomegalovirus is a common infection worldwide and in the immunocompromised individual it can be a major cause of morbidity and mortality. In patients with inflammatory bowel disease cytomegalovirus infection has been described in both immunocompetent and immunocompromised individuals. A 34 year old man with an exacerbation of his colitis was diagnosed as having both cytomegalovirus colitis and hepatitis. The diagnosis was made on the classical appearance of "owl's eye" inclusion bodies on colonic and hepatic biopsies and, in addition, viral serology and polymerase chain reaction (PCR) analysis of the cytomegalovirus DNA copy number. Fourteen days of treatment with ganciclovir led to a prompt improvement in the symptoms of colitis, resolution of the pyrexia, normalisation of the liver function tests, and clearance of the virus, as measured by a negative cytomegalovirus DNA PCR. Cytomegalovirus infection is a potentially fatal complication of treatment induced immunosuppression in patients with inflammatory bowel disease. As in this case, infection may be systemic and not confined to the intestine. Prompt diagnosis using histology, serology, and PCR analysis allows prompt introduction of therapy and an improved prognosis.

Neurologic complications of liver transplantation in adults.

OBJECTIVE: To describe the incidence and nature of neurologic complications following liver transplantation. METHODS: Adult patients who received liver transplants at St. James's University Hospital between September 1, 1990, and August 31, 2000, were identified. Case notes were reviewed and demographic data, details of the liver disease, neurologic complications, and discharge information were recorded. RESULTS: The authors identified 657 patients and traced the case notes of 627 (95.4%). These patients had a total of 711 transplants. Neurologic complications occurred following 185 transplants (26%) affecting 170 patients (27%). The most common complications were diffuse encephalopathies, which affected 66 patients (11%), and seizures, which affected 37 patients (6%). Forty-three percent of patients with alcoholic liver disease and 41% of patients with primary biliary cirrhosis experienced a neurologic complication. These proportions were higher than for other transplant indications (p < 0.001). Patients who experienced a neurologic problem spent longer in hospital (p < 0.01) and had a poorer outcome (p < 0.001). CONCLUSIONS: Neurologic complications occur following 26% of liver transplants. A higher proportion of patients who received transplants for alcoholic liver disease and primary biliary cirrhosis experienced neurologic complications than those receiving transplants for other reasons. Patients who experience a neurologic problem spend longer in hospital and have a poorer outcome.

Primary small-bowel malignancy in the UK and its association with coeliac disease.

BACKGROUND: Malignancies of the small intestine are rare, accounting for <2% of all cancers of the gastrointestinal tract. There is little information about the presentation and prognosis of these tumours, and the frequency of established risk factors. AIM: To estimate the frequency of small-bowel malignancy in the UK, and its relationship to the presence of coeliac disease. DESIGN: Survey of clinicians registered with the British Society of Gastroenterology. METHODS: Data were collected monthly from June 1998 to May 2000. Clinicians (n=1327) were asked by post to report newly diagnosed cases of primary small-bowel malignancy. A form was sent to reporting clinicians, requesting an anonymous identifier, type of malignancy, and whether coeliac disease was present. A detailed questionnaire followed, requesting further clinical and pathological details. RESULTS: Clinico-pathological data were ascertained for 395 cases, including 175 adenocarcinomas, 107 lymphomas and 79 carcinoid tumours. In 13% of adenocarcinoma cases and in 39% of lymphomas, there was a diagnosis of coeliac disease. Survival rates at 30 months for adenocarcinomas, lymphomas and carcinoid tumours were 58%, 45% and 78%, respectively. Prognosis of all tumours was inversely related to stage at presentation, and lymphomas associated with coeliac disease were associated with a poorer prognosis. DISCUSSION: This study provides additional evidence that coeliac disease confers susceptibility to adenocarcinoma of the small bowel, as well as lymphoma. The long time from the onset of symptoms to diagnosis of small bowel tumours is of concern, as this delay is reflected in the high proportion that presented with metastatic disease. Although the absolute risk of malignancy is small, coeliac disease complicated by malignancy appears to be poorly controlled.

Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease.

Susceptibility to coeliac disease involves HLA and non-HLA-linked genes. The CTLA4/CD28 gene region encodes immune regulatory T-cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta-analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non-parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0.004 and 0.039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0.0001 and 0.0014 at D2S2214, respectively, and 0.0008 and 0.0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.

Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant?

