INTRODUCTION:Patients with Barrett's esophagus have a much increased risk of esophageal adenocarcinoma but recent evidence suggests no increase in overall mortality. We have reexamined this surprising finding in a large, prospectively population-based cohort study.METHODS:Cohorts of patients having Barrett's esophagus (n = 1,677), esophagitis (n = 6,392), simple reflux (n = 6,328), and a standard reference cohort representing the general population in the United Kingdom (n = 13,416) were selected from General Practice Research Database. The last three cohorts were matched to the Barrett's cohort by general practice, age, and sex. Mortality rates and hazard ratios with their 95% confidence intervals were calculated for deaths due to all causes and deaths due to all causes except esophageal cancer occurring beyond the first year of the follow-up.RESULTS:A total of 1,725 deaths were analyzed including 49 deaths in subjects having esophageal cancer. Of 111 deaths in the Barrett's cohort, 13 (12%) were in subjects with esophageal cancer. Compared with the reference cohort, hazard ratios for all causes of death were 1.37 (1.12–1.66) for the Barrett's, 1.16 (1.02–1.32) for the esophagitis, and 1.16 (1.01–1.33) for the reflux cohorts. The corresponding figures for deaths due to all causes except esophageal cancer were 1.23 (1.00–1.51), 1.13 (0.99–1.30), and 1.15 (1.00–1.31). Of the excess mortality rates in the Barrett's, esophagitis, and reflux cohorts, at the most 45%, 20%, and 13%, respectively, could be attributed to esophageal cancer.CONCLUSION:People with Barrett's esophagus and gastroesophageal reflux disease have higher mortality rates than the general population, and an increase in esophageal cancer risk accounts for less than half the excess mortality in Barrett's.

BACKGROUND & AIMS:Previous studies have raised concern about reduced fertility and increased adverse pregnancy-related events in women with celiac disease, but none has estimated overall fertility compared with the general female population.METHODS:We compared computerized primary care data for 1521 women with celiac disease with data for 7732 age- and practice-matched women without celiac disease. We estimated population-based rates of fertility and adverse pregnancy outcomes.RESULTS:Crude fertility rates were 48.2 and 47.7 live births per 1000 person-years for women with and without celiac disease, respectively (rate ratio, 1.01; 95% confidence interval, 0.90-1.14). Age-specific fertility rates showed that women with celiac disease had lower fertility when younger but higher fertility when older compared with women without celiac disease. This increase in relative fertility with increasing age held whether women had treated or untreated celiac disease. Risks of cesarean section (odds ratio, 1.33; 95% confidence interval, 1.03-1.70) and miscarriage (rate ratio, 1.31; 95% confidence interval, 1.06-1.61) were moderately higher in women with celiac disease, but risks of assisted birth, breech birth, preeclampsia, postpartum hemorrhage, ectopic pregnancy, stillbirth, and termination were similar.CONCLUSIONS:Overall, women with celiac disease have fertility similar to that of the general female population, but they have their babies at an older age. Although our findings may reflect a disease effect, the age shift in fertility rates and the increase in cesarean section risk is consistent with socioeconomic or educational advantages of women with celiac disease.

BACKGROUND:Population data supporting an association between the autoimmune cholestatic liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis and coeliac disease, is limited and at times contradictory.AIM:To explore the relationship between coeliac disease and both primary biliary cirrhosis and primary sclerosing cholangitis within the General Practice Research Database, a UK-based longitudinal primary care database.METHODS:We identified 4732 people with diagnosed coeliac disease and 23 620 age- and sex-matched controls within the General Practice Research Database. We calculated the prevalence of primary biliary cirrhosis and primary sclerosing cholangitis for both the coeliac disease and control group.RESULTS:There was a higher prevalence of primary biliary cirrhosis in adults with coeliac disease, compared with controls [0.17% vs. 0.05%, odds ratio 3.63 (95% confidence interval: 1.46-9.04)]. Primary sclerosing cholangitis was also more common in the coeliac disease group [0.04% vs. 0%, fishers exact test (P = 0.03)].CONCLUSIONS:There was a threefold or greater increase in risk of both primary biliary cirrhosis and primary sclerosing cholangitis in people with coeliac disease compared with the general population. The association with primary biliary cirrhosis was weaker than in some reports and it is difficult on the basis of this study to justify screening patients with coeliac disease for either primary biliary cirrhosis or primary sclerosing cholangitis.

