Environmental Factors in the Epidemiology of Inflammatory Bowel Disease

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

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, and 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].

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. 1.1 and 1.2). Although 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. 1.3 and 1.4; Tables 1.2 and 1.3) [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 [15–17]. 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.

Fig. 1.1

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: 1504–17. ©2004 with permission from Elsevier]

Fig. 1.2

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: 1504–17. ©2004 with permission from Elsevier]

Fig. 1.3

Incidence of CD in children (Table 1.2)

Fig. 1.4

Incidence of CD in children (Table 1.3)

Table 1.2

Incidence of pediatric IBD in the Nordic countries

Country	Year	Incidence of CD	Incidence of UC	N
Norway (IBSEN)	1990–1993	2.7	2.0	29 <16 years
Norway (AHUS)	1993–2004	2.8	3.9	49 <16 years
Norway (IBSEN II)	2005–2007	6.7	3.9	48 <16 years
West Norway	1984–1985	2.5	4.3	27 <16 years
Denmark	1998–2006	3.1	1.6	50 <15 years
Sweden	1990–2001	4.9	2.5	152 <16 years
Finland	1987–2003	1.9	3.9	604 <18 years

Table 1.3

Incidence of pediatric IBD in Europe

Country	Year	Incidence of CD	Incidence of UC	N
Scotland	1981–1995	2.5	3.8	665 <16 years
	1980–1990	2.2		107 <16 years
	1990–1999	4.4		107 <16 years
Iceland	1990–1994	8.5
Wales	1996–1997	1.36	2.6	38 <16 years
	1996–2003	3.6	5.4	39 <16 years
England	1998–1999	3.1	5.2	739 <16 years
Czechoslovakia	1990–1999	1.25		470 <15 years
	1999–2001
North France	1988–1999	2.3	3.1	509 <17 years
Netherlands	1999–2001	2.1	7.3	220 <18 years

When looking for a cause relationship behind CD and UC, the environmental factors of importance mainly seem to be related to the Western lifestyle. Nevertheless, the variation in lifestyle, 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.

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 North America. 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. 1.1 and 1.2).

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 and Mallorca [10], respectively (Fig. 1.5). This might raise interesting questions regarding both genetic and environmental explanations. Recently, also high incidence rates of IBD have been reported from New Zealand and Australia (Wilson J, Hair C, Knight R. High incidence of inflammatory bowel disease in Australia: a prospective population-based Australian incidence study. Inflamm Bowel Dis 2010;16:1550–6), which may 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].

Fig. 1.5

Global incidence of IBD

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 [25–27].

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 and second 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. 1.6). Moreover, the population-based registry of Manitoba, Canada [13] has demonstrated some of the highest incidence rates of IBD in the world.

Fig. 1.6

Incidence of IBD in the USA

In the population based ECCO-Epicom study (Burisch J, Pedersen N, Cukovic-Lavka S, et al. East-West gradient in the incidence of inflammatory bowel disease in Europe: the Ecco-Epicom inception cohort. Gut 2014;63:588–97), an east–west ratio was demonstrated for Europe, with the highest incidence rate in Western Europe. Recent review articles have reported on global variability in IBD and environmental risk factors in adults (Ng SC, Bernstein CN, Vatn MH, et al. Geographic variability and environmental risk factors in inflammatory bowel disease. Gut 2013;62:630–49; Moledecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of inflammatory bowel disease with time, based on systematic review. Gastroenterology 2012;142:46–54) and children (Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423–39).

Variations Within European Countries: Population-Based Studies (Fig. 1.7)

Fig. 1.7

Incidence of IBD in Europe—adults

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 and Spain [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].

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 population-based studies [1, 10–12]. 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, East and the South of Europe, but with a smaller difference in the South [9]. In Canada and the USA, however, 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] (Sjucic BM, Vuculic B, Persic M, et al. Incidence of inflammatory bowel disease in Primorsko-Gromska county, Croatia, 2002–2004: a prospective population based study. Scand J Gastroenterol 2006;41:437–44), 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.

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 a 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 abovementioned 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 lifestyle, 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]. Resent publications have further developed our understanding of the changed bacterial composition in IBD (Manishanh C, Bourruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol 2012;9:599–608; Hold GL, Smith M,, Grange C, et al. Role of gut microbiota in inflammatory bowel disease pathogenesis: what have we learned in the past 10 years? World J Gastroenterol 2014;20:1192–1210; Sartor RB, Mazmanian SK. Intestinal microbes in inflammatory bowel diseases. Am J Gastroenterol Suppl 2012;1:15–21; Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol 2015;37:47–55) 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 the one hand be characterized by an imbalance between commensal bacteria, and on the other hand, by secondary development of pathogens, which by omitting the immunocompromised 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 immunocompromised host, from a molecular perspective, 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 (MAP ) , Johne’s 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 Escherichia 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 [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 the 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.

For testing of dysbiosis , a genetic test applied on human feces has been published recently, comparing IBD with IBS and controls. Such comparisons need to be performed globally to be relevant to all populations (Casén C, Vebo H, Sekelja M, et al. Deviations in human gut microbiota: determining dysbiosis in a diagnostic setting in IBS and IBD patients. Aliment Pharmacol Ther 2015).

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 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] Geographic patterns related to IBD seem to involve complex interactions between genetics and sun exposure, both related to latitude (Scilagyi A, Leighton H, Burstein B, Xiaoquing Xue. Latidude, sunshine, human lactase phenotype distributions may contribute to geographic patterns of modern disease: the inflammatory bowel disease model. Clinical Epidemiology 2014;6:183–98).

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 [57–61]. 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 [64–67].

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 population-based 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].

As socioeconomic differences within each of the Western countries have been reduced, the relationship to IBD seems somewhat unclear, however, on a global level these differences are obvious. For future examinations, the factors of importance will have to be clearly defined for each country under study.

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].

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