Chapter 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease

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1 Chapter 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease Morten H. Vatn Keywords Environment Geography Socioeconomy Nutrition Microbiology Pharmacology Smoking Risk factors Introduction The occurrence of IBD has been increasing in Western Europe and North America [ 1, 2 ] over several decades after the Second World War. It has been assumed that socioeconomic factors represent the most important explanation for this increase [ 3 ]. A part of this increase may have been related to more awareness and recognition of the diseases, as well as generally better registration in all countries. It is important to realize that the general acceptance of endoscopy as the main internationally accepted diagnostic procedure, is quite young, and that we may divide the history into, a preendoscopic area before 1970, an early endoscopic period between 1970 and 1990 characterized by a relatively large heterogeneity among studies, and a post-endoscopic period from around 1990, where after a widespread distribution of equipment and skills of endoscopy enabled all countries to perform uniform diagnostic procedures (Table 2.1 ). Moreover, after this point in time, most international studies have been performed according to generally accepted definitions and criteria of diagnosis [4 ]. However, even if we generally include only endoscopy-based studies, the heterogeneity of even the Western materials is striking and difficult to compare, regarding incidence, prevalence, and subtypes. One important reason for this is the selection of cohorts in the different countries. In most centers, the registration of IBD has been hospital based, by which the type of recorded patients were depending on the level of each hospital in the health-care system of each country, including access to health care. Additionally, great variations exist in the recording systems, both between hospitals and between countries, in how well the patients were characterized on the basis of first or later admissions [4, 5 ]. The centers which have achieved most experience in IBD are second or third line hospitals with large databases, including patients with relatively more complicated disease [ 6 8 ]. M.H. Vatn, MD, PhD ( ) Section of Gastroenterology, Oslo University Hospital, P.O. Box 4959, Nydalen, Oslo 0424, Norway University of Oslo, Institute of Clinical Medicine, Akershus University Hospital, 1474 Nordbyhagen, Akershus, Norway m.h.vatn@medisin.uio.no D.C. Baumgart (ed.), Crohn s Disease and Ulcerative Colitis: From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach, DOI / _2, Springer Science+Business Media, LLC

2 18 M.H. Vatn Table 2.1 Registration of IBD Possible causes for change over time Before 1970 Retrospective data Hospital based Cross sectional studies Unclear definitions Pre-endoscopic period After 1970 Early endoscopic period Defined populations Prospective registration GP/hospital based After 1990 Endoscopy-based diagnosis International criteria Subgroups: proctitis/indeterminate Controlled on specialist level Follow-up controls Possibility for Case control studies Fig. 2.1 Temporal trends in incidence rates (cases per 100,000 person-years) of Crohn s disease in selected areas (Olmsted County, Minnesota; Cardiff, Wales, UK; Rochester, New York; Iceland; Aberdeen, Scotland, UK; Helsinki, Finland; and Florence, Italy). [Reprinted from Gastroenterology; 126(6). Loftus E. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences: with permission from Elsevier] In population-based studies, in which the cohorts better represent the total number of patients with IBD in an area, increased number of patients are recorded with light to moderate disease and less complications, and with a relatively higher age at diagnosis [ 8 14 ]. In spite of the variation in incidence and prevalence of IBD between the Western countries, the recognition of increased occurrence has been a common feature (Figs. 2.1 and 2.2 ). Although

3 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 19 Fig. 2.2 Temporal trends in incidence rates (cases per 100,000 person-years) of ulcerative colitis in selected geographic regions (Olmsted County, Minnesota; Rochester, New York; Iceland; Florence, Italy; Malmo, Sweden; Heraklion, Crete, Greece; and Seoul, South Korea). [Reprinted from Gastroenterology; 126(6). Loftus E. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences: with permission from Elsevier] follow-up studies have given increased knowledge of outcome of disease, repeated prospective studies on incidence have only recently been performed [ 9 ], and mostly in children (Figs. 2.3 and 2.4 ; Tables 2.2 and 2.3 ) [15, 16 ]. These studies tend to suggest that the incidence of CD may still be increasing in the Western world, despite signs of a stable frequency of UC in the same cohorts [ ]. In spite of the reported higher incidence rates of CD than of UC from Canada and the middle of Europe, UC is the predominant phenotype of IBD in the rest of Europe. Moreover, studies from certain areas of Northern [ 18, 19 ] and Eastern Europe [ 20 ], as well as New Zealand [ 21 ], may suggest that UC is still increasing among adults. When looking for a cause relationship behind CD and UC, the environmental factors of importance mainly seem to be related to the Western life style. Nevertheless, the variation in life style, between countries and areas within countries, is great. Additionally, the emerging increase in prevalence reported from outside the Western countries, makes the focus on environmental factors even more important. A burning question is therefore, whether certain specific risk factors for the development of IBD are related to increased socioeconomic status, regardless of geography, and in addition to public awareness and access to health care? Additionally, we have to bear in mind that in diseases like IBD, with a multifactorial etiology, different risk factors may cause imbalance of the environmental host relationship in different parts of the world. Suspected consequences of industrialization might not necessarily be relevant for disease development in different geographic regions, although our traditional reductionism of logic thinking tends to look for a simplified explanation for cause relationships. In the following, it seems necessary to relate environmental factors to the reported occurrence of IBD in the different geographic areas, and thereafter discuss the degree of potential risk factors of disease present in each specific region, to the best of our present knowledge.

