Pathophysiology in Crohn's Disease
The exact cause of Crohn's disease (CD) has not been identified. However, researchers have hypothesized various mechanisms of disease development.1 One theory is that the seal formed by tight junctions of epithelial cells is impaired and the helper T (TH) cell response that maintains tolerance to enteric bacteria is not working properly.1,2 Development of CD is likely a result of a combination of factors, including host susceptibility (possibly determined by genetics), gastrointestinal (GI) immune responses, environmental, and behavioral factors.1
Environmental and behavioral influences may explain some of the reasons for predisposition to, or exacerbation of, CD.1 Host susceptibility influenced by genetics and GI immune responses is discussed in detail in this section, and it can be related to a 4-step process of disease development.
Watch the video below to learn more about the underlying causes of CD.
The following are proposed steps in the pathogenesis of CD:
Step 1: Antigen Trigger: An antigen trigger, present in the lumen of the GI tract, initiates the inflammatory cascade. Pathogens may include bacteria (possibly normal intestinal flora) and paramyxovirus (which causes childhood measles).1
Step 2: Genetic Susceptibility: The antigen trigger requires a degree of susceptibility in the host, which may be mediated by genetic defects leading to abnormal immune response.1
Step 3: TH1/TH2 Imbalance: An imbalance between TH1 and TH2 cell responses to antigen presentation can result in immune hyperactivity in the patient with CD. A defect in the immune system leads to overexpression of the proinflammatory cytokines released by TH1 cells without regulation by cytokines released by TH2 cells.1
Step 4: Inflammation: Finally, proinflammatory cytokines such as TNF-alpha and iFN-y initiate and perpetuate inflammation.1,3
Interestingly, a dramatic increase in incidence of CD has been seen in certain parts of the world over the past 50 years. One hypothesis for this phenomenon is that improved hygiene, consumption of sterile and non-fermented foods, and vaccination at the age at which they are first exposed to bacterial pathogens may prevent people from developing a strong commensal bacteria population in the GI tract.4
Several studies have been conducted to determine a link between CD and environmental and behavioral influences. Some of this research has demonstrated possible associations of diet, smoking, alcohol consumption, and oral contraceptive use with adverse disease outcomes. Also, it has been found that there is an increased risk of CD in patients who have had an appendectomy—up to 20 years after having the surgery.1
The strongest association of the factors just listed is smoking. Smoking is not necessarily an initiator of CD, but it likely promotes or exacerbates the disease. Smokers seem to have a more severe disease course and higher recurrence rates than do nonsmokers. Conversely, smoking seems to have a protective effect against disease in patients with ulcerative colitis.1
References:
- Shanahan F. Crohn's disease. Lancet. 2002;359:62-69.
- Fiocchi C. The normal intestinal mucosa: a state of ‘controlled inflammation’. In: Targan S, Shanahan F, Karp LC, eds. Inflammatory Disease: From Bench to Bedside. 2nd ed. Great Britain: Kluwer Academic Publishers; 2003:101-120.
- Monteleone I, Vavassori P, Biancone L, Monteleone G, Pallone F. Immunoregulation in the gut: successes and failures in human disease. Gut. 2002;50:iii60-iii64.
- Ardizzone S, Bianchi Porro G. Biologic therapy for inflammatory bowel disease. Drugs. 2005;65:2253-2286.
