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Although several studies have examined the effects of cimetidine on pituitary-thyroid function, few have investigated ranitidine in this respect. We found no changes in thyroid-stimulating-hormone (TSH) or prolactin responses to TSH-releasing-hormone (TRH) in 10 patients with peptic ulcer disease given oral ranitidine. Serum total and free thyroxine (TT4 and FT4) concentrations declined slightly, whereas total and free triiodothyronine (TT3 and FT3) increased slightly following ranitidine. None of these changes achieved statistical significance. Both the ratio of TT4/TT3 and FT4/FT3, however, declined (P less than 0.05) following ranitidine. Thus ranitidine may have a minor influence on peripheral deiodination of thyroxine but has little effect on hormone production from the thyroid gland. The diagnostic value of biochemical tests of thyroid function is not seriously compromised in patients receiving ranitidine. [ABSTRACT FROM AUTHOR]

Background: Coeliac disease affects adult Asians from north India, Pakistan and Bangladesh in the UK but how commonly this occurs is unknown. An audit of coeliac disease was therefore conducted in a well-defined area in southern Derbyshire., Methods: All white and Asian patients with biopsy-confirmed coeliac disease diagnosed between 1958 and 2008 were identified. Population data from the Office of National Statistics allowed the calculation of prevalence. Presenting symptoms, adherence to a gluten-free diet and follow-up record were determined for Asians and compared with matched white patients., Results: Among 1305 coeliac patients diagnosed between 1958 and 2008, 82 were Asian. Coeliac disease occurred significantly more frequently in Asian than white individuals and this could be attributed to the significantly higher prevalence in women 16 years and older and under 60 years of age. No Asian man over the age of 65 years was diagnosed with coeliac disease. Asians are more likely to present with anaemia and less likely to present with diarrhoea than white individuals. Asians are less likely to adhere to a strict gluten-free diet than white patients., Conclusions: This baseline audit indicates that increased efforts should be directed towards diagnosing coeliac disease in Asian men over the age of 65 years, in whom at present it is unrepresented. Strategies also need to be developed to help more Asian patients adhere strictly to the gluten-free diet.

Objectives: The objective of the study was to compare cause-specific mortality risks in the periods before and after the introduction of accurate and specific serological tests for diagnosing celiac disease., Methods: This was a prospective cohort study of people with celiac disease diagnosed in Southern Derbyshire, United Kingdom, from the late 1950s onward, and followed-up from 1978 until death or 31 December 2006. Standardized mortality ratios (SMRs) were calculated for all-cause mortality and various cause-specific groups concentrating on the period commencing 2 years after diagnosis of celiac disease., Results: A total of 1,092 celiac patients (of whom 90% were incident) contributed 10,152 person-years of follow-up beyond 2 years of diagnosis and 142 deaths. A statistically significant increase in all-cause mortality was observed (SMR 1.37; 95% confidence interval (CI) 1.16-1.62), along with an increase in deaths from cancer (SMR 1.61; 95% CI 1.19-2.13), digestive disease (SMR 2.19; 10 deaths, 4 due to liver disease), and respiratory disease (SMR 1.57; 21 deaths, 11 due to pneumonia). The overall increase in mortality risk was higher for males (SMR 1.86; 95% CI 1.45-2.34) than it was for females (SMR 1.10; 95% CI 0.86-1.38). When results were stratified by period of diagnosis (pre-1990, 1990-1999, and 2000 onward), we found no evidence of differing all-cause mortality between cases diagnosed within these periods., Conclusions: Mortality in people with celiac disease has not materially changed over the 25 years of this study with the introduction of serological tests to aid diagnosis. The excess overall mortality we observed was partly explained by deaths from cancer, digestive disease, and respiratory diseases, of which the majority were deaths from pneumonia, supporting existing guidelines that advise pneumococcal vaccination for celiac patients.

Celiac disease is one of the most common chronic diseases encountered in the Western world with a serological prevalence of approximately 1%. Since it is so common, much comorbidity will occur either as associations or simply by chance, or as complications of the disorder. Many of the published studies purporting to establish the frequency of these occurrences have been limited by factors such as the source and number of patients considered, choice of control groups and ascertainment bias. Recent epidemiological studies have attempted to minimize these sources of error and provide more reliable information. Autoimmune diseases constitute clinically important associations, of which Type 1 diabetes mellitus and thyroid disorders are the most important. Several liver disorders, including primary biliary cirrhosis and primary sclerosing cholangitis, are also associated. The frequency of malignant complications of celiac disease is much lower than earlier studies have indicated, with lymphoma increased by approximately fivefold and the absolute number of tumors is small. The increase in fracture risk in celiac disease is only modest. Although neurological and psychiatric conditions affect celiac patients, no disorder specifically associated with celiac disease has been identified. Reproductive problems have been overexaggerated. It is important that these co-morbidities are recognized because if not, symptoms will be falsely attributed to deliberate or inadvertent ingestion of gluten, rather than prompt a search for a second diagnosis. Furthermore, in a patient with an established diagnosis that is considered falsely to account for the whole clinical picture, celiac disease is likely to remain undetected.

