A role for inherited factors in inflammatory bowel disease

Crohn's disease and ulcerative colitis are types of inflammatory bowel disease - chronic inflammatory disorders affecting the intestine (Box 9.4). The evidence to support a role for inherited factors is much stronger for Crohn's disease than ulcerative colitis, although clustering of both diseases within families has been recognized since the 1960s (Kirsner and Spencer 1963). A Danish study of 637 patients with inflammatory bowel disease showed that first degree relatives of individuals with either Crohn's disease or ulcerative colitis had a ten-fold increased risk of the same disease (Orholm et al. 1991), while a Swedish study showed that for 1048 patients with Crohn's disease, the risk was even greater with a 21-fold higher prevalence among first degree relatives than the general population (Monsen et al. 1991). Based on many studies, the risk ratio for siblings relative to the population prevalence, Is, is currently estimated at 20-35 for Crohn's disease (Barrett et al. 2008).

Other evidence supporting a role for inherited factors has also been found. For families with inflammatory bowel disease, high rates of concordance (75% in

Box 9.4 Inflammatory bowel disease

Crohn's disease and ulcerative colitis are chronic inflammatory diseases affecting the gastrointestinal tract. Inflammatory bowel disease is common, with a peak age of onset between the second and fourth decade of life, and associated with very significant morbidity and long term complications. The highest incidence and prevalence of inflammatory bowel disease is seen in northern Europe, the United Kingdom, and North America; in the latter the prevalence of Crohn's disease is reported as 26-199 cases per 100 000 population, and ulcerative colitis at 37-246 cases per 100 000 (Loftus 2004). Both types of inflammatory bowel disease are characterized by symptomatic flare-ups manifesting with diarrhoea, abdominal pain, rectal bleeding, and malnutrition. Bloody diarrhoea is less common in Crohn's disease, in which abdominal masses, perianal disease, and malabsorption are other common clinical features.

The pathological changes seen in the two diseases are distinct in a number of ways. Crohn's disease involves inflammatory changes across the bowel wall (transmural), which are often localized with a discontinuous distribution along the intestine (most commonly the ileum and colon are involved); there are often granulomas, cobblestone ulcers, bowel narrowing (strictures), and fistulas. By contrast the inflammatory changes seen in ulcerative colitis always involve the rectum and are continuous in distribution, sometimes extending as far as the caecum; fine ulceration is seen, with superficial inflammatory changes involving the mucosa and submucosa. In both types of inflammatory bowel disease, extraintestinal manifestations may occur such as arthralgia, and other chronic inflammatory diseases are more common such as psoriasis (Box 4.6). Treatment options involve anti-inflammatory and immunosuppressive drugs. Unfortunately for many patients surgical treatment with bowel resection can become necessary. The pathogenesis of inflammatory bowel disease remains unresolved but a combination of environmental factors in a genetically susceptible individual are thought to result in disease, notably involving dysregulation of the normal immune response to commensal bacteria in the intestine (Xavier and Podolsky 2007).

child-parent pairs and 81% among affected sib pairs) were observed for disease type, extent, and other clinical features (Satsangi et al. 1996). Twin studies were also supportive of a significant role for genetic factors, notably in Crohn's disease. Two large Scandinavian studies demonstrated rates of Crohn's disease among monozygous twins to be significantly higher than among dizygous twins (50% versus 0-3.8%), and to a lesser extent in ulcerative colitis (14.3-18.8% versus 0-4.5%) (Orholm et al. 2000; Halfvarson et al. 2003). It should be noted that intensive study has failed to reveal any simple mendelian model of inheritance for Crohn's disease and that this is demonstrably a multifactorial disease trait with environmental factors being highly significant; a longstanding model is one of an infectious trigger(s) in a genetically susceptible individual.

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