Risk Factors

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The etiology and pathogenesis of IBD probably involve an interaction between genetic and environmental factors; the precise mechanism for the beginning of the intestinal inflammation remains unclear. There is increasing evidence that both environmental and host genetic factors are important in determining not only disease susceptibility, but also disease clinical course and response to therapy. Many factors have been suggested including family history of IBD, cigarette smoking, appendectomy, oral contraceptive agents, diet, breastfeeding, perinatal or early childhood infections, hygienic factors and physical activity.

Evidence for genetic factors includes epidemiolog-ical data showing differences in IBD among different races and ethnic groups, familial aggregation and high concordance for the IBD type in monozygotic vs. dizygotic twins [34-35]. The incidence is highest among whites, somewhat lower among blacks and lowest among Asians, although it is increasing among the latter [36]. Among Caucasians, the most consistent observation has been that the Ashkenazi Jewish population has been shown to be at higher risk than other ethnic groups (ratio 4:1) and this risk is maintained irrespective of geographical location and time period [37].

A family history is the single greatest known risk factor for the development of IBD. Between 6 and 32% of patients with IBD have an affected first or second-degree relative and the prevalence of family history is highest in Jewish patients and in patients with early onset of disease [38-39]. The risk is greatest among siblings, whereas it is lower among offsprings and second-degree relatives; the relative risk to a sibling of a patient with CD is 13-36% and for UC

7-17%. Therefore, a positive family history is more common in CD than in UC and relatives of patients with CD have a higher risk of developing IBD than those of patients with UC, suggesting a stronger genetic influence for CD [40-42].

Three twin studies have examined the relative genetic and environmental contributions to IBD by studying a total of 322 twin pairs. Combining these results produces CD concordance rates of 37 and 7% for monozygotic and dizygotic twins respectively, with equivalent results for UC of 10 and 3%. The genetic contribution is clearly less strong in UC than in CD, but the discordance between monozygotic and dizygotic prevalence rates again argues for a genetic contribution to UC. However, genes alone are not sufficient to cause the disease and complex environmental triggers are required for disease expression [43-45].

In genetic terms, the IBD are "complex" because classical Mendelian inheritance attributable to a single gene locus is not exhibited. The model which appears most pertinent at the present time suggests that CD and UC may be related heterogeneous poly-genic disorders, sharing some but not all susceptibility loci. The disease phenotype is likely to be determined by the interaction between allelic variants at a number of loci and the interaction between genetic and environmental factors [46].

Recently the candidate genes have been selected on the basis of their location within an area of replicated linkage in multiplex IBD pedigrees (Fig. 7). The first susceptibility locus was identified in the pericen-tromeric region of chromosome 16 (IBD1) [47]. The importance of this locus has been confirmed by various groups, including the GISC [48] and the International IBD Genetics Consortium [49]. In 2001, three independent studies reported the identification of the IBD1 gene as NOD-2 [50-52]. Three coding region variants of this gene are associated with CD but not with UC. Patients carrying one high-risk allele have a 1.5-3-fold increased risk of developing CD, whereas those carrying two high-risk alleles have a 14-44-fold increased risk of developing CD [53]. The NOD2 gene has recently been renamed CARD15 (caspase recruitment domain gene) and is involved in the regulation of innate immune response and apoptosis; the leucine-rich repeat (LLR) domain of the gene appears to function as a sensor for bacterial products such as lipopolysaccharides (LPS; Fig. 8). Recently several genetic studies have been carried out in order to relate NOD2/CARD15 variants to specific clinical features of patients. The studies have generally correlated NOD2 mutations with younger age at onset, ileal localisation and fibrostenotic behaviour of CD [54-57].

It has now been 23 years since the association of

Loci

Chromosomes

Genes

IBD]

16ql2

NOD;,

IBD2

!2ql3

7

IBD3

6pl3

HLA, TNF?

IBD4

!4ql 1

7

IBD5

5q31-33

?