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.

Background: Coeliac disease affects about 1% of the population, with the majority being undetected. As a consequence, there have been calls for the introduction of screening. Before screening is given serious consideration, it is important to assess how acceptable early diagnoses and treatment would be., Aim: To assess patients' views as to the diagnosis and treatment of disease., Methods: Coeliac disease patients who had taken a gluten-free diet for at least 12 months (mean 60 months) were mailed a questionnaire. Coeliac patients presenting with typical classical symptoms were compared with those diagnosed without such symptoms., Results: Overall, 83% (147/177) of coeliac patients returned the questionnaires. Two-thirds (68%, 101/147) reported that their dietary restrictions reduced their enjoyment of food; 46% (68/147) believed their food cost them more and estimated this to be an extra 10 pounds sterling (16 euros) per week. Of those reporting greater cost, 31 (21%) said this was a problem for them. Half (54%, 80/147) reported doing things they enjoyed less often because of their diet, with the most common activity sacrificed being dining out (n = 65). In spite of these findings, 81% (119/147) reported being pleased that they were diagnosed, with 66% (59/89) of cases with classical symptoms wishing they had been diagnosed earlier compared with 45% (23/51) of those without such symptoms (chi(2) = 6.0, P < .05). In contrast, 27% (14/51) of coeliacs diagnosed without classical symptoms regretted being diagnosed with their condition compared with 10% (9/89) of those with classical symptoms (chi(2) = 7.1, P < .01)., Conclusions: Even after several years of a gluten-free diet, many patients with coeliac disease regard it as a substantial burden, with a quarter of screen detected patients reporting regret at being diagnosed. Our findings question how acceptable screening for coeliac disease would be in people with minimal or no symptoms.

Background: In view of the high diagnostic accuracy of immunoglobulin-A-tissue transglutaminase antibodies for detecting coeliac disease, we have explored whether a small bowel biopsy is always required to establish the diagnosis., Aim: To define the transglutaminase antibody level giving a positive predictive value for coeliac disease of 100% and to subsequently assess the proportion of new diagnoses of coeliac disease having such a result., Methods: The Celikey kit (Phadia GmbH, Frieburg, Germany) was used to measure transglutaminase antibody levels., Results: All patients with transglutaminase antibody levels >30 U/mL, i.e. 10 x upper limit of normal in 2002/2003 had characteristic small bowel mucosal lesions. In a subsequent audit, 58% of 112 new diagnoses of coeliac disease in 2004/2005 had levels above this cut-off value., Conclusions: We have shown that a transglutaminase antibody level can be defined which gives a positive predictive value of 100% for coeliac disease. From published data, these observations can be extended to most second-generation transglutaminase antibody kits. Our data provide further evidence that diagnostic guidelines could be modified so that small bowel biopsy is no longer regarded as mandatory in patients with such high transglutaminase antibody levels. This will avoid an invasive procedure and lead to a more rapid diagnosis and earlier treatment for over half of the new patients with coeliac disease.

Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

Background and Aims: Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut function that in excess causes nausea, vomiting, and diarrhea. We recently showed that patients with post-infective irritable bowel syndrome have increased postprandial release of 5-HT associated with low-grade T-cell mediated inflammation. Celiac disease is another common disease in which a T-cell enteropathy is associated with increased mucosal 5-HT levels. Our aim was to determine how this inflammatory lesion influenced 5-HT bioavailability and how changes in 5-HT related to the symptoms of nausea, vomiting, and diarrhea seen in untreated celiac patients., Methods: Fasting plasma and platelet 5-HT and postprandial plasma 5-HT levels were measured after a high-carbohydrate meal in celiac patients (n = 18) and healthy controls (n = 18) using high-pressure liquid chromatography. Dyspepsia was assessed during the postprandial period using a questionnaire. Finally, we compared the histology and mucosal 5-HT levels in duodenal biopsy specimens from celiac patients and controls., Results: Celiac patients had increased 5-HT-containing enterochromaffin cell numbers and significantly higher peak plasma 5-HT levels (P = .0002), postprandial area under the curve (P = .0006), and platelet 5-HT stores (P = .031) than controls. Peak 5-HT levels correlated significantly with postprandial dyspepsia scores (P = .005). Celiac patients had higher duodenal 5-HT levels (P = .007) than controls., Conclusions: Celiac disease is associated with increased mucosal 5-HT content and enhanced 5-HT release from the upper small bowel, which correlates with postprandial dyspepsia. Serotonin excess may mediate dyspeptic symptoms in untreated celiac disease.