4 20 M.H. Vatn Fig. 2.3 Incidence of CD in Children (Table 2.2 )

5 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 21 Fig. 2.4 Incidence of CD in Children (Table 2.3 ) Table 2.2 Incidence of pediatric IBD in the Nordic countries Country Year Incidence of CD Incidence of UC N Norway (IBSEN) <16 years Norway (AHUS) <16 years Norway (IBSEN II) <16 years West Norway <16 years Denmark <15 years Sweden <16 years Finland <18 years

6 22 M.H. Vatn Table 2.3 Incidence of pediatric IBD in Europe Country Year Incidence of CD Incidence of UC N Scotland <16 years 107 <16 years 107 <16 years Iceland Wales <16 years 39 <16 years England <16 years Checkoslovacia <15 years North France <17 years Netherlands <18 years Geography Variation Between Countries The fact that IBD occurs with the highest frequency in the Western world is undisputable, and the experience is based on hospital materials from the large centers in Europe and the USA. These areas also have in common that remarkable increasing prevalence rates have been recorded during the second half of the twentieth century [ 1, 2 ] (Figs. 2.1 and 2.2 ). In addition to that, differences between regions of Europe and North America have been recorded. In Europe, a North South gradient for incidence rate, phenotype, and recurrence, has been demonstrated [10, 22, 23 ] based on modern diagnostic procedures and prospective follow up. Interestingly, the highest incidence rates of both the North and South of Europe have been demonstrated in the islands of Iceland and Faroe Islands [ 10 ], and the islands of Crete and Sicily [ 10 ], respectively, (Fig. 2.5 ). This might raise interesting questions regarding both genetic and environmental explanations. The recently reported high incidence rates of IBD in New Zealand may also contribute to this discussion. In Japan, most of the experience in IBD is based on the reports from large hospital-based centers, all reporting on increased prevalence rates, although definitively much lower than in the Western world [ 24 ]. Some reports have also come from South America [ 25 ]. Racial differences of IBD prevalence rates have been reported from North America [ 26 ], showing much lower rates among Hispanic and Asian people compared to whites and African Americans. High prevalence rates for Crohn s disease and ulcerative colitis have also been shown for North American Ashkenazi and Israeli Jews [ 27, 28 ]. The suggested effect of ethnicity on disease location, complications, and anticipation may be partly explained by genetic and environmental factors [ ]. Developing regions have traditionally reported lower prevalence of IBD, which seems to increase, probably as a consequence of a rising incidence of IBD in many of these nations, such as India and China, as they have become industrialized [ 29, 30 ]. Furthermore, migrant studies have demonstrated that individuals immigrating from regions with low prevalence to countries with higher prevalence rates are at an increased risk for developing IBD, particularly among first-generation children [ 30, 31 ]. In the USA, also, a North South gradient has been shown by hospital-based registrations [ 6, 32, 33 ], whereas in Canada, an East West gradient has been demonstrated in a nationwide comparison [13 ] (Fig. 2.6 ). Moreover, the population-based registry of Manitoba, Canada [ 13 ] has demonstrated some of the highest incidence rates of IBD in the world.

7 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 23 Fig. 2.5 Global Incidence of IBD Fig. 2.6 Incidence of IBD in the USA

8 24 M.H. Vatn Other data on intracontinental differences of IBD in general are few, and mostly based on results from single countries. Standardized population-based data of comparisons between the East and West of Europe are underway. Variations Within European Countries: Population-Based Studies (Fig. 2.7 ) In Europe, great differences have been reported regarding variation in frequency of IBD between centers within countries. In Greece, the island of Crete showed a markedly higher incidence of IBD compared to Joannina in the North [ 10 ] similar to a higher incidence in Sicily compared to the North of Italy [ 10 ]. Based on comparisons on the Italian continent, also a North South gradient is indicated, similar to a North South gradient in Portugal [ 10 ]. In France, a higher incidence and prevalence in the North compared to the South has been reported, based on a partly hospital-based Nationwide registry [ 34 ]. Fig. 2.7 Incidence of IBD in Europe-adults