IBD6

19p

7

IBD7

lq

7

IBD/t

3, x

7

Fig. 7. Significant areas of replicated linkage

Fig. 8. Schematic representation of the NOD2/CARD15 [51]

Fig. 7. Significant areas of replicated linkage

Fig. 8. Schematic representation of the NOD2/CARD15 [51]

non-smoking with UC was first identified by Harries et al. in 1982 [58], which was followed within 2 years by the observation that patients with CD were more often smokers [59]. This remarkable finding of "opposite associations" for smoking with IBD has been the subject of intense scrutiny in the hope that it may help identify important pathogenic mechanisms responsible for the two conditions and perhaps provide the key to alternative therapeutic options.

In 1989, Calkins reviewed the available studies on the association with IBD. A meta-analysis showed an increased risk of ulcerative colitis among lifelong non-smokers and ex-smokers compared with current smokers (OR 1.64) [60]. The M/F ratio, at diagnosis of UC, increases progressively with age in relation to the ex-smoker's habit compared with the M/F ratio that remains constant in non-smoking patients [33]. Moreover, it appears that ex-smokers are 70% more likely than those who never smoked to develop UC. In contrast to UC, several studies have implicated cigarette smoking as a risk factor for CD and the same meta-analysis suggests that in smokers the risk of having the disease is double in comparison to non-smokers. This association may not apply to all ethnic groups or geographic regions, a recent multicentre study performed in Israel has stressed the lack of association between smoking and CD and a negative association for UC [61]. Passive cigarette smoking has also been linked to IBD risk, but results have been conflicting. For UC the effect of passive smoking in childhood was comparable with that of active smoking in adulthood [62]. However, another study demonstrated that passive smoking exposure and maternal smoking at birth were significantly associated with development of either subtype of IBD; in CD the association had a dose-response relationship [63].

Cigarette smoking may also influence the clinical course of IBD. Active smokers were half as likely to be hospitalised for UC as non-smokers, whereas ex-smokers had higher hospitalisation and colectomy rates [64]. In another study, approximately 45% of UC patients who resumed smoking noted improvement in symptoms [65]. Moreover, significantly fewer smokers developed pouchitis compared with non-smokers among patients who had a restorative proctocolectomy for UC [66], and smoking is associated with decreased risk of primary sclerosing cholangitis (PSC) [67].

Patients with CD who smoke (>10 cigarettes/day, >150 cigarettes/year) are more likely to have ileal than colonic or ileocolonic involvement and fistulis-ing or stenosing than inflammatory disease [68-70]. Most of the studies show severe symptoms, more frequent relapses, higher recurrence rate after surgery and more frequent treatments with steroids and immunosuppressors in smokers compared with non-smokers [71-73]. Young women with CD who continued to smoke, suffered more bowel and systemic symptoms in addition to more emotional dysfunction than female non-smokers [74].

More recently the role of the appendix in IBD epidemiology has become the subject of increasing interest. Appendectomy appears to be protective for the development of UC; important factors associated with a lower incidence of UC include an appendectomy before the age of 20 and appendectomy for appendicitis or mesenteric lymphadenitis [75-77]. Similar to the effect of cigarette smoking, an appendectomy also influences the clinical course of UC. In fact, patients who developed UC after appendectomy were diagnosed at an older age, showed few recurrent symptoms and were significantly less likely to require colectomy [78-79].