Purpose: To assess gallbladder contraction, gastric emptying, and antral motility in untreated celiac patients and healthy controls using a single MRI examination., Materials and Methods: Gallbladder emptying, gastric emptying, and antral motility were measured in 15 celiac patients and 15 age/sex-matched healthy controls following a 323-kcal test meal using EPI techniques. Postprandial dyspepsia scores were recorded on a questionnaire., Results: Fasting gallbladder volume (P=0.01) and the volume of bile ejected postprandially (P=0.014) were increased in celiacs. Gastric emptying tended to be slower in celiacs (P=0.142). Three celiac patients with severe postprandial dyspepsia and total villous atrophy had pathologically delayed gastric emptying and increased fasting gallbladder volume. Antral contractions were absent in five out of 14 patients (36%) five minutes after the meal, but in none of 10 volunteers in whom the antrum could be visualized (P=0.128)., Conclusion: This study shows that using MRI, multiple parameters related to upper gastrointestinal function in celiac disease can be measured in a single noninvasive study, whereas previously three separate visits would have been required. Celiacs have increased fasting gallbladder volumes and tend to have slower gastric emptying., (J. Magn. Reson. Imaging 2005. (c) 2005 Wiley-Liss, Inc.)

Celiac disease (CD) is associated with intestinal lymphoma and other forms of cancer, especially adenocarcinoma of the small intestine, of the pharynx, and of the esophagus. Enteropathy-associated T-cell lymphoma (EATL) is a rare form of high-grade, T-cell non-Hodgkin lymphoma (NHL) of the upper small intestine that is specifically associated with CD. This NHL subtype arises in patients with either previously or concomitantly diagnosed CD. In a subgroup of patients, there is progressive deterioration of a refractory form of CD. EATL derives from a clonal proliferation of intraepithelial lymphocytes and is often disseminated at diagnosis. Extraintestinal presentations are not uncommon in the liver/spleen, thyroid, skin, nasal sinus, and brain. The outlook of EATL is poor. Recent studies indicated that (1) CD is associated with a significantly increased risk for NHL, especially of the T-cell type and primarily localized in the gut (EATL); (2) the CD-lymphoma association is less common than previously thought, with a relative risk close to 3; (3) CD screening is not required in patients with NHL of any primary site at the onset, unless suggested by specific findings (T-cell origin and/or primary gut localization). The risk of NHL associated with clinically milder (or silent) forms could be lower than in typical cases of CD. Several follow-up studies suggest that the GFD protects from cancer development, especially if started during the first years of life. Strict adherence to the GFD seems to be the only possibility of preventing a subset of rare but very aggressive forms of cancer.

Background: The diagnostic accuracy of IgA tissue transglutaminase antibodies (TGA) for coeliac disease (CD) has been assessed following the introduction of the test into routine practice in 2002., Methods: Specificity was assessed in serum samples received from 1554 adults for routine coeliac serology. The population for assessing sensitivity was 75 consecutive new adult diagnoses of CD. TGA was measured by enzyme-linked immunoassay using human tissue transglutaminase as antigen. Concordance between TGA and endomysial antibody (EMA) was also assessed., Results: The prevalence of new diagnoses of CD in the population tested was 2.8% with similar proportions of new diagnoses in males and females. The positive predictive values at a cut-off of 3 units/mL were 0.77 for samples from Primary Care and 0.92 for samples from Hospital sources, with a sensitivity of 92%. At TGA <3 units/mL, EMA was usually negative; when TGA was >4.9 units/mL, EMA was rarely negative., Conclusions: We have assessed the role of TGA in routine clinical practice and confirmed high diagnostic accuracy. Sensitivity (92%) is identical to the sensitivity for EMA. IgA deficiency should be excluded in samples showing low absorbance readings in the TGA assay and interference from monoclonal and polyclonal IgA should be excluded in samples with slightly raised TGA levels and negative EMA. TGA is recommended as the first-line serological test for coeliac disease.