9 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 25 Within Germany, Spain, and the UK, National variations based on direct comparisons have not been reported, although variations between single center studies are obvious within countries. High incidence rates have been reported from Ireland, Scotland, and the Netherlands compared to the UK and Western Germany [ 10 ]. Many of these differences, however, might be explained by variation in type of cohorts and organization of health care. From Denmark and Norway, generally high incidence rates have been reported in populationbased studies [ 1, ]. In Norway, similar incidence rates have been shown between the Northern [ 35 ], Western [36 ], and the South-eastern part [ 12 ], whereas great differences were shown between counties for the two latter areas compared to a more even distribution within the former [ 35 ]. This could be explained by a generally mixed urban rural population in the North and a better separation between urban and rural areas in the two others. Both the Western and South-Eastern part showed a generally higher incidence rate in the scattered rural populations, opposite to previous international experience, in which urban areas have been considered to be areas of increased risk of IBD. An explanation for this discrepancy within the literature might be that different risk factors are acting concomitantly within an area in addition to the existence of different risk factors between areas. One should not, however rule out the possibility of variations in efficiency and quality of registration between areas. In Norway, the counties with most scattered and rural populations were also the areas with only one hospital, in contrast to the many recording hospitals and multidisciplinary doctors in the cities. This gave a variation in incidence rate between 17/100,000 in Oslo and 28/100,000 in the scattered populated area of Aust Agder, with one hospital in the only city of the county. These data may provide evidence for the importance of access to health care and awareness of the population under examination. To increase the understanding of the complexity of this problem, one might add, that the area with the highest incidence of IBD, had the highest increase in socioeconomic status during the decade prior to the incidence study, as measured by the number of individuals obtaining higher education. Although a much higher level of education was seen for Oslo, this level had been stable during the previous decades. With this respect, a factor that might be of importance in the Western societies is the increasing rate of immigration. Recent reports from the UK, reported on an unexpected high prevalence rate of IBD among immigrants from Southeastern Asia [ 37 ]. Relationship Between UC and CD Although a change in socioeconomic level seems to be a common risk factor for UC and CD, it is important to note that these diseases may react quite differently, not only genetically, but also to environmental risk factors. A solid background of geographic examinations is therefore important. In addition to variations between countries and regions regarding incidence and prevalence of IBD in general, the ratio between UC and CD has also shown geographic variations. A generally higher incidence rate for UC than for CD has been shown both in the North and the South of Europe, but with a smaller difference in the South [ 9 ]. Both in Canada and the USA, CD seems to occur with a higher frequency than UC [ 13 ], similar to Northern France [ 10 ]. Since this now also seems to be the case for Southern Germany [ 38 ] and parts of Eastern Europe [ 20 ], we may no longer describe this as a French enigma, but rather as a tendency for middle Europe. The variation in ratios of UC/ CD between countries and areas might reflect differences in environmental risk factors, although genetic predispositions may occur. It might be interesting to note that in Europe, the incidence of NOD2-mutations seems to be highest in the middle part, corresponding to the region with an increased CD to UC ratio.

10 26 M.H. Vatn Although unsolved questions exist regarding patterns of IBD in Europe, the risk factors and frequency of IBD in Eastern Europe must principally be regarded as related to the same socioeconomic trends as the rest of the continent and North America, in contrast to the developing countries. It is, therefore, relevant to discuss the environmental risk factors of IBD generally for the whole Europe as one area. The question, if the incidence and prevalence rates of IBD still are increasing, is generally an unsolved question in most parts of the world. The reasons for this are different in the Western world compared to the developing countries. In the USA and Europe, few data exist based on comparable prospective studies performed during different time periods within the same area. A study from Copenhagen may suggest that the incidence of CD in adults is still increasing during the last decade [9 ]. In children, however, studies from several countries have suggested that the incidence still is increasing for CD but not for UC [ 15, 16 ]. The relationship between this increase and immigration is unclear, but studies on the risk of acquiring IBD among first-generation immigrants are underway. In the recent study from Oslo [ 17 ], the incident cases of CD representing first-degree immigrants from developing countries, were partly responsible for the 100% increase in incidence of CD over the last decade. To what extent the shift of environment has an impact on the development of IBD, will have to be focused in the future. The geographic difference between the North and South of Europe was the same for UC as for CD [10, 22, 23 ], also with regard to outcome and complications. For the above-mentioned reasons, it is not quite clear if the incidence of UC has stabilized or in some areas still is changing. A recent study from Finland indicates a dramatic increase in UC, based on partly population-based data from a regional registry. For all registry-derived data, some uncertainty exists, regarding reliability of the recording system over time. On the other hand, since recently also an increase of UC has been suggested in Hungary, a combined causality of environmental factors and ethnicity could explain a parallel increase in Finland and Hungary. Reports from developing countries on the incidence and prevalence of IBD are still missing as regards population-based studies. Regional studies from India [ 24 ], may, however, suggest an increase over time in well-defined regions. Documented increase of incidence or prevalence in Japan would, however, be of particular interest, since Japan may be the only country in Asia with stable socioeconomic conditions over several decades. An eventual increase in frequency of IBD would then have to be related to other than direct socioeconomic factors, and rather to other changes in the environment or life style, such as dietary habits. Environmental Factors Relationship to Microbiology Today, the most important environmental factor, with a cause relationship to the development of IBD, is considered to be related to an imbalance in the microbial host relationship with mucosal barrier dysfunction and reduced microbial diversity [ 39 ]. The hygiene hypothesis is an attempt to explain why improvement of hygienic conditions may result in intestinal dysbiosis as a primary event, resulting in IBD among genetically predisposed individuals. This hypothesis implies that the rising frequency of immunologic disorders can be attributed to lack of childhood exposure to enteric pathogens. This dysbiosis may on one hand be characterized by an imbalance between commensal bacteria, and on the other hand, by secondary development of pathogens, which by omitting the immunocompromized cells of the different barrier systems, may lead to chronic inflammation. The suggested Cold chain hypothesis represents a more direct explanation of a cause relationship between specific bacteria and the immunocompromized host, from a molecular perspective,