On the other hand, many studies have suggested that appendectomy is associated with future risk of CD even after excluding a diagnosis within 1 year of the procedure; moreover, patients who developed CD following a surgery for perforated appendicitis had a more aggressive form, requiring intestinal resection

[80]. A recent study suggested that appendectomy performed before CD diagnosis can predict a worse clinical course of disease and a higher risk of resec-tive operations for these patients. In addition, disease localisation seems to be influenced by the occurrence of a previous appendectomy, resulting in a significantly lower frequency of Crohn's colitis (9.8 vs. 27.3%, OR 0.3) compared with controls. This fact may suggest some hints on the pathogenic role of the appendix in CD; it could be hypothesised that an etiopathogenic process may be phenotypically expressed in the form of appendicitis avoiding the expression of CD in the colon, similar to the protective role of appendectomy regarding the development of UC. In addiction, the occurrence of an appendectomy before CD diagnosis seems to show a negative association with articular manifestations

Several case-control and cohort studies have suggested an increased risk of IBD in women who take oral contraceptives. In some studies, a positive association between oral contraceptives use and risk of CD was confined to women who were current smokers (OR 2.64) [62], whereas the opposite finding has been reported in other studies in which the elevated risk was found only among non-smokers (OR 3.1 vs. 0.91) [82]. There was no association between oral contraceptive use and UC (OR 0.70). Therefore, there is no evidence suggesting that women predisposed to the development of UC should be advised to avoid oral contraceptive use [83]. However, a 1995 meta-analysis demonstrated an elevated risk both for UC (OR 1.29) and CD (OR 1.44) [84]. Since this meta-analysis, other studies have been published with the same pattern of results: an overall weak association for both diseases but non-sufficiently compelling to infer a causal association [85-86]. The mechanism for this association is not definitively known, but it is thought that the thrombogenic properties of oral contraceptives, in the setting of a process of multifocal, microvascular gastrointestinal infarction, might play a role [87].

Because dietary agents are, next to bacterial antigens, the most common type of luminal antigen, it is logical to surmise that diet might play a role in the expression of IBD. Furthermore, differences in diet might explain the significant differences in IBD risk across geographic regions and the increase in IBD incidence in migrant populations. However, numerous studies have investigated dietary factors in IBD, and the methodological problems related to studies of this kind (type of population studied, recall bias, measure) have brought contradictive results. The most consistent association noted in dietary studies has been the link between increased sugar intake and CD [88]. A population-based case-control study from The Netherlands implicated chocolate and cola drink consumption as possible risk factors for IBD [89]. Finally, high intake of dietary fibre, fruit or vegetables may be protective against the development of IBD, but results vary from study to study [90-91].

It has been proposed that the expression of IBD may be influenced by events in early childhood such as mode of feeding, domestic hygiene or perinatal infections. Although several studies have suggested an inverse association between breastfeeding and IBD [86, 92, 93], in most cases the odds ratios were not statistically significant and other studies have not demonstrated such an association [94-95]. In general, the association has been stronger for CD than for UC.

Perinatal infections, either in the infant or the mother, might influence the expression of IBD. It has been proposed that perinatal or childhood paramyx-oviral infection might result in persistent infection of the vascular endothelium of the mesentery, resulting in a chronic granulomatous vasculitis (CD) [96]. However, other studies have not been able to confirm these findings [97]. The same investigators who initially proposed persistent measles infection as a cause of CD suggested that attenuated live measles virus vaccine might lead to IBD [98], but several case-control studies in different locales have not demonstrated significant differences in vaccination rates among IBD cases and unaffected controls [99]. Based on the available evidence, it would be difficult to conclude that measles vaccination is a risk factor for IBD. A study of IBD from central Sweden noted that IBD patients with an infection or serious illness, mother or child, had a fourfold increased risk for IBD. In the same study, infants from families of low socioeconomic status were 3 times more likely later to develop IBD [100]. On the other hand, some have suggested that the absence of infections might be a risk for IBD; CD, but not UC, is more common in those who lived in houses with a hot water tap during childhood [101]. In addition, toothpaste has been proposed as a risk factor for CD; it contains such microparticles that could serve as a proxy measure of hygienic conditions or have an impact on the microbiological intestinal flora [102]. However, no observational studies have shown such an association implicating toothpaste as an independent risk factor. Finally, Klein et al. have investigated the physical activity levels of patients with IBD and controls for the period prior to onset of the disease: IBD patients were over-represented in the low-activity group vs. controls [103].

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The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

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