BACKGROUND: A raised intraepithelial lymphocyte (IEL) count with normal villous architecture is a recognised finding in latent coeliac disease. Little information is available in cases without gluten sensitive enteropathy in adults. AIMS: To assess the frequency of such a finding in routine practice and to determine whether it is clinically relevant. METHODS: Patients with subjectively increased IELs as the only abnormality were identified prospectively from a routine duodenal biopsy series over a 12 month period. The biopsy specimens in these index cases were re-examined together with two controls with normal histology for each case, and three counts of IEL/100 epithelial cells were made in all samples. The index cases were then contacted and interviewed to obtain clinical information, approximately 12 months from the initial biopsy. Further data were obtained from their clinical records. RESULTS: Fourteen of 626 (2.2%) patients who had duodenal biopsies over the 12 month period had a subjective increase in IELs with normal villous architecture. Fifteen patients with newly diagnosed gluten sensitive enteropathy were also identified during the study period. Formal counting of the index cases and controls revealed a significant difference in IELs/100 epithelial cell counts between the two (mean, 38 (SD, 6.2) v 12.4 (4.6); p < 0.0001). Three of the 14 index cases tested had a positive coeliac antibody test compared with 12 of 15 newly diagnosed patients with coeliac disease and 10 of 93 patients with normal histology. The major clinical diagnostic categories in raised IEL cases were those with positive coeliac serology (n = 3), unexplained anaemia (n = 3), and chronic liver disease (n = 3). Six of 10 patients who were interviewed had ongoing gastrointestinal symptoms one year later. Three patients had had follow up duodenal biopsies, at the discretion of their responsible clinicians, with no change in IEL counts despite the commencement of a gluten free diet in two patients. CONCLUSION: A raised IEL count with normal villous architecture is not uncommon. Six of the 14 patients may have had latent coeliac disease. The cause in at least half of cases is not obvious at present. The finding of a raised IEL count with normal villous architecture is of sufficient clinical importance to be highlighted in routine duodenal biopsy reports.

Teaching in the new NHS: the specialised ward based teacher.

OBJECTIVES: To evaluate the effects of introducing specialised ward based teachers (WBTs) who had a broad remit to improve third year medical undergraduates' clinical experience. DESIGN: Quantitative and qualitative methods including interviews with WBTs, participating consultants and SIFT co-ordinator; student questionnaire and evaluations; analysis of Objective Structured Clinical Examination (OSCE) scores to ascertain if exposure to WBTs affected OSCE scores. SETTING: Two university teaching hospitals. PARTICIPANTS: Third year undergraduate medical students from one school of medicine; four WBTs; 25 consultants; SIFT co-ordinator. MAIN OUTCOME MEASURES: Student evaluations. Student questionnaires. Student OSCE scores. Interview data. RESULTS: WBTs had a demonstrable effect on student performance in OSCE examinations. 94% of students either agreed or strongly agreed that WBTs had helped them develop their examination skills and 87% either agreed or strongly agreed that WBTs had helped them develop their history taking skills. Interview data indicated that the consultants and SIFT co-ordinator considered that WBTs made an important contribution to clinical teaching. CONCLUSIONS: This study suggests that specialised WBTs are one way to manage clinical experience and enhance learning of undergraduate medical students. As clinical teaching moves into earlier parts of the undergraduate curriculum and into the community there is potential for this role to be developed.

A new cause of 'non-responsiveness' in coeliac disease?

A 42 year old man presented with gluten-responsive coeliac disease and secondary pancreatic insufficiency. Subsequently his symptoms relapsed and repeat small intestinal biopsy showed villous atrophy and infiltration by leukaemic cells, despite continuation of a gluten-free diet. Serious causes of relapse and non-responsiveness in coeliac disease include enteropathy-associated T-cell lymphoma, ulcerative jejunitis and an end-stage hypoplastic mucosa. This is the first report of non-responsiveness due to infiltration by leukaemia.

No polymorphism in the tissue transglutaminase gene detected in coeliac disease patients.

BACKGROUND: The autoantigen for the anti-endomysial antibody (AEA) found in coeliac disease has recently been reported to be the enzyme tissue transglutaminase (tTG). Polymorphisms in the gene for tTG would result in different enzymic isoforms being expressed. Certain isoforms may interact with gliadin to create antigenic neoepitopes, which could then generate an immune response in genetically predisposed individuals possessing major histocompatibility complex (MHC) class II DQ2. METHODS: We have sequenced the coding region of tTG in coeliac patients and normal controls. Total RNA was extracted from mucosal biopsies from eight AEA-positive histologically proven coeliac disease patients and four control patients with a histologically normal duodenum and a negative AEA. The 2-kb coding region of tTG was amplified in overlapping fragments by reverse transcription polymerase chain reaction (PCR), using five sets of PCR primers. Each overlapping PCR fragment was sequenced using the fmol DNA sequencing system. RESULTS: tTG transcripts were detected in all samples. There was no difference in the coding sequence of tTG between the four control and eight coeliac patients, even though we observed differences in sequence between our study and the original published sequence. These differences have also been reported in sequences published subsequent to the original description. CONCLUSIONS: Polymorphisms in the tTG gene have not been observed in coeliac disease patients and therefore cannot explain the creation of neoepitopes.