Inflammatory Bowel Diseases:
-Epidemiology
-Causes and Mechanisms
-Classification
Marina Rizzi, Cosimo Prantera.
Azienda Ospedaliera San Camillo-Forlanini
There are several reports concerning the incidence of inflammatory bowel diseases (IBD) in many regions of the world [1]. Some parts of the world are historically associated with IBD. Specifically, Northern Europe [2,3], the UK [4,5], and North America [6–10] have the highest incidence and prevalence of the disease. More recently, however, the incidence and prevalence of IBD have been increasing in other areas of the world, i.e., Southern and Central Europe [11–13], Asia [14], Africa, and South America [15]. In North America, incidence rates range from 3.6 (South California) to 14.6 (Manitoba, Canada) cases per 100,000 person-years and prevalence from 26 to 199 cases per 100,000 persons. In Europe, incidence rates are between 0.7 (Croatia) and 9.8 (Scotland) cases per 100,000 person-years while prevalence ranges from 8.3 (Croatia) to 214 (UK).Thus, a “north-south gradient” is often cited because the rates seem to be highest in northern countries [7–9], but this difference has lessened [2] as developing countries “gain affluence” [16]. Typical examples of this trend are Eastern Europe countries [17]. Historically, IBD were rare in Middle and South America, Asia, and Africa, with the exceptions of Israel and South Africa. Recently, the incidence of IBD has grown in many countries of these regions, including in Japan, South Korea, Singapore [14], India, South America while all of which were previously characterized by a very low incidence [15]. Data from Japan and Korea suggest that urbanization and industrialization, and ultimately a more “Western” lifestyle as responsible for the change in the incidence [18]. Nonetheless, it must be underlined that in most of these areas IBD remain rare diseases. Also noteworthy is the fact that the incidence of IBD is stable in many high-incidence areas, such as Scandinavia and Minnesota. In Olmsted County, Minnesota, the prevalence of IBD is rising while its incidence is stable, perhaps because of the increase in the average life span of IBD patients, the earlier age of disease onset or earlier diagnosis, and the growing number of immigrants [19]. An analysis of the temporal and geographic tendencies in IBD incidence and of the time course of the disease shows that the incidence appears to be low in developing countries. This observation may reflect the limited availability of diagnostics and in general the low diagnostic capacities. Moreover, in these areas there is a frequent diagnostic overlap with infectious causes of diarrhea.
The 1990s saw a steady rise in IBD genetics publications. The identification of the first IBD genes in the early part of this decade fuelled a publication explosion. Many of these studies have explored the relationship between genotype and IBD phenotype.
A stronger indication of the existence of a genetic susceptibility in IBD is offered by family and twin studies. It is well known that approximately 5-20% of the patients with CD or UC have a family history of IBD [20,21]. However, in most familial cases the disease clearly does not segregate as a Mendelian trait. Robust data collected by multiple studies show that monozygotic twin concordance is higher than dizygotic twin concordance, i.e. 20%-50% vs. 0%-7%, respectively, for CD and 14%-19% vs. 0%-5%, respectively for UC [22-25]. However, the lack of complete concordance among monozygotic twins further supports a role for one or more environmental factors in disease pathogenesis.
In IBD (particularly CD), the strongest known association is with the NOD2 gene [26,27]. NOD2 is a 12-exon gene located in the long arm of chromosome 16 (i.e., 16q12) and encoding for a protein chain of 1040 aminoacids. The NOD2 protein is a pattern recognition receptor, which, acting as an intracellular sensor activated by the peptidoglycan-muramyl dipeptide, is directly involved in the innate immune response.
The NOD2 polymorphisms Arg702Trp, Gly908Arg and 3020insC are the most common genetic variants associated with IBD. In particular, approximately 33% of the IBD patients have one of these polymorphisms in one or both alleles compared with 10-15% of the normal population of European ancestry [28,29]. On the other hand, NOD2 polymorphisms are absent in Japan, China and Korea [30-32], and are rare in African Americans [33]. The odds ratio for NOD2 heterozygote’s is 2.4 while for homozygote’s is 17.1 [34]. This strongly indicates that the molecular pathogenesis of IBD is different among populations and that NOD2 is neither necessary nor sufficient for disease development.