11 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 27 postulating that CD is a result of a defect in the host recognition of pathogenic bacterial components that usually escape the immune response (e.g., Yop molecules), leading to an excessive host response to bacteria, such as Yersinia spp. and Listeria spp., which can survive refrigerator temperature [40 ]. The definition relies on the introduction of refrigeration in society, which was related to the time of increased prevalence of CD. A support for this hypothesis has been reported in case control studies, partly in combination with other socioeconomic risk factors [ 41, 42 ]. In support of the hygiene hypothesis are the generally negative association to the epidemiology of Helicobacter pylori [ 43 ] and the inverse association to the prevalence of helminthic colonization [ 44, 45 ]. It is still an issue if primary pathogens like Mycobacterium Avium Paraturbeculosis spp (MAP), Jones disease [ 46 ], may be an etiologic factor, but problems related to the biologic methodology has been a major concern, and further studies are expected in the years to come. Clinical studies up to now have been inconclusive with regard to the impact of MAP in IBD, and a study of seropositivity showed a high prevalence for IBD, but failed to demonstrate a difference between CD, UC, and controls [47 ]. Several studies, however, have detected a high prevalence rate of MAP in CD patients, and a meta-analysis of 28 case control studies showed a positive association, both for enzyme-linked immunosorbent assay (ELISA) and PCR [ 48 ]. A recent examination [ 49 ], however, performed with highly sensitive methods in intestinal mucosa, could not detect the presence of MAP in newly diagnosed, treatment naïve cases, in contrast to many affected cases among hospitalized CD patients on treatment, in the same catchment area. MAP was not found among patients with long-standing UC. According to these results, MAP is probably not an etiologic factor, but a bystander appearing during the course of disease and appearing in patients on treatment. Another interpretation could be that MAP remains elusive to detection during the early phase of disease, and that a longer duration of immune decompensation is needed for diagnosis by the present methods. The high prevalence of adherent-invasive Eschirichia coli spp. associated to ileal CD may represent another primary pathogenic strain of bacteria, which is able to adhere to intestinal epithelial cells, to invade epithelial cells via a mechanism involving actin polymerization and microtubules, and to survive and replicate within macrophages [ 50 ]. Other hospital-based studies have demonstrated a geographic covariation related to hospitalization and mortality for IBD and Clostridium difficile spp. [51 ]. Since IBD is most common in the Northern hemisphere, most studies with regard to microbial risk factors have been performed in this region. As, on one hand, one might speculate that improvement in sanitary conditions is responsible for reduced microbial diversity, industrial pollution in society might serve as another explanation for changed environment. It is probably unlikely that the exogenous predisposition for IBD can be explained by one single environmental factor. At the moment, our knowledge regarding possible risk factors derived from industrialization must be divided mainly into primary direct effects of endogenous dysbiosis and secondary effects on this microbial imbalance. The latter explanation will include all the risk factors that will either increase the microbial instability or increase the vulnerability of the host organism. Relationship Between Environment and Geography Of factors that may act on the intestinal microbial composition, geography may represent a risk in addition to socioeconomic development. Living on the Northern hemisphere may therefore explain the increased incidence of IBD, only based on this single factor, which might be explained by increasing intestinal dysbiosis. It has been suggested that this risk increases with increasing latitude from the

12 28 M.H. Vatn Equator to the North Pole [ 52 ]. This explanation needs support from more comparable studies, which need to be performed by standardized examinations on preferentially unselected materials. Although latitude alone may represent a risk for development of IBD, the reports from Canada, showing a marked East West gradient, which at least up to now, might have been the case also for Europe, seems to indicate that contemporary differences within a society or within a region over time, represent the most important risk factors. These two examples of East West gradients may therefore strengthen the argumentation for industrialization as a main causative factor for IBD. The North South gradient in Europe does not necessarily depend on the same differences, because industrialization and socioeconomic growth patterns have in part ran more parallel in the North and South of Europe. Other environmental factors, such as water supply, may act in addition to, or increase, the instability, primarily caused by the dysbiotic intestine. In a recent study, a strong association between iron concentration in the sources of drinking water and the community incidence of IBD, both CD and UC, was found [ 53 ]. Other metals showed no association to IBD, opposed to the proposed focus on aluminum as a risk factor [ 54 ]. One explanation why inorganic iron might be a risk factor is its known ability to cause oxidative stress, whereas another might be its effect on bacterial growth. The results might generally agree with a role for oxygen radicals in animals and humans [ 55 ]. Relationship to latitude might also be explained by changes in sun exposure and vitamin D [ 56 ]. Socioeconomic Factors One might speculate that the role of latitude is part of the North South gradient in Europe, although other environmental factors, such as diet or socioeconomics, may be responsible for the variation in the occurrence of IBD. Several studies have reported on increased incidence of both UC and CD in more densely populated areas [ ]. Both family size and number of older siblings, as well as birth order, have been related to increased risk of UC, and with smaller families and few older siblings related to CD [ 62 ], which might be a sign that UC is more directly affected by environmental factors than CD. This explanation was also supported by a shorter interval between first-degree relatives acquiring UC compared to CD [ 63 ]. The relationships between these diseases and other household-related conditions, such as pets, are unclear [ ]. It has previously been reported that both UC and CD are affecting white collar more than blue collar employees [68 ]. Further studies among German employees suggested that work in the open air and physical exercise were protective, while being exposed to air conditioned, artificial working conditions or extending and irregular shift working increased the risk of IBD [ 69 ]. In populationbased studies in Norway, the incidence of IBD was higher in rural areas with a recent increase in socioeconomic status, based on years of education, compared to urban areas with a stable high socioeconomic level [ 12, 36 ]. Other factors which might be related to socioeconomics are sanitary conditions, which actually formed the basis for the hygiene hypothesis. In an epidemiological study in the UK, the availability of a fixed hot water supply in childhood before the age of 11 was associated with Crohn s disease [ 3 ]. Smoking Smoking has generally been accepted as a risk factor in Crohn s disease, for worsening of the disease course, such as reduced response to treatment, increased relapse rate, and complications [ 70 ], whereas in UC, smoking has a protective effect against the same outcomes of disease [ 23 ].

