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General incidence and prevalence

A recent systematic review by Loftus et al3 analyzed the epidemiology and natural history of Crohn's disease in population-based cohorts from North America. The prevalence rates of Crohn's disease ranged from 26.0 to 198.5 cases per 100 000 persons. The incidence rates ranged from 3.1 to 14.6 cases per 100 000 person-years. Based on an estimate of 300 million people in North America, there are approximately 400 000 to 600 000 patients living with Crohn's disease and approximately 9000 to 44 000 people are newly diagnosed in North America with Crohn's disease each year.3 There appears to be a slight female predominance, with the percentage of females with Crohn's disease ranging from 48% to 66%.3

The prevalence and incidence of IBD is higher in North America and Northern Europe than in Asia,

Africa and southern Europe.4-9 This geographic difference is also observed within individual countries including the USA.10 Despite the low incidence and prevalence of IBD in Africa,11 similar rates for Crohn's disease have been observed between African-American and Caucasian people.12 Both Crohn's disease and ulcerative colitis appear to have a higher incidence among the Jewish people.13,14

Incidence and prevalence in children with inflammatory bowel disease

There is significantly less information about prevalence and incidence rates in children with Crohn's disease. From a study in Sweden,15 the incidence of Crohn's disease in children appears to be increasing, from 2.4 per 100 000 persons between 1990 and 1992 to 5.4 per 100 000 persons between 1996 and 1998. Similar findings have also been observed by other investigators.15-17 The peak incidence occurs between the ages of 15 and 25 years, and about 25-30% of patients with Crohn's disease develop the illness before the age of 20 years.5 In a recent study performed in Wisconsin,18 the incidence of Crohn's disease was 4.56 per 100 000 children, more than twice the rate of ulcerative colitis (2.14 per 100 000 children). An equal incidence occurred among all ethnic groups, and children from sparsely and densely populated counties were equally affected.18 A report from the British Pediatric Surveillance Unit revealed an estimated incidence of IBD in the UK of 5.3 per 100 000 children under the age of 16, with Crohn's disease being at least twice as common as ulcerative colitis.19 The mean age at diagnosis was 11.8 years (median 12.6 years) and 13% of cases occurred in children aged less than 10 years of age.19 There was a median delay of 5 months from the onset of symptoms to a diagnosis; furthermore, 25% of children experienced symptoms for more than 1 year prior to diagnosis.19

Etiology Genetic factors

Recent studies in identifying susceptibility genes for human IBD have supported the hypothesis that genetic factors play an important role in the devel opment of IBD. Several clinical observations with variations in incidence and prevalence among different populations, co-segregation of IBD in rare kindreds with various genetic disorders and familial aggregation of IBD have suggested that genetic factors contribute to an individual's susceptibility to IBD.2 First-degree relatives of an affected patient with IBD are 4-20 times more likely to develop the disease than are the background population.20-23 The absolute risk of IBD is approximately 7% among first-degree family members.24 In addition, a family history of Crohn's disease is associated with an earlier age of diagnosis in affected patient.25-27 Observations in twin studies have strongly supported the role of genetic factors in the development of Crohn's disease.24,28 However, the absence of simple Mendelian inheritance suggests that multiple gene products contribute to a person's risk of IBD.2

DNA linkage analyses have identified an area on chromosome 16, designated IBD1, with apparent linkage to Crohn's disease but not ulcerative colitis.29 Several other genomic loci have also been identified in patients with both Crohn's disease and ulcerative colitis.30-32 Detailed mapping analysis revealed that the NOD2 gene on chromosome 16 was linked to Crohn's disease.33,34 The NOD2 gene encodes a cytoplasmic protein expressed in macrophages known as CARD 15 (caspase activation and recruitment domain). CARD 15 is thought to function as a pattern-recognition receptor for bacterial lipopolysaccharide and to regulate nuclear factor-KB (NFkB) activation and macrophage apoptosis.2 European and North American patients with Crohn's disease, including those without a family history of IBD are more likely to have a variant of NOD2 than are persons without Crohn's disease;2 however, the number of individuals with Crohn's disease who also have a variant of NOD2 remains very small. A more than 20-fold increase in susceptibility to Crohn's disease (ileal disease in particular) is observed in individuals homozygous for variant NOD2.35-37 In children with Crohn's disease, not only are NOD2/CARD15 variants associated with ileal disease, but they are also associated with lower weight percentiles at the time of diagnosis.37 Another putative locus on chromosome 5 has been identified in strong association with early-onset Crohn's disease.38,39 A list of putative genes identified for IBD is given in Table 23.1.