Background: There is recent evidence from studies of hospitalized and of undiagnosed patients that the risk of lymphoma for people with coeliac disease may be lower than previously thought. In addition, there have been no precise estimates of small bowel lymphoma risk due to a lack of population data., Aim: To examine these and other malignant risks in a cohort of patients more typical of those seen in routine clinical practice., Methods: A prospective cohort study of incident malignancy rates in patients with coeliac disease in southern Derbyshire compared with general population figures., Results: During 5684 person years of follow-up 31 malignancies (excluding non-melanoma skin cancer) occurred in comparison with 30.30 expected [standardized incidence ratio (SIR) 1.02 (0.69-1.45)]. There were four non-Hodgkin's lymphomas (0.69 expected) SIR 5.81 (1.58-14.86), of which one originated in small bowel (0.02 expected) SIR 40.51 (1.03-225.68). GI malignancy occurred in nine (5.71 expected) SIR 1.58 (0.72-2.99), and breast cancer in three (5.08 expected) SIR 0.59 (0.12-1.73)., Conclusions: There is no increase in the risk of incident malignancy in this population and the risk of non-Hodgkin's lymphoma in general or of the small bowel is lower than previously found from UK coeliac cohorts.

Purpose: The relation between celiac disease and epilepsy is uncertain. Previous studies have suggested an association, whereas others have not., Methods: We ascertained the prevalence of active epilepsy in a cohort of 801 celiac patients by patient interviews and retrospective case note review. All the celiac patients had diagnostic confirmation by small bowel biopsy., Results: Twenty-one patients had a history of epileptic seizures, but only nine (1.1%) had active epilepsy. No specific epileptic syndrome was identified., Conclusions: This study suggests that a causal relation between gluten sensitivity and active epilepsy is unlikely.

Objective: To examine the seroprevalence, correlates, and characteristics of undetected coeliac disease in a large adult population sample in Cambridge, UK., Methods: The Cambridge General Practice Health Study invited individuals from 12 general practices, aged 45-76 years, to attend for a health survey that included a bone density measurement, between 1990 and 1995. A total of 7550 participants' serum samples were tested for antiendomysial antibody (EMA). Seroprevalence of undetected coeliac disease was based on EMA positivity. Differences between EMA positive and negative participants of various physiological correlates and reported characteristics were estimated by multivariate logistic and linear regression and adjusted for age, sex, social class, and smoking behaviour., Results: The seroprevalence of undetected coeliac disease in this general population sample aged 45-76 was 1.2% (95% confidence interval (CI) 0.9-1.4). EMA positive participants (n=87) were on average slightly lighter by 2.2 kg (p=0.08), were more likely to have reported their general health as being "good or excellent" (odds ratio (OR) 1.76 (95% CI 0.90-3.46)), and were less likely to report being a current smoker (OR for current versus never 0.36 (95% CI 0.14-0.90)) than EMA negative participants. EMA positivity was associated with an 8% reduction in mean serum cholesterol (0.5 mmol/l; p<0.01) and reductions in mean haemoglobin (0.3 g/dl; p<0.01), total protein (1.0 g/l; p<0.05), and corrected serum calcium (0.02 mmol/l; p<0.05). There was an increased risk of osteoporosis in EMA positive participants (OR 3.1 (95% CI 1.3-7.2)) and of mild anaemia (OR 4.6 (95% CI 2.5-8.2)) compared with EMA negative participants., Conclusions: Undetected coeliac disease is likely to affect approximately 1% of the population of England aged 45-76 years, a value similar to several other countries. Those affected report "better health" but they do have an increased risk of osteoporosis and mild anaemia. In contrast, they have a favourable cardiovascular risk profile that may afford protection from ischaemic heart disease and stroke.

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.

Background: While coeliac disease is now recognised as being associated with both osteoporosis and osteomalacia, the size of any increase in the risk of fracture in patients with coeliac disease compared with the general population has not been quantified., Aim: To examine the fracture experience of adults with coeliac disease compared with the general population., Subjects: Patients with coeliac disease diagnosed in adulthood and born before 1950, selected from two large population based disease registers, and age and sex frequency matched controls identified from local general practitioner lists., Methods: A four page lifestyle and general health questionnaire which included specific questions about fracture experience., Results: Analysis was performed on 244 patients with coeliac disease and 161 controls, giving response rates of 89% and 72%, respectively. Eighty two (35%) coeliac patients and 53 (33%) controls reported ever having sustained one or more fractures, giving an age and sex adjusted odds ratio of 1.05 (95% confidence interval (CI) 0.68-1.62). The most common fracture site reported was the forearm or wrist, with an adjusted odds ratio of 1.21 (95% CI 0.66-2.25) for patients with coeliac disease having had a forearm or wrist fracture. Low trauma fractures were reported by 37 patients with coeliac disease (15.7%) and by 21 controls (13.8%), with an adjusted odds ratio of 1.16 (95% CI 0.65-2.10). The risk of low trauma fracture was slightly higher in coeliac men than women (odds ratio 1.28 compared with 1.12), but this difference was not statistically significant (p=0.84). After adjustment for age, sex, body mass index, and smoking status, patients with coeliac disease reported 13% more low trauma fractures than controls (odds ratio 1.13, 95% CI 0.60-2.12). There was no difference in low trauma fracture risk before and after diagnosis of coeliac disease., Conclusion: No overall increased fracture risk in patients with coeliac disease was observed. Although severe osteoporosis may develop in a subset of patients, as a whole patients with coeliac disease do not represent a population at particularly high risk of osteoporotic fracture and thus targeting them for osteoporosis screening and treatment is not justified.

