Influence of environmental factors on the onset and course of inflammatory bowel disease

Numerous environmental factors have been linked with inflammatory bowel disease. These include smoking, diet, hygiene, drugs, geographical and psychosocial factors. These factors may either increase the risk of or protect against developing this condition and can also affect the course of illness in a positive or negative manner. A number of studies have examined the influence of environmental factors on inflammatory bowel diseases as a whole as well as on ulcerative colitis and Crohn's disease separately. As there are differences in the pathogenesis of ulcerative colitis and Crohn's disease, the effect of environmental factors on their onset and course is not always similar. Some factors have shown a consistent association, while reports on others have been conflicting. In this article we discuss the current evidence on the roles of these factors on inflammatory bowel disease, both as causative/protective agents and as modifiers of disease course.     

Appendectomy, tonsillectomy, and risk of inflammatory bowel disease

PURPOSE: Appendectomy has been suggested as a possible protective factor in ulcerative colitis and as a risk factor in Crohn's disease. Tonsillectomy has also been associated with Crohn's disease. We performed a case-controlled study to investigate these associations in a homogeneous Greek population. METHODS: One hundred thirty-four consecutive cases of ulcerative colitis and 76 cases of Crohn's disease were included in the study. For each inflammatory bowel disease patient and a corresponding healthy control subject, matched for gender, age, and educational level, a standard record on various risk factors was completed by interview. The association between disease status and risk factors was assessed by Pearson's chi-squared test and the independent contribution of each risk factor was analyzed by means of logistic regression analysis. RESULTS: Appendectomy had been performed in 11 (8.2 percent) patients with ulcerative colitis, in 18 (13.4 percent) of their matched healthy control cases, in 19 (25.0 percent) patients with Crohn's disease, and in 10 (13.2 percent) of their matched healthy control cases. Odds ratio for development of ulcerative colitis after appendectomy was 0.6 (95 percent confidence interval, 0.26–1.27). Odds ratio for Crohn's disease was 2.2 (95 percent confidence interval, 0.94–5.12). Odds ratio for development of ulcerative colitis or Crohn's disease after tonsillectomy was 0.95 (95 percent confidence interval, 0.49–1.82) and 3.29 (95 percent confidence interval, 1.29–8.37), respectively. The logistic regression analysis showed that appendectomy and tonsillectomy have no independent association with the risk of developing ulcerative colitis, whereas in Crohn's disease both appendectomy and tonsillectomy have positive associations. Wellestablished risk factors, such as family history and smoking status, were also verified in this study. CONCLUSIONS: This case-control study, using multivariate logistic regression analysis, showed a less pronounced association between ulcerative colitis and appendectomy than previous reports. Our data also support the conclusion that tonsillectomy is a risk factor for developing Crohn's disease.Poster presentation at the World Congress of Gastroenterology, Vienna, Austria, September 6 to 11, 1998.     

Smoking, physical activity, nutrition and lifestyle: environmental factors and their impact on IBD

Current smoking increases the risk of developing Crohn's disease and worsens its course, increasing the need for steroids, immunosuppressants, and re-operations. On the contrary, smoking protects against ulcerative colitis and after disease onset improves its course, decreasing the need for colectomy. Smoking cessation improves Crohn's disease and worsens ulcerative colitis. Achieving smoking cessation in Crohn's disease is thus an important goal of therapy, whereas patients with ulcerative colitis should not be discouraged to quit, because the beneficial effect of smoking for their disease is counterbalanced by the deleterious respiratory and cardiovascular effects of tobacco. Physical activity improves quality of life without detrimental effect on disease activity, and may contribute to increase muscle mass and to prevent osteoporosis. Regarding nutrition, a Western diet may be associated with an increased risk of IBD, and a case-control study revealed an increased consumption of linoleic acid before diagnosis of ulcerative colitis. Liquid diets may improve Crohn's disease flares and decrease the need for steroids; however, there are no defined diets able to improve the disease course, and in Crohn's disease, supplementation with omega-3 fatty acids did not show a significant benefit. Obesity is becoming more prevalent in IBD and may be associated with higher disease activity. In total, adhering to four simple lifestyle factors - never smoking, physical activity, prudent diet and body mass index <25 - may have a strong impact both on the prevention of major chronic diseases and on the course of IBD.     

Passive Smoking is Associated with an Increased Risk of Developing Inflammatory Bowel Disease in Children

Adult cigarette smoking is associated with the development of Crohn's disease and protection from the development of ulcerative colitis. Children usually are nonsmokers whose risk of developing inflammatory bowel disease (IBD) may he related to passive smoking. The purpose of this matched case-control study was to evaluate passive smoking exposure in 72 nonsmoking children with recently diagnosed IBD (39 with ulcerative colitis and 33 with Crohn's disease), and in an equal number of peer-nominated controls. Passive smoking exposure at birth was significantly associated with the development of IBD (odds ratio 3.02, 95% confidence interval 1.28-7.06). The effect was greater in Crohn's disease (odds ratio 5.32) than in ulcerative colitis (odds ratio 2.19). Maternal smoking at birth also was significantly associated with the development of IBD (odds ratio 2.09,95% confidence interval 1.02–4.29), an effect that also was greater in Crohn's disease than in ulcerative colitis. There was a dose-response relationship between packs smoked per day and IBD, and packs smoked at home per day and IBD. At symptom onset, the risk of developing IBD from passive smoking exposure was increased hut was not significant (odds ratio 1.88, 95% confidence interval 0.84–4.18). The magnitude of the effect was greater in Crohn's disease than in ulcerative colitis, and the association demonstrated dose-response. In conclusion, passive smoking exposure and maternal smoking at birth and, to a lesser extent, passive smoking exposure at symptom onset are associated with an increased risk of developing IBD in children. The association is stronger in Crohn's disease than in ulcerative colitis, and there is a dose-response effect. The specific toxic exposure is more likely to he inhaled rather than passed through the placenta or in breast milk.     

Cholelithiasis in inflammatory bowel disease

Cholelithiasis is considered an extraintestinal manifestation of Crohn's ileitis but has not been associated with ulcerative colitis. To evaluate if an increased risk of cholelithiasis exists in patients with ulcerative colitis, biliary ultrasonography was performed on 159 patients with inflammatory bowel disease, 114 patients with ulcerative colitis, and 45 patients with Crohn's disease. A control population of 2453 residents of the town near the authors' institute was also studied. An echographic survey of gallstones was performed on the control subjects, who participated in the Multicentrica Italiana Colelitiasi (MICOL). Seventeen patients with inflammatory bowel disease had gallstones (10.7 percent), 11 patients with ulcerative colitis had gallstones (9.6 percent), and 6 patients with Crohn's disease had gallstones (13.3 percent). In the control population, diagnosis of cholelithiasis was made in 239 subjects (9.7 percent). An estimate of the relative risk (odds ratio) of gallstones in ulcerative colitis and Crohn's disease and also in 4 subgroups formed on the basis of the extent of disease (total ulcerative colitis, partial ulcerative colitis, Crohn's disease with ileitis, Crohn's disease without ileitis) with respect to the general population was calculated using logistic regression with gallstones, sex, age, and body mass index as independent variables and inflammatory bowel disease as a dependent variable. The author's findings show an increased risk of gallstones in both patients with Crohn's disease (odds ratio = 3.6; 95 percent confidence limits = 1.2 - 10.4; P = 0.02) and patients with ulcerative colitis (odds ratio = 2.5; 95 percent confidence limits = 1.2 - 5.2; P = 0.01). The risk was highest in patients with Crohn's disease involving the distal ileum (odds ratio = 4.5; 95 percent confidence limits = 1.5 - 14.1; P = 0.009) and in patients with total ulcerative colitis extending to the cecum (odds ratio = 3.3; 95 percent confidence limits = 1.3 - 8.6; P = 0.01). These results confirm that there is an increased risk of gallstones in Crohn's ileitis but they show that there also exists an increased risk in patients with total ulcerative colitis.     

Ulcerative colitis and Crohn's disease: is Mycobacterium avium subspecies paratuberculosis the common villain?

Mycobacterium avium, subspecies paratuberculosis (MAP) causes a chronic disease of the intestines in dairy cows and a wide range of other animals, including nonhuman primates, called Johne's ("Yo-knee's") disease. MAP has been consistently identified by a variety of techniques in humans with Crohn's disease. The research investigating the presence of MAP in patients with Crohn's disease has often identified MAP in the "negative" ulcerative colitis controls as well, suggesting that ulcerative colitis is also caused by MAP. Like other infectious diseases, dose, route of infection, age, sex and genes influence whether an individual infected with MAP develops ulcerative colitis or Crohn's disease. The apparently opposite role of smoking, increasing the risk of Crohn's disease while decreasing the risk of ulcerative colitis, is explained by a more careful review of the literature that reveals smoking causes an increase in both diseases but switches the phenotype from ulcerative colitis to Crohn's disease. MAP as the sole etiologic agent of both ulcerative colitis and Crohn's disease explains their common epidemiology, geographic distribution and familial and sporadic clusters, providing a unified hypothesis for the prevention and cure of the no longer "idiopathic" inflammatory bowel diseases.     

A meta-analysis of the role of smoking in inflammatory bowel disease

A relationship between not smoking and ulcerative colitis has been examined in all English reports. This paper evaluates the ulcerative colitis/nonsmoking and the Crohn's disease/smoking association by meta-analysis and against causality criterion for chronic diseases. A review of the literature, meta-analysis of selected studies, and assessment of causality criterion all suggest that not smoking and ulcerative colitis and smoking and Crohn's disease are consistent with a causal relationship. It is not inconceivable that tobacco may contain some substance beneficial to ulcerative colitis patients. Identification of the specific product in tobacco producing a beneficial effect would be a prudent next step in the study of this association. In spite of the findings of this review and analysis, the author finds no justification for health care providers to change the Surgeon General's recommendations on smoking or tobacco use for ulcerative colitis patients specifically.This work was partially supported by R01 DK38829-01 and R01 DK38693-01.     

Cigarette smoking and inflammatory bowel disease

In a case-control study 280 patients with inflammatory bowel disease and matched community controls taken from general practitioner lists were questioned about their smoking habits. Whether assessed by current or previous habits, patients with Crohn's disease were more likely to be or have been smokers than their matched controls and the association appeared strongest at disease onset (matched relative risk 4.1, p less than 0.001). In contrast, patients with ulcerative colitis assessed in the same way were less likely to be smokers compared with their matched controls, with the association being equally strong at disease onset and currently (matched relative risk 0.17, p less than 0.001). Among patients with ulcerative colitis who were exsmokers, 76% reported stopping smoking before disease onset compared with 13% of exsmokers with Crohn's disease. Contrary to earlier reports, there were only small and nonsignificant increases in the risk of Crohn's disease or ulcerative colitis in exsmokers. The strength, temporal precedence, and contrasting nature of the associations are evidence that smoking has an important etiologic role in inflammatory bowel disease. Smoking appears to be a factor in determining whether Crohn's disease or ulcerative colitis develops in predisposed individuals.     

Smoking in inflammatory bowel diseases： Good,bad or ugly？

Smoking is an important environmental factor in inflammatory bowel disease （IBD）, having different effects in ulcerative colitis （UC） and Crohn＇s disease （CD）. A recent meta-analysis partially confirmed previous findings that smoking was found to be protective against ulcerative colitis and, after onset of the disease, might improve its course, decreasing the need for colectomy. However, smoking increases the risk of developing Crohn＇s disease and worsens its course, increasing the need for steroids, immunosuppressants and re-operations. Smoking cessation aggravates ulcerative colitis and improves Crohn＇s disease. Data are however, largely conflictive as well as the potential mechanisms involved in this dual relationship are still unknown. In this review article, the authors review the role of smoking in inflammatory bowel diseases.     

Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice

Current smoking protects against ulcerative colitis and, after onset of the disease, improves its course, decreasing the need for colectomy. However, smoking increases the risk of developing Crohn's disease and worsens its course, increasing the need for steroids, immunosuppressants and reoperations. Smoking cessation aggravates ulcerative colitis and improves Crohn's disease. The effects of smoking are the sum of contradictory effects of various substances, including nicotine and carbon monoxide, and are modulated by gender, genetic background, disease location and activity, cigarette dose and nicotine concentration. Smokers with ulcerative colitis should not be discouraged from stopping smoking but encouraged to stop, to reduce their risk of cardiopulmonary tobacco-related diseases. In Crohn's disease, smoking cessation has become a major therapeutic goal, particularly in young women and in patients with ileal involvement. A large amount of supportive information, use of nicotine-replacement therapies and antidepressants, and individual counselling might aid the patient in quitting.     

Thrombotic vascular risk factors in inflammatory bowel disease.

BACKGROUND--Thrombosis may be an important effector mechanism in the pathogenesis of Crohn's disease. METHODS--This study therefore investigated the prevalence of independent thrombotic risk factors (factor VII coagulant activity, lipoprotein (a), fibrinogen, plasma triglycerides, and smoking) in patients with Crohn's disease, ulcerative colitis, and normal controls. RESULTS--In Crohn's disease (n = 75), the mean plasma VII:C, lipoprotein (a) and fibrinogen concentrations were significantly greater than in the normal population (n = 85). In ulcerative colitis (n = 35), only the mean factor VII:C concentration was significantly higher than normal. Ninety three per cent of patients with Crohn's disease and 86% of those with ulcerative colitis had at least one risk factor for thrombotic vascular disease, compared with 61% of the normal population (p < 0.001). CONCLUSIONS--In many young patients with inflammatory bowel disease, plasma concentrations of these prothrombotic factors were in excess of the limits that are regarded as posing an increased risk for the development of occlusive vascular disease.     

Epidemiology of inflammatory bowel disease in Italy

The incidence of inflammatory bowel diseases is similar throughout Italy. Two prospective multicentre studies in the same period have shown an incidence very similar to Northern Europe. The incidence of ulcerative colitis ranged from 3.4 to 10.5. The incidence of Crohn's disease ranged from 1.9 to 6.6. The time trends seem to indicate an increase in both diseases. The need to set up General Registries of disease is underlined. The clinical behaviour and the diagnostic approach are homogeneous throughout the country. Compared to Northern Europe, surgery was less common in ulcerative colitis. Among the risk factors, familial occurrence has been shown to have the same prevalence as in Northern Europe suggesting a common genetic background. Studies on other risk factors are warranted considering the lack of data. Data on mortality show that there is a decrease in deaths in ulcerative colitis and a slight increase in mortality for Crohn's disease in the first few years after diagnosis. A retrospective study on costs has shown a greater economic burden from ulcerative colitis, however, new multicentre prospective studies are necessary.     

A case-control study of childhood environmental risk factors for the development of inflammatory bowel disease

OBJECTIVE : To clarify the relationship between childhood environment and the risk of subsequent development of Crohn's disease or ulcerative colitis. DESIGN AND OUTCOME MEASURES : A case-control study, assessing the risk of inflammatory bowel disease in relation to a series of historical and serological markers of childhood circumstance, analysed using the maximum likelihood form of conditional logistic regression. SETTING : District general hospital (secondary care institution). PARTICIPANTS : Subjects with Crohn's disease (n = 139) or ulcerative colitis (n = 137) aged between 16 and 45 years, each matched for sex and age with an outpatient control. RESULTS : Helicobacter seroprevalence was substantially reduced in Crohn's disease (OR 0.18; 95% CI, 0.06-0.52) but not in ulcerative colitis (OR 0.91; 95% CI, 0.38-2.16). In ulcerative colitis, a strong negative association with childhood appendectomy was confirmed (OR 0.05; 95% CI, 0.01-0.51). Crohn's disease was associated with childhood eczema (OR 2.81; 95% CI, 1.23-6.42) and the frequent use of a swimming pool (OR 2.90; 95% CI 1.21-6.91). There was no association between hepatitis A seroprevalence and either disease. CONCLUSION : The findings are consistent with the hypothesis that improved childhood living conditions are associated with increased risk of Crohn's disease. The study confirms that the negative association between appendectomy and ulcerative colitis relates primarily to events in childhood. Overall, the findings strongly support the assertion that childhood environment is an important determinant of the risk of inflammatory bowel disease in later life, with quite distinct risk factors for ulcerative colitis and Crohn's disease.     

Gender differences in the response of colitis to smoking.

BACKGROUND AND AIMS: The aim of this study was to examine in parallel the effect of smoking on ulcerative colitis and Crohn's colitis and assess the effect of gender on the response of colitis to smoking. METHODS: Medical charts of 1784 adult consecutive patients (978 patients, ulcerative colitis; 118 patients, indeterminate colitis; and 688 patients, Crohn's colitis), whose smoking habits were specified by direct interview, were reviewed. RESULTS: The proportion of ever smokers was 42% in ulcerative colitis, 43% in indeterminate colitis, and 61% in Crohn's colitis. Smoking cessation preceded the onset of colitis in 279 patients with ulcerative colitis or indeterminate colitis (61%) and only 52 patients (12%) with Crohn's colitis. In ulcerative colitis and indeterminate colitis, current smoking delayed mean age at disease onset in men (from 32 to 41 yr; P < 0.001), but not women (from 33 to 33 yr), and decreased the need for immunosuppressants in men (10-yr cumulative risk, 26% +/- 4% in nonsmokers vs. 8% +/- 4% in smokers; P < 0.01), but not significantly in women. Conversely, in Crohn's colitis, current smoking hastened disease onset in women (from 35 to 29 yr; P < 0.001), but not men (from 32 to 31 yr), and increased the need for immunosuppressants in women (10-yr cumulative risk, 48% +/- 5% in nonsmokers vs. 58% +/- 4% in smokers; P < 0.01), but not men. CONCLUSIONS: The dual effects of smoking in colitis, beneficial in ulcerative colitis and harmful in Crohn's colitis, are modulated importantly by gender, with women having more disadvantage than men.     

Inflammatory Bowel Disease and Smoking—A Review

The relationship between smoking and inflammatory bowel disease is a curious but well-established one. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. It also has opposite influences on the clinical course of the two conditions with possible beneficial effect in ulcerative colitis and detrimental effect in Crohn's disease. The diametrically "opposite" relationship of smoking status with the two conditions has been the subject of much interest in the hope that it may reveal pathogenic mechanisms responsible for the two conditions and possibly offer the key to alternative therapeutic options. Nicotine may be the principal agent in smoking responsible for the association; trials have shown it to be of some benefit in ulcerative colitis, but further research is required to establish its therapeutic role and possible mechanisms of action. In this article, we review the historical, clinical, and therapeutic aspects of the association between smoking and inflammatory bowel disease.     

Kardiovaskuläre Begleiterkrankungen und Komplikationen bei Darmerkrankungen

Vascular diseases are not encountered very often in gastroenterology, though in cases of ischemic colitis a coronary heart disease is often present. In addition, heart diseases such as coronary heart disease, atrial fibrillation, and congestive heart failure are important risk factors for ischemic colitis and should be treated to avoid further ischemic episodes of the gut. The most common extraintestinal manifestations of Crohn's disease and ulcerative colitis are observed in the eye, on the skin, and in the liver region. Involvement of the cardiovascular system does not seem to be very common, though systematic epidemiological data on the significance of these extraintestinal complications--which certainly influence the prognosis--are lacking. Other patients with Crohn's disease or ulcerative colitis suffer from vasculitis, which reflects a further manifestation of inflammatory diseases affecting the cardiovascular system. Another important complication is activation of coagulationfactors, especially during active flare-up of intestinal disease; this can result in thromboembolic events. Systematic studies or investigations on the epidemiology of cardiovascular complications are still lacking, so that an overview of the published data is given. Metastatic tumors of the heart are rare, but there are case reports of cardiac metastases in patients with carcinomas of the colon. Carcinoid heart syndrome, another cardial complication of malignant disease, can prejudice the prognosis of patients with neuroendocrine tumors of the gastrointestinal tract.     

Stomal adenocarcinoma in Crohn's disease.

Malignant change occurring at the site of a stoma in two patients with proved Crohn's disease is described. Patients with ulcerative colitis have an increased risk of colonic malignancy and Crohn's disease is also associated with both small and large bowel carcinoma. Most previous reports of stomal carcinoma have been associated with ulcerative colitis although Crohn's disease seems to carry a greater risk of associated small bowel carcinomas. This is the first report of stomal carcinoma complicating Crohn's disease. Epithelial dysplasia is associated with gastrointestinal carcinomas in both ulcerative colitis and Crohn's disease and a dysplasia-carcinoma sequence has been suggested as the origin of these tumours. In both our patients with stomal adenocarcinoma, dysplasia was identified in adjacent tissues, which suggests a similar mechanism. Malignant change should be suspected if epithelial dysplasia is discovered in a biopsy specimen from the mucosa of an ileostomy in Crohn's disease, and this risk is increased if the dysplasia is of a high grade.     

Smoking habits in patients with inflammatory bowel disease. A case-control study

In a case-control study there were significantly fewer smokers among patients with ulcerative colitis both at disease onset and at interview, the relative risk compared with non-smokers being 0.33 and 0.12, respectively. Among female patients with Crohn's disease there were significantly more smokers, the relative risk being 2.70 and 2.33, respectively. Of the ex-smokers with ulcerative colitis, two-thirds became ill after they stopped smoking, and most of these during the first years after stopping. Neither in ulcerative colitis nor in Crohn's disease could any relation be found between the localization of disease and smoking habits at the time of diagnosis. The findings in the present study support the hypothesis that smoking may influence the course of inflammatory bowel disease.     

Etiology and pathophysiology of inflammatory bowel disease--environmental factors

Environmental factors play an important role in the pathophysiology of inflammatory bowel disease. There is a strong and consistent association between smoking and Crohn's disease, and between nonsmoking and ulcerative colitis. Despite extensive research, the exact pathophysiological mechanisms for these associations remain unclear. In spite of this, some clinical trials with nicotine-patches showed beneficial effects for the treatment of ulcerative colitis. Associations of Crohn's disease and ulcerative colitis with other environmental factors are weaker like the association with use of oral contraceptives or those less well investigated such as the association with childhood hygiene. Most studies suggesting a potential pathogenetic role of Mycobacterium paratuberculosis or an effect of tuberculostatic therapy in Crohn's disease could not be reproduced by others. Perinatal or childhood infections by viruses like measles are heavily debated, but not proven to be causal for inflammatory bowel disease. Coagulation disorders have been described as protecting from inflammatory bowel disease, suggesting hypercoagulability to be a pathogenetic factor. Some studies described that appendectomy may prevent the onset of ulcerative colitis in man and mice. Other environmental factors such as hydrogen sulfide, tonsillectomy, diet, blood transfusions, and Listeria also require confirmation. There are, however, convincing data from genetic animal models and twin studies that environmental factors as the intestinal bacterial flora interact with susceptible hosts to cause inflammatory bowel disease. Inflammatory bowel diseases have multifactorial etiologies, which require a differentiated approach for treatment and prevention.     

Inflammatory bowel disease and tobacco smoke--a case-control study.

A case-control study was carried out in Stockholm, Sweden between 1984 and 1987 to evaluate the association of cigarette smoking and exposure to environmental tobacco smoke during childhood and the subsequent development of inflammatory bowel disease. Information on smoking was obtained by a postal questionnaire. The relative risk of Crohn's disease in current smokers compared with those who had never smoked was 1.33 (95% confidence limits 0.7; 2.6) in men and 4.99 (2.7; 9.2) in women; the corresponding results for ulcerative colitis were 0.96 (0.5; 1.8) and 0.72 (0.4; 1.4). The relative risk of ulcerative colitis in recent exsmokers compared with those who had never smoked was 2.18 (0.9; 5.0). Furthermore, an increase in the risk of Crohn's disease was found in those who were exposed to environmental tobacco smoke during childhood, the relative risk being 1.50 (1.0; 2.3). The corresponding relative risk of ulcerative colitis was 0.98 (0.6; 1.5).