13 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 29 Regarding onset of disease, the connection to smoking is less clear, but a meta-analysis showed an OR of 0.58 for UC and 1.76 for CD among smokers [ 71 ] in the general population which could implicate that smoking is a part of a primary event, and not only as a secondary factor influencing the course of disease. Passive exposure to smoking during childhood has also been shown to influence the risk of IBD [72 ]. A possible relationship between age at diagnosis and smoking has also been suggested [ 73 ]. No single explanation for the mechanism behind smoking and the onset of IBD has been postulated, but among siblings discordant for smoking, smokers tended to develop CD, whereas nonsmokers tended to develop UC [ 74 ]. This may suggest an interaction between smoking and genetic susceptibility. In UC, the significantly reduced frequency of panca positivity among smokers, and a tendency of increased frequency of ASCA positivity, may either be supportive of such a mechanism or may be explained by other mechanisms, such as direct reaction to yeast, a result of disease activity or exposure to treatment [ 23 ]. The meta-analysis of 245 articles [ 71 ], reported on evidence for an association between current smoking and CD (OR, 1.76) and former smoking and UC (OR). Current smoking had a protective effect on the development of UC when compared with controls (OR, 0.58). These results confirmed that smoking is an important environmental factor in IBD with differing effects in UC and CD. Nutrition and Diet Considerable efforts have been made in the search for nutritional factors related to, and maybe even responsible for the development of IBD. The methodology of this research has been hampered by the problems of confounding factors and the fact that many patients will change their nutritional habits as a consequence of the disease. There are many studies in small cohorts of patients, who claim that intake of certain diet constituents like fat, refined sugar, fruits, vegetables, and fiber affect the expression of IBD. These studies do not provide unequivocal evidence to incriminate any particular dietary factor. A recent survey of Medline and the Cochrane database concluded that, based on the current levels of knowledge concerning dietary risk factors for IBD and the therapeutic efficacy of dietary and nutritional interventions, the results need to be supported by well-designed trials in large cohorts of patients [ 75 ]. A multitude of factors, including drug nutrient interactions, disease location, symptoms, and dietary restrictions can lead to protein energy malnutrition and specific nutritional deficiencies. Studies have revealed that nutritional deficiencies are relatively common in IBD, both regarding reduced intake of food and vitamin and mineral deficiencies. It is estimated that up to 85% of hospitalized IBD patients have protein energy malnutrition, based on abnormal anthropometric and biochemical parameters [ 76, 77 ]. It is clear that nutrition plays an important role in the management of patients with IBD. The need and advice for nutritional therapy is, due to the heterogeneity of the diseases, quite variable and based on the individual subtype of disease, disease stage, and the patients total situation. Consequently, there are no specific nutritional therapies that may be recommended to all patients. Attention to weight changes, to eating habits, and to GI symptoms are the best guides for the clinician. Any abnormality, regarding general health, clinical, or biochemical measurements, must be considered as risk factors regarding disease outcome. Nutritional factors of importance for the outcome of IBD represent the basis for prophylaxis against complicated disease and malnutrition. Specific dietary therapy to avoid symptoms and supplements to meet nutritional depletion are active measures to avoid complications to disease. Metabolic dysfunction and secondary osteoporosis and osteomalacia are serious complications related to malabsorption in CD. Regarding primary risk factors for development of disease, studies have focused on preventive measures and potential risk factors.