The average prevalence of coeliac disease among children with diabetes mellitus in 26 reports was 4.5% (0.97-16.4%). Malabsorption, unstable diabetes, and growth failure, indicate that coeliac disease may be present. Even those who are apparently asymptomatic may have subtle complaints indicative of coeliac disease if a careful history is taken. Ill health may only be recognised in retrospect following the benefits conferred by a gluten free diet. For these reasons it is recommended that a screening programme should be instituted to detect coeliac disease in these children. Parents and where possible children themselves, should be fully involved at all stages of the screening, diagnostic, and treatment process.

Background: Using selected sample populations, we compared sensitivity and specificity of autoantibodies to guinea pig and human tissue transglutaminase to assess if the human antigen is superior for predicting coeliac disease., Methods: Four commercial enzyme-linked immunoassay kits using human tissue transglutaminase as antigen were used to measure autoantibody levels in serum samples from untreated adult coeliacs (n = 32). They were from a series of 130 cases diagnosed between 1997 and 1999 and chosen to bias the group towards subjects with negative autoantibodies when measured with guinea pig tissue transglutaminase as antigen. Samples from 38 control subjects (biased towards false-positive levels with guinea pig antigen) were used to compare specificity. We also assessed if human antigen kits could differentiate between levels in normal subjects and in selective IgA deficiency., Results: Sensitivity for coeliac disease in this selected group using the human antigen kits ranged from 88% to 100%. Three kits showed significantly higher specificity (82%-97%, P < 0.05) than the guinea pig antigen kit (71%) for the samples studied. No kit achieved complete separation between normal autoantibody levels and lower levels in selective IgA deficiency., Conclusions: All human antigen kits showed significantly higher sensitivity for coeliac disease compared to guinea pig antigen (P < 0.001). Receiver operating characteristic curves confirmed the superior diagnostic accuracy of the human antigen kits.

Background: While coeliac disease is clearly induced by dietary gluten ingestion in genetically susceptible individuals, other environmental factors may influence the onset of disease. Two studies have suggested that cigarette smoking has a protective role, but a third has not., Methods: We examined the relationship between cigarette smoking and coeliac disease in individuals with coeliac disease diagnosed in adulthood from two large population-based disease registers and age and sex-matched controls from local general practitioner lists. Participants were mailed a three-page lifestyle and general health questionnaire. Smoking habits of coeliacs were compared with controls and with habits reported in the Health Survey for England 1995., Results: An inverse association between current smoking and adult coeliac disease was identified (odds ratio: 0.77 (95% CI 0.56-1.06)) and remained when comparing ever smoked versus never smoked (odds ratio: 0.83 (0.68-1.00)). When the smoking habits of the coeliacs were compared with the national figures, the number of coeliacs who currently smoked was 40% lower than expected (smoking ratio 0.60, 0.46-0.78). This inverse association was accounted for by the behaviour of the 35-54-year age group (odds ratio for ever smoked 0.67 (0.51-0.89)). There was no association with having ever smoked in the younger age group (odds ratio: 1.44 (0.75-2.78)) or the older group (odds ratio: 0.92 (0.67-1.26))., Conclusions: There was an inverse association between adult coeliac disease and cigarette smoking which was accounted for by middle-aged coeliacs having never smoked. These results are consistent with an age-dependent interaction between cigarette smoking and the other environmental factors implicated in coeliac disease, including gluten.

A variety of neurological disorders have been reported in association with coeliac disease including epilepsy, ataxia, neuropathy, and myelopathy. The nature of this association is unclear and whether a specific neurological complication occurs in coeliac disease remains unproved. Malabsorption may lead to vitamin and trace element deficiencies. Therefore, patients who develop neurological dysfunction should be carefully screened for these. However, malabsorption does not satisfactorily explain the pathophysiology and clinical course of many of the associated neurological disorders. Other mechanisms proposed include altered autoimmunity, heredity, and gluten toxicity. This review attempts to summarise the literature and suggests directions for future research.

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.