Table 23.1

Putative genes for inflammatory bowel disease (IBD)




Putative genes









TCR a/8 complex

32, 164



IL-3, 4, 5, 13, and CSF-2




1 9p13

ICAM-1, C3,




1 p36

TNF-R family, CASP9

1 65














CD, Crohn's

disease; UC,

ulcerative colitis

Despite the genetic association of Crohn's disease, lack of total concordance among monozygotic twins indicates that additional factors may contribute to the pathogenesis of Crohn's disease. Multiple environmental factors have been studied, but when critically evaluated, many do not provide consistent results. The evolving role of epigenetics may be significant in explaining some of these observations.

Dietary component

To date, no specific dietary component has been consistently identified as a cause for IBD. Diets high in refined sugar appear to be associated with the development of Crohn's disease,40 but not ulcerative colitis.41 Decreased dietary consumption of fruits and vegetables may be associated with an increased risk of developing Crohn's disease.40 Increased dietary n-6 polyunsaturated fatty acids relative to n-3 polyunsaturated fatty acids also may be associated with Crohn's disease.42 Dietary components may alter intestinal flora, which then may modify the mucosal immune response in the susceptible host. Modified carbohydrate diets are used by many patients with Crohn's disease and one should not disregard patients' observations about the impact of specific foods on disease activity. As long as dietary restriction does not impact on nutritional well-being, patient observation will guide these therapies in the absence of randomized controlled studies.

Breast feeding and perinatal exposures

The data supporting the positive or negative association of breast feeding with IBD is not strong. Although studies on children with Crohn's disease and their unaffected siblings suggest that children with Crohn's disease are three to four times less likely to have been breast fed,43 no apparent association existed between breast feeding and the development of ulcerative colitis.44 Other data do not indicate an association between breast feeding and Crohn's disease.45 The negative association between breast feeding and Crohn's disease may be related to early exposure to pathogens. Children with Crohn's disease are three times more likely to have had a diarrheal illness in infancy.43 Furthermore, in a Swedish study, a four-fold increased risk of IBD was observed in patients who had a history of illness in early infancy.46

Cigarette smoking

Cigarette smoking appears to have different effects on the development of Crohn's disease and ulcerative colitis. Smoking doubles the risk for developing Crohn's disease,47,48 and cessation of smoking may decrease the risk of exacerbation in patients with established Crohn's disease.49 In contrast, smoking decreases the risk of developing ulcerative colitis.48,50,51 Although current smokers have about a 40% lower risk of developing ulcerative colitis than non-smokers, former smokers are about 1.5 times more likely to develop ulcerative colitis than those individuals who have never smoked.51

Non-steroidal anti-inflammatory drugs

Taking non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased risk for the development and exacerbation of IBD.52-55 A retrospective study by Bonner et al failed to demonstrate an association between NSAID use and an increased risk for active IBD;56 however, there may be subsets of IBD patients who can tolerate NSAIDs with less likelihood of an exacerbation of disease.57 Although the mechanisms of NSAID-associated gastric toxicity have been extensively studied, the mechanisms leading to intestinal damage are poorly understood, but may be related to damage of enterocyte mitochondria causing enhanced intestinal permeability,58 inhibition of cyclo-oxygenase (COX),59 enterohep-atic recirculation,60 and formation of drug entero-cyte adducts.61,62