All these data indicate that no single gene mutation is sufficient and/or necessary to cause IBD, which, in turn, can be considered a multifactorial disorder. In contrast to monogenic conditions, in multifactorial (or complex) disorders genetic variants do not cause the disease, but rather merely modify the individual susceptibility to the disease. Genetic variations (i.e., polymorphisms) involved in multifactorial disorders are usually frequently (>1%) encountered in the general population. Therefore, in any given individual, the presence/absence of specific polymorphisms increase or decrease her/his relative risk of developing the associated disorder. The disease is ultimately caused by a variable mixture of genetic, environmental and, probably, stochastic factors, which co-operate in the disease etiopathogenesis and behavior.
For instance, several studies have shown that cigarette smoking is a risk factor for CD and that smokers have a two-fold higher risk of developing CD than non-smokers [35]. Nevertheless, this association between smoking and CD is not seen in some ethnic groups or geographic regions, for example in the Israeli Jewish population [36]. Moreover, the clinical course and expression of CD may be influenced by smoking. In smokers, CD more frequently involves the ileum [37] and the disease is purely inflammatory [38]. If CD patients continue their smoking habit after surgical resection, the risk of recurrent disease is increased [39,40] and the need for second surgery is more than four times higher than in non-smokers [39]. Also, CD patients who smoke have a greater need of immunosuppressants [40]. The discontinuation of smoking reduces the number and the severity of disease flares and thus spares patients the need for corticosteroid and immunosuppressant therapy [41]. In children, the exposure to passive cigarette smoke seems to increase the risk of developing CD, according to a Swedish study [42].
Moreover, NSAIDs are probably one of causes of disease flares, while gut microbiota can have an influence on disease location and/or on extra intestinal manifestation.
One of the first steps towards knowledge is recognizing similarity between things. This leads to taxonomy, as it permits us to classify similar things together.
Unlike astronomy, medical science has to grant patients’ requests in a short time, and this is the one of the main reasons why medicine tends to place patients together in categories.
But taxonomy is a changeable box, which modifies itself according to momentary knowledge.
The prognosis of UC including survival, colectomy rate, activity of disease, and working capacity was estimated from a follow-up study of 783 patients with UC comprising all patients from the county of Copenhagen [43]. The period of observation ranged from 1 to 18 years with a mean of 6.7 years. The following observations were made:
• The survival rate of woman did not differ from that of the general population.
• At diagnosis, men over age 40 had a slight excess mortality rate in the first 2 years after diagnosis.
• Colon cancer was seen in only 7 of 783 patients. Annual risk was 0.07%.
• The colectomy rate was 9.6% in first year of diagnosis.
• After 10 years, the colectomy rate was 23%.
• After 18 years, the colectomy rate was 31%.
• At 3 years after diagnosis, the capacity to work including those with colectomy was not different from that of the general population.
The study also indicated that, at any given time,
• 50% of those with UC were without symptoms,
• 30% had low disease activity, and
• 20% had moderate to high disease activity.
Within 10 years of diagnosis, 97% of patients experienced at least one relapse.
In an attempt to define the different localizations of CD, in 1998, at the World Gastroenterology meeting in Vienna, a clinical classification based on four distinct locations was proposed:
• Terminal ileum, with or without spillover into the cecum
• Colon, any colonic location between cecum and rectum
• Ileocolon, disease of the terminal ileum and any location of the colon
• Upper gastrointestinal tract, any location proximal to the terminal ileum irrespective
of the other locations of the disease.
Only a minority of CD patients has involvement of the duodenum or jejunum, mainly associated with ileitis, and only a very small number of patients have isolated jejuna disease. The evolution of endoscopy, e.g., single- and double-balloon enteroscopy and capsule endoscopy, as well as the development of routine endoscopy in recent years, has revealed a higher frequency of CD in the upper gastrointestinal tract (5–7%) [44,45]. Approximately 1–4% of patients suffer from atypical manifestations, with oral lesions, pharyngeal and esophageal disease, and gastric involvement, which seldom occur without additional involvement of the ileum and/or of the large bowel. The location of the disease remain relatively stable over its course; while the proportion of patients with a change in disease location becomes significant after 5 years, over 10 years only 16% of patients typically experience a change in location [44]. The chronic transmural inflammatory process of CD may lead to stricture of the intestinal lumen by the formation of fibrosis within the bowel wall and to penetration throughout the bowel wall, with fistulae connecting to the skin or to nearby organs. This behavior of CD is defined as stricturing or penetrating. The behavior of CD varies throughout its course; over 10 years, nearly 50% of patients have a change in disease behavior [44]. The majority of patients start with non-stricturing and non-penetrating disease at diagnosis, but after 25 years the majority progress to either a stricturing or a penetrating pattern.