We have evaluated a commercial assay for serum IgA class antibodies to tissue transglutaminase, the enzyme identified as the major endomysial autoantigen in coeliac disease (CD). Sera were available from 130 adults diagnosed with CD in Southern Derbyshire between 01 01 97 and 31 12 99. Sera from 100 patients without villous atrophy on small intestinal biopsy were controls. The ability of the assay to detect abnormally low total IgA levels was assessed using sera from 18 subjects with IgA deficiency. Sensitivity and specificity of this IgA-anti tissue transglutaminase (tTGA) assay (86.2%, 91.0%) were inferior to endomysial antibody (EMA; 93.8%, 100%). tTGA has significantly higher sensitivity than IgA-antigliadin (76.2%). tTGA was appropriately undetectable (<0.03 U/mL) in 17 of 18 subjects with selective IgA deficiency. The high likelihood ratio (35) for tTGA at levels >9.0 U/mL and methodological advantages over EMA suggest that tTGA could be used as a first line diagnostic test for CD. At tTGA levels of 4-9 U/mL, use of EMA as a second line test would improve specificity.

This case report details a child with coeliac disease and giardiasis. Treatment of the infection without recourse to a gluten-free diet cured the symptoms of diarrhoea and returned the small intestinal morphology to normal. Thus, the patient moved from active to latent coeliac disease. Potential and latent forms of coeliac disease are being increasingly recognized, since markers have become available to identify patients and investigations developed to test for gluten sensitivity in the small intestinal mucosa. This case provides an opportunity to consider potential and latent forms of coeliac disease and how these impact on clinical practice and the wider understanding of the disorder.

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.

Background: The rise in the incidence of Crohn's disease (CD) suggests the role of an environmental factor in the development of the disease in susceptible individuals. Perinatal exposure to infection has been proposed as such an environmental factor., Aim: To investigate the influence of birth date on the development of CD in later life., Patients and Method: Four registers of patients with CD, diagnosed from 1972 to 1989, were combined, and data from 1624 patients were examined. The birth dates of CD patients were compared with national birth figures for three decades (1941-50, 1951-60, and 1961-70) to avoid temporal changes in birth trends, and year of birth was compared with epidemic measles years between 1951 and 1967. Risk ratios with 95% confidence intervals (CI) and chi(2) tests were performed., Results: There were marginal differences between the birth dates of the CD patients and those predicted from the general population. Further analysis of both season of birth and year halves revealed a very weak association with the first half of the year (relative risk 1.14 (95% CI 1.01-1.30)). There was no association between developing CD and birth during measles epidemics between 1951 and 1967., Conclusions: In utero or perinatal exposure to seasonal environmental factors are unlikely potential aetiological agents in the later development of CD.

Background: Weight loss is commonly recommended as part of first-line management of gastrooesophageal reflux disease (GORD) despite the paucity of published clinical trials. The aim of this study was to prospectively assess the independent effect of weight loss on reflux symptoms in overweight individuals with either normal endoscopic findings or grade-I oesophagitis., Methods: Thirty-four patients were recruited on the basis of a body mass index (BMI) of greater than 23 and symptoms of GORD for at least 6 months. All patients were advised to lose weight. Symptoms of gastro-oesophageal reflux (GOR) were scored, using a modified DeMeester questionnaire at 0, 6, and 26 weeks. Patients who were unable to stop taking all medication for control of symptoms were excluded from the study. Changes in weight and symptom score were analysed by using a paired t test. Correlation between change in weight and symptom score was assessed with the Pearson correlation test., Results: Thirty-four patients were studied (18 men and 16 women) with a mean age of 65 years (range, 24-70 years). The mean weight at recruitment was 83.4 kg (standard deviation (s), 4.5 kg; BMI, 23.5 kg/m2 (s, 2.3 kg/m2). Twenty-seven patients (80% of the total) lost weight with a mean of 4.0 kg (P < 0.01) and improved by a mean reduction of 75% from the initial symptom score (P < 0.001). In nine patients the symptoms disappeared completely. Three patients gained weight and had a deterioration of their symptoms, whereas four patients gained weight but still improved their symptom score. There was a significant direct correlation between weight loss and symptom score (R = 0.548, P < 0.001)., Conclusions: This study has shown a significant association between weight loss and improvement in symptoms of GOR. Patients who are overweight should be encouraged to lose weight as part of the first-line management.