14 30 M.H. Vatn In a relatively large surveillance of patients with UC and CD in Italy [ 78 ], in addition to the previously documented relationships between these diseases and smoking, the study reported that lack of breast feeding was associated with increased risk of both UC (OR 1.5) and CD (OR 1.9). A meta-analysis of 14 case control studies reported on a protective role for breastfeeding in both CD and UC [ 79 ]. In a French case control study of incident cases with CD and UC occurring before 17 years of age, performed between January 1988 and December 1997, 140 variables covering familial history of IBD, events during the perinatal period, infant and child diet, vaccinations, childhood diseases, household amenities, and family socioeconomic status were recorded. Among nutritional factors, regular drinking of tap water was protective against IBD, whereas breast feeding was a risk factor [ 80 ], opposite to the previously mentioned report [ 79 ]. The preponderance of evidence suggests that breastfeeding is a protective factor for IBD, with a greater effect for CD than UC, based on a recent meta-analysis [81 ]. The role of dietary macronutrients in the etiology of IBD was recently examined in a large prospective cohort of women living in France, aged years. Based on questionnaires on disease occurrence and lifestyle factors that were completed every 24 months, high total protein intake, specifically animal protein, was associated with a significantly increased risk of IBD [ 82 ]. This could fit well with the previously reported association with consumption of fast food for both UC (OR 3.4, ) and CD (OR 3.9, ) in a population-based incidence study in Sweden. The study, performed by a questionnaire, covered retrospectively the 5 years prior to diagnosis of IBD [ 83 ]. Another study showed that total fat and intake of mono-unsaturated and polyunsaturated fats, as well as intake of vitamin B6, were related to UC, whereas a negative association was found for carbohydrates [84 ]. A relationship to fat consumption was also found in another study, for UC [ 75 ], whereas intake of dietary fiber, fruit, and vegetables were reported to be protective for both [ 85, 86 ]. In another prospective controlled study of pre-illness changes in IBD, approximately one-third of patients changed their diet prior to the diagnosis of IBD due to nonspecific symptoms. Of the patients not changing their diet, moderate and high consumption of margarine (OR = 11.8 and OR = 21.37) was associated with ulcerative colitis, while high consumption of red meat (OR = 7.8) and high intake of cheese were associated with Crohn s disease [ 87 ]. In a retrospective study performed within 3 years after diagnosis, the results also showed different, but significant associations for both UC and CD with regard to food consumption [ 86 ]. Especially, the French study [ 82 ], being the first large-scale prospectively performed study of diet recorded before the onset of disease, lends strong support to fat and meat consumptions as risk factors of IBD. Especially, the animal proteins from meat and fish represented a risk factor, whereas dairy and vegetable proteins did not. Again the risks were increased for both UC and CD; however, the study was limited to middle aged females. Nevertheless, the study partly supported the previous findings from Japan, where the reported increase of CD during the period was strongly associated to increased intake of animal protein and somewhat less to increased n 6/ n 3 polyunsaturated fatty acid ratio [ 88 ], by multivariate analysis. A nested case control study of a prospective cohort study within seven regions in Europe, identified linoleic acid, in contrast to docosahexaenoic acid, as a significant risk factor for the development of UC [ 89 ], however, failed to find a significant association between micro- or macronutrients and disease, based on data from partly the same regions [ 90 ]. The evidence for these dietary risk factors in IBD, therefore, has to await further documentation from different populations and subgroups of patients in the future. Based on epidemiological data, case control studies, and search in Medline, it has been speculated that the reported relationships between changes in food consumption would fit, in a timely manner, with a change of intestinal microbes associated to IBD [ 91 ]. A time relationship between IBD and change in dietary consumption has also been reported for intake of carbohydrates.

15 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 31 Case control studies from Germany [ 92 ] and the UK [93 ] demonstrated an association between intake of sugar and CD. Another case control study from the UK showed that intake of sugar and smoking were separate but interactive risk factors [ 94 ]. The association between both monosaccharide s and disaccharides and CD was also shown in Israel [ 95 ], Japan [96 ], and Italy [97 ]. The general question regarding the carbohydrate hypothesis is, to what extent reporting of increased consumption is related to early change of diet due to onset of disease, or if it represents an etiologic factor. This question may also be raised regarding the increased frequency of bran eaters among patients with CD [ 98 ]. Another factor of increasing interest is the host response to yeast. Several studies have shown increased IgG and IgA antibodies to baker s yeast ( Saccharomyces cervisiae spp. ) in patients with CD but not UC [ 99, 100 ] as a consequence of intake of wheat. A recent report from studies in twins, however, suggested ASCA to be a marker of shared environment but with a genetic susceptibility, other than NOD2/Card15, as regards the titer level [ 101 ]. Recent reports have focused on the possibility of a nutrient gene interaction, which might be a part of an individualized immunogenic therapy in the future [ 102 ]. Mechanisms by way of food consumption might also be further elucidated by studies on the role of epigenetic factors for the development of IBD in the future [ 103, 104 ]. Micronutrients and Microparticles Both in food and water supply, metals and minerals, as well as other microparticles, are abundant, and as such more common as part of pollution in industrialized areas. These particles may act in different ways with the immune system, causing primary or secondary effects. It has been suggested that exposure to xenobiotic-like metals may induce immune responses in autoimmune diseases. Such reactions have been related to effects of mercury [ 105 ], cobalt, zirconium, beryllium, silver, and aluminum [ 54 ]. Especially aluminum is ubiquitous in the Western culture and represents the most widely used trace element in food, water, soil, and pharmaceutical agents. Moreover, food additives and processed foods, such as cheese, baked goods, grain products, cake, and pancake mixes, vending machine powdery, milk, cream powder substitute, and soy-based milk formulae, sugar and frozen dough, add substantial amount to Al intake. Additionally, different substances, when added to water and even water purification procedures, may increase the bioavailability and toxicity in aqueous organisms resulting in facilitating Al entry into the food chain. On these grounds, a hypothesis of a bacterial metal interaction was put forward as a factor in CD induction [ 106 ]. In line with this, the recently reported strong association between iron concentration in the sources of drinking water and the community incidence of IBD, both CD and UC, may support a bacterial metal interaction [ 53 ]. In this study, however, other metals showed no association to IBD, opposed to the proposed focus on aluminum as a risk factor in IBD. Interactions between microparticles and the immune system, possibly by accumulation in macrophages, has also been postulated as a basis for the use of low microparticle diets in the treatment of IBD [ 107 ]. Nonsteroidal Anti-inflammatory Drugs Nonsteroid anti-inflammatory drugs have been considered as potential risk factors for outbreak of inflammation, relapse, and increasing activity of established IBD.