Recently, perianal disease was found to be associated with an increased likelihood and rate of progression to more complicated CD [46].
About the use of serological marker for IBD diagnosis, ASCA and ANCA have been proposed. We know that ASCA is highly specific for Crohn’s disease-especially ileitis, pANCA is specific for Ulcerative Colitis and Crohn’s Colitis, but if pANCA and ASCA are negative the diagnosis remains indeterminate Colitis and if pANCA or ASCA are positive it can change diagnosis to CD or UC. The use of serological markers for defining the subgroups of CD, at the present time is not advisable.
However measurement of the acute phase reactants can be helpful for identifying which symptoms are related to inflammation. CRP, ESR, Serum iron and Ferritin have a high correlation with disease clinical activity. In particular, CRP is one of the most important acute-phase reactants. Its elevation can be a sign of inflammation, tissue necrosis or neoplasia, its elevation in CD is caused by inflammation, necrosis and bacterial over-infection, and in some trials with biological and antibiotic therapies the response to placebo, in comparison with active drugs, seems to be lower in patients with increased CRP.
References:
1. Loftus EV Jr, Sandborn WJ (2002) Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am 31:1–20
2. Shivananda S, Lennard-Jones J, Logan R et al (1996) Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC–IBD). Gut 39:690–697
3. Bjornsson S, Johannsson JH (2000) Inflammatory bowel disease in Iceland, 1990–1994: a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol 12:31–33
4. Yapp TR, Stenson R, Thomas GAO et al (2000) Crohn’s disease incidence in Cardiff from 1930: an update for 1991–1995. Eur J Gastroenterol Hepatol 12:907–911
5. Rubin GP, Hungin APS, Kelly PJ, Ling J (2000) Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther14:1553–1559
6. Kurata JH, Kantor–Fish S, Frankl H et al (1992) Crohn’s disease among ethnic groups in a large health maintenance organization. Gastroenterology 102:1940–8194
7. Loftus EV Jr, Silverstein MD, Sandborn WJ et al (1998) Crohn’s disease in Olmsted County,Minnesota, 1940–1993: incidence, prevalence, and survival [published erratum appears in Gastroenterology(1999) 116:1507. Gastroenterology 114:1161–1168
8. Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A (1999) Epidemiology of Crohn’s disease and ulcerative colitis in a central Canadian province: a population–based study. Am J Epidemiol 149:916–924
9. Loftus EV Jr, Silverstein MD, Sandborn WJ et al (2000) Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gut 46:336–343
10. Loftus CG, Loftus EV, Sandborn WJ et al (2003) Update on incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota (abstr) Gastroenterology 124:A36
11. Manousos ON, Koutroubakis I, Potamianos S et al (1996) A prospective epidemiologic study of Crohn’s disease in Heraklion, Crete. Incidence over a 5–year period. Scand J Gastroenterol 31: 599–603
12. Trallori G, Palli D, Saieva C et al (1996) A population–based study of inflammatory bowel disease in Florence over 15 years (1978–92). Scand J Gastroenterol 31:892–899
13. Tragnone A, Corrao G, Miglio F et al (1996) Incidence of inflammatory bowel disease in Italy: a nationwide population–based study. Intl J Epidemiol 25:1044–1052
14. Lee YM, Fock KM, See SJ et al (2000) Racial differences in the prevalence of ulcerative colitis and Crohn’s disease in Singapore. J Gastroenterol Hepatol 15:622– 625
15. Linares de la Cal JA, Canton C, Hermida C et al (1999) Estimated incidence of inflammatory bowel disease in Argentina and Panama (1987–1993). Rev Esp Enferm Dig 91:277–286
16. Ekborn A (2003) The changing faces of Crohn’s disease and ulcerative colitis. In: Targan SR, Shanahan F, Karp LC et al (eds) Inflammatory bowel disease, from bench to bedside. Dordrecht: Kluwer Academic, pp.:5–21
17. Lakatos L, Lakatos PL (2006) Is the incidence and prevalence of inflammatory bowel disease increasing in Western Europe? Postgrad Med J 82:332–337
18. Yang SK, Loftus EV, Sandborn WJ (2001) Epidemiology of Inflammatory Bowel Disease in Asia. Inflammatory Bowel Diseases 7(3):260–270
19. Loftus CG, Loftus EV, Harmsen WS et al (2007) Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota, 1940–2000. Inflamm Bowel Dis 14:254–261