Background/aim of Study: Laser therapy is effective in relieving malignant dysphagia, but repeated treatments at 4 to 6 week intervals are usually required. This prospective randomised trial is designed to determine if addition of brachytherapy offers any advantages over laser therapy alone., Methods: Patients with inoperable carcinoma of the oesophagus were randomised to receive either endoscopic Nd:YAG laser therapy alone, or laser followed by brachytherapy. Patients who developed worsening dysphagia during follow-up were offered further treatment as appropriate., Results: Fourteen patients were randomised to receive laser only, and 12 to receive laser followed by brachytherapy. Of these 12, one was lost to follow-up and four did not receive brachytherapy because they were unfit, had extension into the cardia or had mainly extrinsic compression. These 4 are included on an 'intention-to-treat' basis. The mean therapeutic interval for the brachytherapy group was significantly longer, 83 days compared to 36 days for the laser group (p = 0.026). There were no differences in the degree of dysphagia relief, number of endoscopic procedures or survival times., Conclusion: The preliminary results of this trial suggest that brachytherapy in addition to laser therapy prolongs the first therapeutic interval. However, no long-term advantages have been shown.

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.

Neurological complications are a recognized but unusual manifestation of celiac disease. We present here our experiences with four current cases. Age of patients at presentation with neurological signs varied from 7 to 67 yr. In one patient, the neurological disability developed before the diagnosis of celiac disease, whereas, in the other three, it occurred from months to 16 yr after the diagnosis had been established. One patient died of rapidly progressive neuromyopathy. The other three patients had combinations of cerebellar and posterior and lateral column abnormalities. All four patients developed neurological complications despite a strict gluten-free diet. In three of four patients, there was no improvement in duodenal histology on this diet. Treatment with vitamin B12, folic acid, or vitamin D failed to reverse the changes. No other nutritional deficiencies were found. Vitamin E levels were normal in two of three patients. One patient had no response to treatment with immunosuppressive drugs. The mechanisms responsible for these neurological complications are poorly understood, although patients whose duodenal histology fails to improve on a gluten-free diet may be at greater risk. There have been no real advances in the understanding of this condition since the original description nearly 30 yr ago.

Patients with coeliac disease are at increased risk of developing complications which increase morbidity and mortality. Emphasis on malignant complications has often overshadowed the non-malignant risks, which have received relatively little attention, although some of these can be very troublesome and even life-threatening. This article points out that a large population of unidentified or neglected coeliac patients is at potential risk. The challenge is to identify this group by case-finding or screening programmes in selected populations, so that they can be offered a gluten-free diet and other treatments which will not only improve general health but may also prevent or reduce the development of health problems. The non-malignant risks are outlined and bone and neuropsychiatric disturbances considered in more detail because of recent developments in these areas.

Objective: To compare percutaneous endoscopic gastrostomy and nasogastric tube feeding after acute dysphagic stroke., Design: Randomised prospective study of inpatients with acute stroke requiring enteral nutrition., Setting: One university hospital (Nottingham) and one district general hospital (Derby)., Subjects: 30 patients with persisting dysphagia at 14 days after acute stroke: 16 patients were randomised to gastrostomy tube feeding and 14 to nasogastric tube feeding., Main Outcome Measures: Six week mortality; amount of feed administered; change in nutritional state; treatment failure; and length of hospital stay., Results: Mortality at 6 weeks was significantly lower in the gastrostomy group with two deaths (12%) compared with eight deaths (57%) in the nasogastric group (P < 0.05). All gastrostomy fed patients (16) received the total prescribed feed whereas 10/14 (71%) of nasogastric patients lost at least one day's feed. Nasogastric patients received a significantly (P < 0.001) smaller proportion of their prescribed feed (78%; 95% confidence interval 63% to 94%) compared with the gastrostomy group (100%). Patients fed via a gastrostomy tube showed greater improvement in nutritional state, according to several different criteria at six weeks compared with the nasogastric group. In the gastrostomy group the mean albumin concentration increased from 27.1 g/l (24.5 g/l to 29.7 g/l) to 30.1 g/l (28.3 g/l to 31.9 g/l). In contrast, among the nasogastric group there was a reduction from 31.4 g/l (28.6 g/l to 34.2 g/l) to 22.3 g/l (20.7 g/l to 23.9 g/l) (P < 0.003). In addition, there were fewer treatment failures in the gastrostomy group (0/16 versus 3/14). Six patients from the gastrostomy group were discharged from hospital within six weeks of the procedure compared with none from the nasogastric group (P < 0.05)., Conclusion: This study indicates that early gastrostomy tube feeding is greatly superior to nasogastric tube feeding and should be the nutritional treatment of choice for patients with acute dysphagic stroke.

