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Rising incidence and prevalence of Crohn’s disease in Asia: Is it apparent or real?

2006; Wiley; Volume: 21; Issue: 6 Linguagem: Inglês

10.1111/j.1440-1746.2006.04471.x

1440-1746

Govind Makharia,

Celiac Disease Research and Management

See article in J. Gastroenterol. Hepatol. 2006; 21: 1009–1015. Many recent reports have highlighted the rising prevalence of inflammatory bowel disease (IBD) in Asia.1–10 Although ulcerative colitis (UC) is reported more commonly, in recent years Crohn's disease (CD) has also been recognized and reported quite frequently from Asia.11–18 In this issue of the journal the Chinese IBD Working Group has reported a rising incidence of Crohn's disease in China.19 This is based on a retrospective analysis of records of 515 patients with Crohn's disease hospitalized during 1990–2003 in 22 hospitals across China. The authors reported a steady increase in the number of hospitalized patients with Crohn's disease year after year in comparison to all the hospitalized patients. The component ratio of hospitalized patients with CD was 2.78-fold higher in 2003 in comparison to that in the year 1990. That study reinforces the view of the rising incidence of CD in Asian locations. Being a retrospective study, however, that study suffers from some limitations and thus the incidence of CD as reported in it may not be a true reflection of the incidence in the general population. Unlike celiac disease there are no absolute diagnostic criteria for Crohn's disease; the increase in incidence and prevalence of a disease may depend partly on the awareness and belief of its presence in a particular geographic region or country. For example, it was believed until recently that celiac disease was not common in North America (prevalence 1:3000 population) but subsequent well-designed epidemiological studies showed that its prevalence in North America was almost equal to that in Europe (1:100–300 population).20 There are no global diagnostic criteria for ulcerative colitis and Crohn's disease, and the diagnosis is based on a constellation of clinical, endoscopic, histological and radiological features.12,21,22 There is a wide variation in the clinical and endoscopic features of CD. The characteristic features of CD such as deep linear ulcers, cobblestoning, and non-caseating granulomas are not seen in all the patients. The majority (75%) of the patients with CD have involvement of the colon, which is amenable to the endoscopic examination. In the remaining with disease limited only to the small intestine, until recently only radiological examination was possible and hence only advanced forms of the disease (strictures, deep ulcerations, straightening of the intestine and pseudodiverticulae) could be detected, leaving the milder and earlier lesions (aphthous ulcerations) undiagnosed/unrecognized. With the availability now of endoscopic techniques such as capsule endoscopy and push-and-pull double balloon enteroscopy, more and more patients with not only the advanced form but the early and milder form of small intestinal CD are being diagnosed.23,24 In the developing countries, amebic colitis and intestinal tuberculosis pose the greatest difficulty in differentiating from ulcerative colitis and Crohn's disease, respectively. The clinical, endoscopic, histological and radiological features of Crohn's disease are indeed quite similar to those of intestinal tuberculosis. Features such as deep linear ulcerations, aphthous ulcerations, perianal disease, and non-caseating granuloma are, however, quite suggestive of CD. In contrast, epicenter of the disease being the ileocecal area, lack of bleeding per rectum and caseating granulomas are distinguishing features of intestinal tuberculosis.25,26 We recently observed that blood in the stool, malabsorption, perianal involvement and lack of intestinal obstruction are predictors of CD, and these help differentiate it from intestinal tuberculosis.27 The final differentiation between the two, however, comes from demonstration of acid-fast bacilli (Mycobacterium tuberculosis) in the tissue specimen.28,29 In geographic areas where the prevalence of intestinal tuberculosis is lower than that in the general population (except in immunodeficient individuals), the diagnosis of CD is easier. In contrast, in those geographic areas and countries where intestinal tuberculosis is still common (India, China), the diagnosis of CD is not easy. In a given clinical situation, if the diagnosis of CD or intestinal tuberculosis is not established, it is logical and indeed customary to put such patients on antituberculous treatment. A response to antituberculous treatment in such patients helps in the differential diagnosis but offers no definitive diagnosis of CD. However, one should remember that many patients with CD may also respond temporarily to antitubercular treatment. The disease reappears either early or a few months/years later after the treatment is stopped. In many Asian countries, patients with CD are not infrequently misdiagnosed as having intestinal tuberculosis. In a survey of hospitalized Chinese patients, 56.7% of patients with CD were misdiagnosed as having tuberculosis and intestinal obstruction of unknown origin.7,28 The rising incidence of Crohn's disease as reported by Chinese IBD Working Group, has also been observed in other Asian countries such as Japan, Hong Kong, Taiwan, and India.2,4,6,8,11–13,17 This is evident from the increase in publications on CD from these countries. There are of course minor variations in presentation of CD in different countries. These variations may be partly because of the extent of awareness as well as the diagnostic facilities