20. Satsangi J, Jewell DP, Bell JI. The genetics of inflammatory bowel disease. Gut 1997; 40: 572-574.
21.Binder V. Genetic epidemiology in inflammatory bowel disease. Dig Dis 1998; 16: 351-355.
22. Tysk C, Lindberg E, Järnerot G, Flodérus-Myrhed B. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988; 29: 990-996.
23. Thompson NP, Driscoll R, Pounder RE, Wakefield AJ. Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 1999; 312: 95-96.
24. Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000; 35: 1075-1081.
25. Halfvarson J, Bodin L, Tysk C, Lindberg E, Järnerot G. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology 2003; 124: 1767-1773.
26. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599-603.
27. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603-606.
28. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 2001; 357: 1925-1928.
29. Cavanaugh JA, Adams KE, Quak EJ, Bryce ME, O'Callaghan NJ, Rodgers HJ, Magarry GR, Butler WJ, Eaden JA, Roberts-Thomson IC, Pavli P, Wilson SR, Callen DF. CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population. Ann Hum Genet 2003; 67: 35-41.
30. Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease. J Hum Genet 2002; 47: 469-472.
31. Croucher PJ, Mascheretti S, Hampe J, Huse K, Frenzel H, Stoll M, Lu T, Nikolaus S, Yang SK, Krawczak M, Kim WH, Schreiber S. Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet 2003; 11: 6-16.
32.Leong RW, Armuzzi A, Ahmad T, Wong ML, Tse P, Jewell DP, Sung JJ. NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population. Aliment Pharmacol Ther 2003; 17: 1465-1470.
33. Kugathasan S, Loizides A, Babusukumar U, McGuire E, Wang T, Hooper P, Nebel J, Kofman G, Noel R, Broeckel U, Tolia V. Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn's disease. Inflamm Bowel Dis 2005; 11: 631-638
34. Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 2004; 99: 2393-2404.
35. Calkins BM (1989) A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 34:1841–1854
36. Reif S, Lavy A, Keter D et al (2000) Lack of association between smoking and Crohn’s disease but the usual association with ulcerative colitis in Jewish patients in Israel: a multicenter study. Am J Gastroenterol 95:474–478
37. Russel MG, Volovics A, Schoon EJ et al (1998) Inflammatory bowel disease: is there any relation between smoking status and disease presentation? Inflamm Bowel Dis 4:182–186
38. Picco MF, Bayless TM (2003) Tobacco consumption and disease duration are associated with fistulizing and stricturing behaviors in the first 8 years of Crohn’s disease. Am J Gastroenterol 98:363–368
39. Sutherland LR, Ramcharan S, Bryant H, Fick G (1990) Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology 98:1123–1128
40. Cosnes J, Carbonnel F, Carrat F et al (1999) Effects of current and former cigarette smoking on the clinical course of Crohn’s disease. Aliment Pharmacol Ther 13:1403–1411
41. Cosnes J, Beaugerie L, Carbonnel F, Gendre JP (2001) Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology 120:1093–1099
42. Lindberg E, Jarnerot G, Huitfeldt B (1992) Smoking in Crohn’s disease: effect on localization and clinical course. Gut 33:779–782
43. Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis – based on results from a Regional patient group from the county of Copenhagen. Gut 1985; 26:158-163.
44. Louis E, Collard A, Oger AF et al (2001) Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut 49:777–782
45. Vind I, Riis L, Jess T et al (2006) Increasing incidence of inflammatory bowel disease and decresing surgery rates in Copenhagen city and county, 2003–2005: a population –based study from the danish crohn Colitis Database. Am J Gastroenterol 10:1274–1282
46. Tarrant KM, Biomed B, Barclay ML et al (2008) Perianal disease predicts changes in Crohn’s disease phenotype – results of a population-based study of inflammatory bowel disease phenotype. Am J Gastroenterol 103:3082–3093