Both COX-1 and COX-2 serve as constitutive and inducible enzymes in inflammation and cytopro-tection.63 Although selective inhibition of COX-1 or COX-2 is not ulcerogenic, the combined inhibition of COX-1 and COX-2 induced severe lesions in the stomach and small intestine in rats, suggesting an important role for COX-2 in the maintenance of gastrointestinal mucosal integrity.64,65 While COX-2 selective inhibitors have been shown to cause less gastrointestinal injury than standard NSAIDs in healthy animals and humans,66,67 their effect on pre-existing gastrointestinal inflammation is not completely clear. COX-1 expression is detected in both non-inflamed and inflamed gastrointestinal mucosa. In contrast, COX-2 is expressed in epithelial cells in the upper portions of the crypts as well as on the surface of colonic enterocytes in Crohn's colitis and ulcerative colitis and in villous epithelial cells in Crohn's ileitis. COX-2 is not detectable in the epithelium of the normal ileum or colon,68,69 but is up-regulated in the colonic mucosa in both experimental and human colitis68 and appears to have a beneficial effect in healing experimental colitis. On the other hand, COX products are an important part of the inflammatory process and COX inhibition by agents such as mesalamine might be beneficial.70

Oral contraceptive drugs

Data relating oral contraceptive drugs to the development of inflammatory bowel disease have been inconsistent. In two prospective studies,47,71 oral contraceptive use has been associated with increased risk for developing both Crohn's disease and ulcerative colitis. Women who currently use oral contraceptives are 2.5 times more likely to develop ulcerative colitis and 1.7 times more likely to develop Crohn's disease.47 Other case-control studies have not found a strong association between the use of oral contraceptives and the development of either Crohn's disease72 or ulcerative colitis.73

Infectious agents

Although available data do not convincingly incriminate a single, persistent pathogen as a universal cause of IBD, the role of infectious agents is still considered a strong possibility as a trigger for the development of IBD. Many infectious agents including Mycobacterium, Chlamydia, Listeria monocytogenes, cell-wall-deficient Pseudomonas species and reovirus have been proposed as the causative organism of Crohn's disease. Paramyxovirus (measles virus) has been implicated etiologically in Crohn's disease as a cause of granulomatous vasculitis and microinfarcts of the intestine.74 However, the tissue evidence for persistent measles infection in patients with Crohn's disease remains controversial.75,76 One Swedish study demonstrated an increased incidence of Crohn's disease but not ulcerative colitis among individuals born during measles epidemics;77 however, two other studies from the UK failed to establish an association between the development of Crohn's disease and birth during measles epidemics.78,79 The relationship between measles vaccination and the development of Crohn's disease has evoked even more acrimonious discussion. Although one initial study reported that the relative risk for developing Crohn's disease and ulcerative colitis was 3.0 and 2.5, respectively, in children who received the measles vaccine,80 subsequent studies failed to confirm these findings.81,82 Mycobacterium para-tuberculosis has been cultured from the bowel of patients with IBD, but definitive evidence to link a mycobacterium to Crohn's disease is lacking.83-85

Commensal bacterial flora is an important etiolog-ical factor in IBD. Bacteria within the enteric lumen have a complex ecosystem that is in contact with the external environment. There are 1012 bacteria/g feces in the colon, of 400 different species, with anaerobes predominating.86 The numbers of anaerobic bacteria and Lactobacillus are significantly decreased in patients with active, but not inactive, IBD.87 Genetically altered animals that are susceptible to acquiring IBD do not express the phenotype when raised in a germ-free environment.88,89 Furthermore, experimental colitis is attenuated when animals are treated with broad-spectrum antibiotics.90 Further studies by Duchmann et al demonstrated that mucosal, but not peripheral blood mononuclear cells from patients with IBD proliferate when exposed to autologous intestinal bacteria. These data support the hypothesis that normal flora function as a modulator of 'physiological inflammation'.91,92 Patients with IBD have increased numbers of surface-adherent and intracellular bacteria in the colonic epithelium,93,94 and these commensal organisms may be playing a role in the development and maintenance of mucosal inflammation.

Others factors

Several studies have suggested that appendectomy may protect against the occurrence and severity of ulcerative colitis.95-99 However, appendectomy does not affect the disease course of ulcerative colitis.100 The relationship between appendectomy and the risk of developing Crohn's disease is controversial.99,100 In a large, retrospective cohort study, Andersson et al demonstrated that an increased risk of Crohn's disease was found for more than 20 years after appendectomy. This increased risk was dependent on the patient's gender, age and the diagnosis at operation (non-perforated vs. perforated appendicitis).101 In T cell receptor (TCR)-a-deficient mice, appendectomy is protective against the development of colitis.102

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