The aim of this study was to evaluate the expression of blood group Tn and sialyl-Tn antigens in the pancreas to determine whether they could help to interpret histochemically needle biopsies obtained from the pancreas. Lectin and immunohistochemistry was carried out using the biotin-labeled Vicia villosa agglutinin isolectin B4 and the mouse monoclonal antibody MLS102 to detect the Tn and sialyl-Tn blood-group antigens in the pancreas. All the pancreatic ductal adenocarcinomas (11/11) were positively stained by V. villosa agglutinin and MLS102 monoclonal antibody. None of the normals or chronic pancreatitics bound MLS102 monoclonal antibody. The acini of all the normals and chronic pancreatitics were V. villosa agglutinin positive, which was absent in the normal ductal cells and present only sparingly in the chronic pancreatitis ductal tissues (10/16). Thus, both the Tn and the sialyl-Tn blood-group antigens are present in pancreatic ductal tissues that have undergone malignant transformation. MLS102 is superior to V. villosa agglutinin in distinguishing malignant from normal and nonmalignant pancreatic tissues in needle biopsies.

Coeliac disease occurs more commonly in children with insulin-dependent diabetes mellitus (IDDM) than in the general population, but the prevalence of coeliac disease in adults with diabetes is unknown. We therefore screened an adult hospital-based diabetic population using IgA antigliadin antibody (IgA-AGA) to identify those patients requiring intestinal biopsy. In 1 year, 1789 patients (43% IDDM, 57% NIDDM) were screened, and 73 had raised IgA-AGA. Of these patients, 49 agreed to duodenal biopsy and 13 (10 IDDM) had coeliac disease. Selective IgA deficiency was found in eight patients, one of whom had coeliac disease. Of these 14 patients with newly diagnosed coeliac disease, four had microcytic anaemia, nine a low serum ferritin, and four a low albumin-corrected calcium. Eight patients had symptoms which improved on gluten withdrawal. Dietary compliance was maintained in 6/8 symptomatic patients, but only in 1/6 without symptoms. Included in the 1789 patients were four (all IDDM) with known coeliac disease. The overall prevalence of coeliac disease in adult patients with IDDM was 1:50 compared with 1:340 in NIDDM. Coeliac disease is common in adults with IDDM and may cause malabsorption and ill health. It should be suspected in any IDDM patient with gastrointestinal symptoms or unexplained anaemia.

Of 228 patients with adult coeliac disease, 42 (19%) were diagnosed aged 60 years or over. In this series, of 35 patients who did not have dermatitis herpetiformis, 15 had attended family doctors and hospital outpatient departments for an average of 28 years with unexplained symptoms or abnormalities in blood tests but the diagnosis of coeliac disease had been missed. This is unsatisfactory because these patients can both manage and respond to a gluten free diet. Thirty eight patients complied strictly with the diet with resolution of symptoms. Significant improvement in weight, haemoglobin, albumin, calcium, and alkaline phosphatase values after a year on the diet also occurred. Clinicians should be alert to the possibility of coeliac disease in the elderly particularly in patients with non-specific complaints in the presence of unexplained anaemia.

An immunohistochemical study has been carried out to compare and contrast the cellular distribution of two different sialosyl-Tn antigen binding monoclonal antibodies, MLS102 and B72.3, in the pancreas. MLS102 but not B72.3 monoclonal antibody binding increases with the content of the sialosyl-Tn epitopes. It was found that all 13 pancreatic cancer specimens bound both MLS102 and B72.3 monoclonal antibodies. Their cellular distribution in the cancer was virtually identical. Fifteen of 20 (75%) patients with chronic pancreatitis and five of 10 (50%) normal subjects were B72.3 positive, but MLS102 was completely negative in the latter group. Both monoclonal antibodies bound fetal pancreas diffusely. Thus, when pancreatic ductal cells have undergone malignant transformation, like the fetal pancreas, they express cell surface and secreted glycoconjugates with increased sialosyl-Tn epitopes suggesting enhanced 2-6 sialosyltransferase activity. This study shows that MLS102 is an extremely sensitive and specific tumour marker in the pancreas and that it is better than B72.3 in distinguishing pancreatic cancer from normal and chronic pancreatitis.

Helicobacter pylori infection of the stomach is associated with gastritis and peptic ulceration and may be causative. A noninvasive test for this organism might be useful in managing some patients with dyspepsia without the need for further investigation. We have evaluated a new commercially available serological test (Helico-G ELISA, Porton Cambridge, UK) for this infection to assess its diagnostic accuracy in a retrospective study of 115 patients with non-ulcer dyspepsia. Sixty-three of these patients (55%) were found to have H. pylori infection and gastritis on histology. A sensitivity of 81% and specificity of 90% were obtained. No significant fall in the antibody titres was found in a subgroup of 15 patients who were selected to complete a course of triple therapy despite significant improvement in their dyspepsia score and confirmed eradication of H. pylori organism in 80% of these patients. We conclude that the test has limited value in aiding clinical decision of managing patients with dyspepsia.