16 32 M.H. Vatn Several hypotheses have been put forward on the pathophysiology of intestinal damage by NSAIDs [ 108 ], such as, enhanced intestinal permeability, inhibition of cyclooxygenase (COX), enterohepatic recirculation, and formation of adducts. The effects of COX-2 selective inhibitors, which appear to have better gastric tolerability when compared to nonselective NSAIDs, on normal and inflamed intestinal mucosa, as in Crohn s disease or ulcerative colitis, are still largely unexplored. If COX-2 inhibition plays a key role in suppressing the inflammatory process, recent evidence suggests that COX-2 products are involved in maintaining the integrity of intestinal mucosa, in the healing of gastrointestinal ulcers and in the modulation of inflammatory bowel disease (IBD). Animal models of intestinal inflammation have so far yielded conflicting results on the effects of COX-2 selective inhibitors on the intestinal mucosa. It is now clear that NSAIDs do not act through cyclooxygenase inhibition alone, but also have different effects on targets, such as nuclear factor-kappab and/or on peroxisome proliferator-activated receptors (PPAR). The peculiar pharmacological profile of each compound may help to explain the different impact of each NSAID on the inflammatory process and on IBD. Notably, the salicylic acid derivative 5-ASA is widely used in the treatment of IBD and is believed to act through nuclear factor-kappab interaction. Although the use of COX-2 selective inhibitors remains contraindicated in patients with IBD, studying their effects on intestinal mucosa may offer new insights into their subcellular mechanisms of action and open new avenues for the development of novel therapies for IBD. The general agreement that NSAIDs increase intestinal permeability, still makes these drugs potential risk factor for both exacerbation of disease, relapse rate, and increasing activity [ 109 ]. Recent studies of tolerability of selective Cox-2 inhibitors have demonstrated that these drugs are safe and beneficial in most patients with IBD and not associated with exacerbation of the underlying IBD- and GI-related complications [ 110 ]. Oral Contraceptives Several studies have reported an increased risk of IBD following the use of oral contraception [ 111 ]. The association has been shown especially for Crohn s disease, in contrast to ulcerative colitis, and an interaction has been shown for current smoking [ 111 ]. This risk was also shown in a populationbased case control study from the USA. Women who reported oral contraceptive use within 6 months before disease onset were at increased risk for both diseases compared with never users. Women who had used oral contraceptives for more than 6 years had the highest risk of Crohn s disease (RR = 5.1, 95% CI ). In contrast, increasing duration of use was not associated with increased risk of ulcerative colitis. There has been a concern that females on contraceptives are at increased risk of disease relapse and other adverse events, such as thrombosis [ 112 ]. In this research of 207 articles in PubMed, results gave little evidence to suggest an increased risk of disease relapse among women with IBD who use oral contraceptives, and there seemed to be no differences in the absorption of higher-dose combined oral contraceptives, between women with mild ulcerative colitis or small ileal resections and healthy women. A recent meta-analysis reported on a positive association for use of oral contraceptives and both UC and CD [ 113 ], with a reduced effect upon discontinuation. The study was not able to show an effect of dose reduction. Although most of the literature recommend oral contraceptives in IBD, however, monitoring for thromboembolic events has been recommended [ 114 ].