BACKGROUND:It has been suggested that vascular disease mortality may be reduced in coeliac disease because of lower levels of blood pressure, cholesterol and body mass.AIM:To examine whether people with coeliac disease are at reduced risk of various vascular diseases.METHODS:We identified 3,790 adults with diagnosed coeliac disease and 17,925 age- and sex-matched controls in the General Practice Research Database. We estimated odds ratios for diagnosed hypertension, hypercholesterolaemia and atrial fibrillation and hazard ratios for myocardial infarction and stroke.RESULTS:Adults with coeliac disease, compared with controls, were less likely to have had a diagnosis of hypertension [11% vs. 15%, odds ratio 0.68 (95% confidence interval: 0.60-0.76)] or hypercholesterolaemia [3.0% vs. 4.8%, odds ration 0.58 (95% confidence interval: 0.47-0.72)] but slightly more likely to have had atrial fibrillation [2.1% vs. 1.7%, odds ratio 1.26 (95% confidence interval: 0.97-1.64)]. The hazard ratio for myocardial infarction was 0.85 (95% confidence interval: 0.63-1.13), while the hazard ratio for stroke was 1.29 (95% confidence interval: 0.98-1.70).CONCLUSIONS:Although rates of myocardial infarction and stroke were not substantially different, adults with coeliac disease do have a lower prevalence of hypertension and hypercholesterolaemia compared with the general population. The effect of a gluten-free diet on cardiovascular risk factors should be determined before any screening programmes for coeliac disease are instituted.

BACKGROUND AND AIMS:While patients with Barrett's oesophagus develop oesophageal adenocarcinoma more frequently than the general population, it has controversially been suggested that gastro-oesophageal reflux (GORD) itself is a more important determinant of risk. In order to assess the validity of this suggestion, we examined the risk of oesophageal cancer in patients with Barrett's and with GORD compared with the general population in a community based cohort study. METHODS:Cohorts of patients with Barrett's (n = 1677), oesophagitis (n = 6392), and simple reflux (n = 6328), and a reference cohort (n = 13416) were selected from the General Practice Research Database. The last three cohorts were matched to the Barrett's cohort by general practitioner practice, age, and sex. Cox's regression analysis was used to calculate relative risks for oesophageal cancer. Standardised incidence ratio methodology was used to estimate the relative risks for oesophageal adenocarcinoma. RESULTS:A total of 137 oesophageal cancers were identified, of which 94 prevalent cases were excluded. The hazard ratios for oesophageal cancer were 10.6 (5.1-22.0), 2.2 (0.9-5.2), and 1.7 (0.7-4.5) in the Barrett's, oesophagitis, and reflux cohorts compared with the reference cohort, respectively. The corresponding relative risks for oesophageal adenocarcinoma were 29.8 (9.6-106), 4.5 (1.04-19.6), and 3.1 (0.6-14.2). CONCLUSION:Barrett's oesophagus increases the risk of oesophageal cancer approximately 10 times and oesophageal adenocarcinoma approximately 30 times compared with the general population. There is only a modestly increased risk of oesophageal cancer in patients with reflux who have no record of Barrett's oesophagus. Our findings therefore do not support the suggestion that gastro-oesophageal reflux disease itself predisposes to cancer.

Background: Inflammatory bowel disease (IBD) is known to be associated with reduced bone density but the extent to which this results in an increased risk of fracture and the contribution of corticosteroid therapy are unclear. We have conducted a large cohort study to address these issues.Methods: We selected subjects within the General Practice Research Database (GPRD) with a diagnosis of IBD and up to five matched controls for each patient. We derived dates of recorded hip fractures and also information on smoking, use of corticosteroids, and a number of other drugs. We calculated the absolute risk of fracture and the relative risk as a hazard ratio corrected for available confounders by Cox regression.Results: Seventy two hip fractures were recorded in 16 550 IBD cases and 223 in 82 917 controls. Cox modelling gave an unadjusted relative risk of hip fracture of 1.62 (95% confidence interval (CI) 1.24-2.11) for all IBD, 1.49 (1.04-2.15) for ulcerative colitis (UC) and 2.08 (1.36-3.18) for Crohn's disease ( CD). Multivariate modelling showed that both current and cumulative use of corticosteroids and use of opioid analgesics confounded this relationship. After adjusting for confounding, the relative risk was 1.41 (0.94-2.11) for UC and 1.68 (1.01-2.78) for CD.Conclusion: The risk of hip fracture is increased approximately 60% in IBD patients. Corticosteroid use is a contributor to this, both in the long term as previously recognised and also in an acute reversible manner. The majority of hip fracture risk in IBD patients however cannot be attributed to steroid use.

AIM:Patients with primary biliary cirrhosis may be at increased risk of osteoporosis but to what extent this is reflected in an increased fracture risk is unknown. We have enquired about the fracture experience of female primary biliary cirrhosis patients compared with sex- and age-matched controls.METHODS:Patients aged 30-75 with primary biliary cirrhosis and age-matched controls were sent a postal questionnaire asking about their fracture history and details of risk factors for osteoporosis.RESULTS:85 eligible patients with primary biliary cirrhosis and 116 controls responded. Forty-one per cent of patients with primary biliary cirrhosis and 30% of controls reported ever having had a fracture odds ratio 1.5 (95% confidence interval: 0.80-2.89). Twenty-eight per cent of primary biliary cirrhosis patients and 23.3% of controls reported a fracture after the age of 30, odds ratio 1.2 (95% confidence interval: 0.57-2.56), and 14.1% of primary biliary cirrhosis patients and 12.1% of controls reported a low impact fracture of the long bones or of the vertebrae odds ratio 1.0 (95% confidence interval: 0.31-2.68).CONCLUSIONS:No overall increased fracture risk in patients with primary biliary cirrhosis was observed. As a group, unselected patients with primary biliary cirrhosis do not represent a population at particularly high risk of osteoporotic fracture and thus targeting them for osteoporosis screening and treatment is not justified. Further work investigating subgroups of patients with primary biliary cirrhosis at potentially high risk of osteoporosis, such as those with advanced disease or severe cholestasis is required.

Background: Few environmental determinants of Crohn's disease are well established. Some observational data exist to implicate antibiotic use as a risk factor but these are derived from studies using questionnaires to assess reported antibiotic use that were susceptible to recall bias. We have therefore explored this relationship in prospectively gathered data.Methods: We selected incident cases of Crohn's disease from the General Practice Research Database with at least five years of data prior to diagnosis. Controls with five years of complete data were randomly selected. Data were extracted on smoking, drug prescriptions, age, sex, and a variety of symptoms and diagnoses that might be indicative of occult Crohn's disease. Logistic regression was used to investigate the relationship between antibiotic use and Crohn's disease.Results: A total of 587 Crohn's disease cases and 1460 controls were available for analysis. We found that antibiotic use 2-5 years pre-diagnosis occurred in 71% of cases compared with 58% of controls (p<0.001), and the median number of courses was two in the cases and one in the controls (p<0.001). Adjusting for age, sex, smoking, and use of other drugs, antibiotic use had an odds ratio of 1.32 (1.05-1.65). We were unable to show specificity to any subgroup of antibacterials. Associations similar to that with antibiotics were also found with oral contraceptive, cardiovascular, and neurological drugs.Conclusions: We found a statistically significant association between Crohn's disease and prior antibiotic use. This cannot be explained by recall bias, but due to lack of specificity it is unclear whether it is causal.

Aims To examine the relationship between hormone replacement therapy (HRT) and acute myocardial infarction (AMI) adjusting for coronary risk factors and social and behavioural confounders that might indicate a healthy user effect and could account for the discrepancy between randomized and observational studies of HRT use.Methods A case-control study of 864 women aged between 35-65 suffering an AMI with two age matched community controls from the same geographical area. Information was collected by interview and from general practitioner records. Conditional logistic regression was used to calculate odds ratios (OR) adjusted for diabetes, hypertension, smoking, alcohol, social class, family history and a health conscious behaviour score.Results HRT use was recorded for 34% of non-fatal AMI cases and 39% of controls with the adjusted OR for ever-use of HRT versus never-use being 0.74 (95% Cl 0.55-0.99). The pattern of risk of AMI was similar for oestrogen only and combined HRT. During the first 12 months of HRT use there was a small increase in risk of AW with the adjusted OR being 1.14 (0.72-1.80). HRT use for 13-60 months was associated with a small reduction in AW risk (adjusted OR 0.85, 0.55-1.29). Only HRT used for >60 months was associated with a substantial risk reduction (adjusted OR 0.42, 0.24-0.73). Data for deceased cases and controls showed a similar pattern.Conclusion HRT use whether as oestrogen only or combined hormones was only associated with a significant reduction in risk when used for greater than 60 months. These findings could reflect a dual effect of HRT on AMI risk by prothrombotic and anti-atherogenic mechanisms. Neither oestrogen only or combined HRT can be recommended for prevention of coronary artery disease. (C) 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

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: 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.

BACKGROUND & AIMS:There is no consensus regarding any increase in mortality with inflammatory bowel disease (IBD). In general, previous studies were not contemporary and were unable to correct for likely confounders. We have performed a large cohort study to examine contemporary IBD related mortality in the United Kingdom.METHODS:We selected subjects within the General Practice Research Database with a coded diagnosis of inflammatory bowel disease and up to 5 matched controls for each. We derived the date of recorded deaths and information on smoking and a variety of medical conditions. We calculated both the absolute risk of death and the relative risk as a hazard ratio corrected for available confounders by Cox regression.RESULTS:We included 16,550 IBD cases with 1047 deaths and 82,917 controls with 3758 deaths. The mortality rate was 17.1 per 1000 person-years overall for IBD cases and 12.3 for controls; this difference was greatest in the elderly. Conversion of these figures to hazard ratios by Cox regression gave hazard ratios of 1.54 (1.44-1.65) for all IBD, 1.44 (1.31-1.58) for ulcerative colitis (UC), and 1.73 (1.54-1.96) for Crohn's disease. The greatest hazard ratio for UC was among the 40-59-year age group (1.79 [1.42-2.27]) and for Crohn's disease among 20-39-year-olds (3.82 [2.17-6.75]).CONCLUSIONS:IBD is associated with an overall small increase in mortality rate greatest in relative terms in younger subjects but in absolute terms in the elderly.

Prenatal or perinatal environmental exposures have been postulated to change the risk of inflammatory bowel disease (IBD) later in life.1 One manifestation of this, perhaps because of early and seasonal infectious exposure, might be an association between the month of birth and risk of developing IBD later in life.2–4 Two recent publications, one from the UK,3 and the other from Denmark4 have examined cohorts of Crohn’s patients for such seasonality of birth. The findings of these two studies as well as their interpretations differ markedly. The British study was of adult patients diagnosed between 1972 and 1989 by four regional IBD registers in which a weak association was found between Crohn’s disease (CD) and birth in the first half of the year. The second (Danish) study examined national computerised hospital discharge records of children and young people aged less than 20 years coded between 1977 and 1992 for CD. This second study found an apparently stronger association with month of birth with the peak risk being for those born during August with a “sine wave” variation in risk between those born in different months of the year. The authors suggest that the differences compared with the British study might be explained by differences in age mix and nationality of the subjects, and further suggested that their findings give support to the importance of in utero and early childhood events in the aetiology of CD. In view of these inconsistent findings, and the possibility that they may in part be explained by the differences in analytical technique as well as the age mix of the cases, we undertook an analysis of the national cohort of British IBD patients aged less than 20 years collected prospectively by the British Paediatric Surveillance Unit (BPSU) and the British Society of Gastroenterology Research Unit (BSGRU).5 We analysed this series using similar methods to those used by both the previous studies and in addition extended the statistical analysis to take into account possible shortcomings in them.