available. Many of such evolving diseases in a region or community may not be identified by physicians because of a lack of specific symptoms and diagnostic tests with high sensitivity. In a recent review Loftus and Sandborn noted that, although both incidence and prevalence of IBD in Asian countries are still low compared with Europe and North America, they are increasing rapidly.9,10 They documented the emergence of UC and commented that the incidence of CD was still low but postulated that it would rise and match the incidence of UC in the same way as happened during the mid-1990s explosion of IBD in Europe. Yang et al. noted that the gap between areas with conventionally high and low incidence rates was diminishing, but comparisons between different Asian regions was not yet possible because of lack of accurate population data, the mostly hospital-based reports, undefined catchment areas, and non-uniform case ascertainment criteria.4 Let us review the evolution of IBD in North America and Europe. At the very beginning, ulcerative colitis had been reported to be more common than CD. An increase in CD followed UC after a gap of approximately 60 years in these countries.29–31 The rising incidence of CD in these countries coincided with improvement in sanitation and hygiene in these countries. In India and other Asian nations approximately 60 years later, a similar trend is being observed in the emergence of UC and CD.32 If there is indeed a real increase in the incidence of CD in Asia, what are the factors responsible for it? Inflammatory bowel disease results from an interaction between genetic and environmental factors, leading to an abnormal immune response of the gut mucosa to intraluminal antigens.33 Genetic factors appear to play a more dominant role in the causation of CD than UC. However, hereditary factors do not change in a few decades and hence cannot account for the increasing incidence of CD.33,34 Some thing in our environment appears to confer a major risk of developing IBD. The prevalence of IBD varies with time, geography, socioeconomic conditions, and occupation.4,9,10,29–32 The incidence of IBD in North America and Europe increased dramatically during the 20th century. Inflammatory bowel disease is more common in urban than in rural areas.4,9,10 Inflammatory bowel disease is less common in persons who do manual labor and are exposed to dirt. It is less common in military veterans if they were prisoners of war or had served in combat in the tropics.9,30 Similarly, it is common in highly developed industrialized countries but is rare in less developed tropical countries.4,9,10,32 Studies of immigrants and their children show that this is not due to genetic differences between people living in developed versus less developed countries. The offspring of people who moved to developed countries have a much higher risk of IBD than their peers in their country of origin.4,9,10,35 Furthermore, IBD emerges as countries develop. Persons belonging to populations with a low incidence of IBD, on migration to developed countries, develop a higher incidence of IBD, suggesting that environmental factors are important in the pathogenesis of IBD. Inflammatory bowel disease appears to result from a dysregulated immune response to intestinal contents. Inflammatory cells are always present in normal mucosa, and are poised to protect us from potentially harmful luminal agents. In patients with CD or UC, the normal tightly controlled activity of the mucosal immune system becomes excessive, resulting in profound tissue damage. In most animal models of IBD, inflammation results from an excessive T-helper 1 (Th1) response. Cellular immune responses often polarize into the Th1 type, which is characterized by cells that make interleukin (IL)-12, interferon-γ or tumor necrosis factor-α (TNF-α), and the Th2 type, characterized by cells that make IL-4, IL-5, and IL-13. Diseases associated with Th1 responses include CD, multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, and psoriasis. Diseases associated with Th2 responses include UC, atopic dermatitis, allergic rhinitis, and asthma.36,37 The etiology of IBD is centered on the interaction of intestinal microflora with the host immune system.38 Chronic infections acquired in childhood induce immune tolerance to various extrinsic antigens by stimulating regulatory cells of the immune system, which have an anti-inflammatory activity. A reduction in the frequency of childhood infections has been correlated with an increase in autoimmune and allergic disorders in many epidemiological studies.39–41 Children and adults from developing countries are often infested with helminthes such as Ascaris lumbricoides and hookworms.42 Helminths regulate and modulate the immune system of the host. It has been demonstrated that they modulate the immune response away from the Th1 response, meaning thereby that there is depressed Th1 immune response in them.37 Mice harboring helminths have depressed Th1 and augmented Th2 responses to test antigens and mycobacteria.37 The helminths tend to accomplish this task through multiple mechanisms including release of compounds that trigger IL-10 or downregulation of IL-12 and TNF-α production, release of prostaglandin E2, and transforming growth factor-α-like molecules.37,43,44 Elimination of helminths with better sanitation predisposes a susceptible individual to an unlimited activation of Th1-type immune response. Such an effect may explain the rising incidence of CD in developing countries. In conclusion, the rising incidence and prevalence of CD in Asia is real and is probably associated with environmental changes and with a smaller contribution of enhanced awareness of the disease by local physicians.