17 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 33 Seasonal Variability It has been speculated that the reported seasonal variations of relapse rate in Ulcerative colitis [ 115 ] or incidence in UC [ 116 ], may be explained by change in environmental risk factors throughout the year. In the Swedish cohort study [ 115 ], a significantly higher relapse rate was found during the summer, whereas a significantly increased incidence rate of IBD was found during the early winter months of December and January in the Norwegian population-based incidence study. A recent controlled cohort study based on the Hospital Episode statistics (HES) in the UK of all admitted IBD patients between 1997 and 2006 did not show a seasonal birth pattern [ 117 ]. By monthly comparison year by year, different fluctuations were found for CD and UC, with a weak but significant correlation (0.078, p = 0.018). A slight trend for stronger correlation occurred during the later decades. Nevertheless, the author concluded that patterns of birth dates among IBD patients do not support the contention that seasonally or monthly varying environmental factors during early childhood shape the subsequent risk of developing IBD. In a study from the USA, norovirus was associated to exacerbation of both UC and CD in pediatric patients, in all cases associated with bloody diarrhea, and with demand for hospitalization. This was in contrast to diarrhea without hematochezia when the infection occurs in the absence of IBD [ 118 ]. Based on these observations, the relationship between seasonal environmental risk factors may affect the outbreak of IBD differently according to the occurrence of risk factors around the world. One cannot rule out the possibility that also perinatal risk factors might be of importance at the presents of combination of risk factors, such as in selected areas or individual groups. Large nationwide studies might dilute important local variations, which might seem negligible when the results are not broken down into smaller regions, such as communities [ 119 ]. Appendectomy The inverse relationship between previous appendectomy and ulcerative colitis has been confirmed in several studies. In a study including 213 patients with UC, 110 with CD and 337 controls, a highly significant association to appendectomy was found for UC (OR 0.20), and even higher when the operation was performed before the age of 20 (OR 0.14). No association was found for CD, and no association for tonsillectomy for either disease [ 120 ]. Moreover, the study from Spain also showed that appendectomy was less frequent, not only among UC and CD patients, but also among their relatives [ 120 ], compared to the general population. A case control study from Iran confirmed the inverse relationship between appendectomy and UC in contrast to Crohn s disease [ 121 ]. A population-based study from New Zealand reported that not only appendectomy, but also tonsillectomy, infectious mononucleosis, and asthma were more common in CD patients than controls [ 122 ]. Another case control study from Spain [ 123 ] showed that both appendectomy and current smoking were protective for UC. Additionally, this study showed that better living conditions during childhood were associated to increased risk for IBD. A case control study from Greece [ 124 ] could neither confirm a significantly inverse relationship to UC (OR 0.6) nor a significant association to CD (OR 2.2), although well-known risk factors, such as family history and smoking were confirmed. A multivariate regression analysis, however, showed positive associations between appendectomy and tonsillectomy for CD, but no independent inverse association to UC. With some variation in results, however, the literature shows strong relationships between previous appendectomy and the development of CD, and inversely to UC, which again might indirectly support the impact of the hygiene hypothesis as an explanation for the importance of socioeconomic conditions in the development of IBD.

18 34 M.H. Vatn General Remarks and Future Aspects Regarding Global Environmental Risk Factors in IBD The evidence for increased frequency of IBD in the industrialized parts of the world is strong and is mainly explained by environmental risk factors. Of all the identified risk factors, not a single one alone may up to now, totally explain the increasing incidence in any part of the world. This might be explained by a multiplicity of potential routes for disturbances of the microbial host interactions. It is also possible that the strength of influence by risk factors or lack of protective factors in a society is different, depending on geography or urbanization. It is still possible that a common single explanation for the microbial host imbalance will be found in the future, based on an explanation which up to now has been too difficult to grasp. If we hypothesize that change in human adaption to the socioeconomic burden is related to endogenous changes, caused by individually based stressors of psychoimmunological origin, a model for such a hypothesis is at the moment not at hand. If any one new single explanation for the microbial host imbalance was found, it might leave all our present risk factors as confounders. Nevertheless, the increased molecular understanding of disease development in IBD during the last decades must be expected to reveal new and important contributions, also to the evaluation of the different environmental risk factors, together with geographic and individual susceptibility of the person at risk. References 1. Munkholm P, Langholz E, Nielsen OH, et al. Incidence and prevalence of Crohn s disease in the county of Copenhagen, : a sixfold increase in incidence. Scand J Gastroenterol. 1992;27: Lofthus EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126: Duggan AE, Usmani I, Neal KR, Logan RFA. Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case control study. Gut. 1998;43: Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol. 1989;24 Suppl 170: Logan RFA. Inflammatory bowel disease incidence: up, down or unchanged? Gut. 1998;42: Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation in the incidence of and mortality from inflammatory bowel disease. Dis Colon Rectum. 1986;29: Primatesta P, Goldacre MJ. Crohn s disease and ulcerative colitis in England and the Oxford Record linkeage study area: a profile of hospitalized morbidity. Int J Epidemiol. 1995;24: Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn s disease. Inflamm Bowel Dis. 2002;8: Vind I, Riis L, Knudsen E, et al. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen city and county, : a population based study from the Danish Crohn colitis database. Am J Gastroenterol. 2006;101: Shivananda S, Lennard-Jones J, Logan RFA, et al. Incidence of Inflammatory bowel disease across Europe: Is there a difference between north and south? Results of the European collaborative study on inflammatory bowel disease(ec-ibd). Gut. 1996;39: Moum B, Vatn MH, Ekbom A, et al. Incidence of ulcerative colitis and indeterminate colitis in four counties of south-eastern Norway A large prospective population-based study. Scand J Gastroenterol. 1996;31: Moum B, Vatn MH, Ekbom A, et al. Incidence of Crohn s disease in four counties of south-eastern Norway A large prospective population-based study. Scand J Gastroenterol. 1996;31: Bernstein CN, Wajda A, Svenson LW, et al. The epidemiology of inflammatory bowel disease in Canada: a population based study. Am J Gastroenterol. 2006;101: Jess T, Lofthus Jr EV, Velayos FS, et al. Incidence and prognosis of colorectal dysplasia in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Inflamm Bowel Dis. 2006;12: