Epidemiology and Pathogenesis

CD and UC are diseases commonly occurring with increasing frequency in Western countries and are traditionally considered a disorder of the industrialised world [1]. The incidence of UC is approximately 10-20 per 100 000 per year, while that of a CD is between 5-10 per 100 000 per year, and the incidence of the latter is on the increase. It is estimated that up to 240 000 are affected by IBD in the UK [2]. It is interesting to realise that the incidence of UC

and CD has seen an increase in certain parts of Asia and the Middle East, but it remains uncommon in Africa and South America [3].

Several studies have demonstrated that first-degree relatives of an affected patient have up to 10 times an increased risk of IBD. The same investigators showed that the risk of UC in first-degree relatives is higher if the disease had been diagnosed before the age of 20. However, hereditary factors are shown to have stronger association with CD rather than UC [4], and it has been shown that monozygotic rather than dizygotic twins are more susceptible to CD [5].

The disease commonly starts in the third decade with a peak incidence between the ages of 10 and 40; however, several studies have demonstrated that children and young patients below the age of 21 can also be affected. There is a second incidence peak seen in the elderly [6, 7,2]. In young females, the disease usually runs a milder course with fewer complications in contrast to young males where the disease tends to be more active with more complications and more extra-intestinal manifestations. Growth impairment is a particular problem in the paediatric age group in which up to 35% may continue to have permanent growth retardation [8]. Many reports have indicated that the incidence of ulcerative colitis is more common in certain ethnic groups, like for instance the Jewish population living in Western Europe and North America, so therefore their family members are at an increased risk of developing the disease [9,10].

The etiologies of both diseases remain unknown; however, several factors are thought to contribute to their pathogenesis. Some of those factors are thought to result from abnormal activation of the mucosal immune system driven by the intraluminal flora. This consequently leads to an aberrant response facilitated by abnormalities within the intestinal mucosal epithelium and the immune system [1]. The role of the intestinal flora in IBD has been established in animals. If gene-knockout mice that normally develop IBD are made germ-free, the disease will dis appear [11]. Some other environmental factors have also been implicated in the pathogenesis, the most consistent of which is the use of non-steroidal antiinflammatory drugs [12]. These classes of drugs can exacerbate the disease and their use has been associated with an increased incidence of emergency admissions to the hospital for colitis due to IBD. Interestingly, some studies have demonstrated that an early appendectomy is associated with a reduced incidence of UC, and that those patients who had genuine appendicitis or lymphadenitis rather than non-specific abdominal pain and were less than 20 years old at the time of surgery had lower risk of developing UC [13].

Stress has also been implicated in the causation of IBD. Significant association between acute daily stressful events and bowel symptoms in patients with CD has been shown and these patients have a greater risk of active disease [14,15]. Stress-related IBD was also demonstrated in one study where Bedouin Arabs developed UC when moving from their rural life style into government housing [16]. Smoking has been shown to be associated with an increase susceptibility to CD together with rapid disease progression and immune suppression. In contrast, smoking has been demonstrated to have a protective effect against the development of UC through unknown mechanisms [17].

Genetic factors have been shown to play an important part in the causation of both UC and CD and they have a stronger link to the latter. The relative risk to a sibling of a patient with Crohn's disease is 13-36% and for ulcerative colitis it is 7-17% [18]. Additionally, it is estimated that between 6 and 32% of patients with inflammatory bowel disease have an affected first or second-degree relative [19].

Numerous candidate genes have been analysed in inflammatory bowel disease, especially genes related to the HLA system [20]. A gene, located on chromosome 16, named NOD2 (encodes a protein which has a nucleotide-binding oligomerisation domain) with a locus designated IBD1, has recently been shown to be linked with CD [21, 22], and it has been shown that persons who are homozygous for variant NOD2 may have a 20-fold increase tendency for CD with a predominantly ileal involvement [23]. Additionally, it has been shown that possession of the DRB1*103 and DRB1*12 alleles are associated with UC and DR3 DQ2 haplotype is predictive of extensive disease but not of the need for surgery [24]. Interestingly, patients with CD have greater concentration of NOD2 mRNA in the Paneth cells which are found most frequently in the ileum; hence, CD commonly affects this region [20].

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