Epidemiology

Epidemiology

Estimates of the prevalence and incidence of inflammatory bowel disease (IBD) vary widely. The reliability of data is limited by the fact that IBD has not been studied in many non-Western societies. Based on existing studies, this cluster of diseases appears to occur most frequently among people of European origin. The variability of the epidemiological data for IBD from study to study also reflects the difficulty of gathering information on these sensitive diseases as well as uneven access to healthcare across populations. The prevalence (the number of people who have the disease at a given time) and incidence (the number of new cases diagnosed each year) of IBD varies considerably depending on location and the ethnic background of the population.1

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Prevalence in the U.S.

• IBD - 978,000
• UC - 619,000
• CD - 359,0002

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Incidence

• IBD - About 10,000 new cases are diagnosed annually.
• UC - Data assessing the incidence of Ulcerative Colitis varies from 1 to 18 persons per 100,000 per year.2
• CD - Approximately 5 per 100,000.

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Burden of Disease

Focusing on ulcerative colitis (UC) alone, direct medical costs in 1998 were $388 million (U.S. dollars using Medical Consumer Price Index for the year 2000). Of this, $38.2 million was spent on 500,000 office visits. Hospital outpatient and emergency department visits combined reached 90,000 visits. Hospital costs for the period were:

• Emergency department, $2.9 million
• Hospital outpatient department, $15.9 million
• Hospital inpatient, $192.1 million

Inpatient visits totaled 47,000, of which 53% were for a primary diagnosis of UC. These costs accounted for $35.5 million in physician fees and $156.6 million in facility costs. According to Scott Levin SPA and PDDA, pharmaceutical product cost was $214 million in 2001.3

Assessing indirect medical costs is more difficult, in part, because respondents to surveys may be reluctant to report their missed work and nonwork activities as being caused by diarrhea and other associated symptoms of UC. Nonetheless, UC patients spent 280,000 total days in inpatient care in 1998, with an average length of stay of 6.3 days. The value of the total lost time at work while in the hospital and the physician's office was $35.8 million. A National Health Information Survey projected wages lost to UC-related illness at $5.5 million for the survey period.3

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Etiology and Pathogenesis

UC and Crohn's disease (CD), the most common of several relapsing-remitting bowel diseases, damage the gastrointestinal tract and together are known as chronic inflammatory bowel disease (IBD). UC and CD are related diseases with distinct clinical features. Although recognized as clinically and histologically distinct diseases, they may represent extreme ends of a spectrum of related disorders. The disease etiology is unknown but is likely related to a complex interaction among multiple genes and environmental factors.4

Symptomatic overlap of the two diseases, along with irritable bowel syndrome (IBS), can make distinguishing these diseases challenging, and frequently results in a confirmed diagnosis many years after onset for some patients. The only known cure at this time is surgical removal of the colon. Management requires approaches designed to control symptoms, maintain quality of life and minimize the toxicity of therapy.5,6

Various etiologies for IBD have been proposed, ranging from persistent infection and abnormal mucosal permeability to dysregulation of immune response. Over time the specific pathogens speculated to be responsible have included mycobacteria, Helicobacter sp, measles and mumps vaccines, Listeria, and toxigenic E. coli. Studies have been unable to link any mycobacterium species to disease-specific humoral or T cell reactivity. L. monocytogenes and Helicobacter sp. have also been cleared of suspicion. Similarly, no studies have been able to link measles and mumps vaccines to IBD.6,7,8

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Genetics

The genetic component of IBD has long been recognized because of the 5% - 15% concordance of IBD in first-degree relatives. For CD and UC, the differential concordance rate between monozygotic and dizygotic twins is 44% and 3.8% and 6.3% and 0%, respectively. The risk of IBD among siblings is 10% - 30%. UC and CD are most probably related polygenic diseases that share some but not all susceptibility genes. The complementary techniques of genome-wide scanning and candidate gene analysis have identified four areas of linkage on chromosomes: 16 (IBD1), 12 (IBD2), 6 (IBD3 - the HLA region), and on chromosome 14.9,10

The recent identification of NOD2 (CARD 15) on chromosome 16, the first gene associated with susceptibility to CD, has confirmed that CD has a rapid innate immune response to microbial stimuli. Coding region variants in the NOD2 region that is rich in leucine may affect host interactions with bacterial lipopolysaccharide. NOD protein is similar to plant R proteins and mediates resistance to microbial pathogens. Current understanding is that NOD2 is implicated in 10% - 15% of all CD and plays no role in UC. The genetic aspect of CD and UC can only be accounted for by multiple gene variants. It is highly likely that gene-to-gene interactions as well as gene to environment interactions are involved.5,11

A mutation on exon 8 of the hMLH1 mismatch repair gene on chromosome 3p has been associated with refractory and steroid- dependent UC. The mutation was present in 40% of these patients and in only 14% of controls. Only 13.4% of other UC patients and 9.8% of controls were positive for the mutation. Similar findings have been reported for exon 9.12

These findings are the early results of intense work to map the genes responsible for IBD and may be helpful in the future to understand or predict the natural history of the disease.

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Epithelial Cell-Bacterial Interactions

The intestinal epithelium is comprised of a single layer of cells that are exposed to 105 microbial organisms deriving from more than 30 different genera and 500 species. Bacteria have the potential to initiate inflammation in genetically susceptible individuals with a dysregulated immune response. In unaffected individuals, the intestinal epithelium tolerates proinflammatory bacteria in the lumen, controls access of potential antigens and pathogens, and maintains a permeable seal restricting the passage of small molecules and bacteria. In susceptible individuals with defective immunoregulation or mucosal healing, an environmental insult, such as a transient infection, leads to acute and then chronic intestinal inflammation. This process is driven by the chronic antigenic stimulation of normal luminal bacteria.13

An increased influx of activated eosinophils to the intestinal mucosal and an increased release of eosinophil-derived proteins, such as ECP, have been observed. These events may contribute to tissue damage and intestinal inflammation characteristic of UC. Inflammation versus tolerance depends on the relative balance of pro- and anti-inflammatory cytokines, soluble mediators and T lymphocyte subsets. CD is mediated by TH1 and UC by TH2 cells producing IL-4 and IL-5. T cells making IL-10 and transforming growth factor b mediate tolerance.14,15

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References

1. Farrokhyar F, Swarbrick ET, Irvine EJ. A critical review of epidemiological studies in inflammatory bowel disease. Scand J Gastroenterol. 2001;36(1):2-15.
2. Eisen GM, Sandler RS. Epidemiology & IBD. Crohn's and Colitis Foundation of America.
3. Study Advisory Panel. The burden of gastrointestinal diseases. American Gastroenterological Association. Bethesda, Md; 2001:3, 31.
4. Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gatroenterol Clin North Am. 1995;24(3):475-507.
5. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347(6):417-429.
6. Chinyu Su, Lichtenstein GR. Diagnosis of Crohn's disease: a wolf in sheep's clothing? Am J Gastroenterol. 2000;95(12):3345-3350.
7. Davis RL, Bohlke K. Measles vaccination and inflammatory bowel disease: controversy laid to rest? Drug Saf. 2001;24(13):939-946.
8. Fujita H, Eishi Y, Ishige I, et al. Quantitative analysis of bacterial DNA from Mycobacteria spp., Bacteroides vulgatus, and Escherichia coli in tissue samples from patients with inflammatory bowel diseases. J Gastroenterol. 2002;37(7):509-516.
9. Hanauer SB. Inflammatory bowel disease: novel aspects of clinical genetics and potential for probiotic therapy. 2002. [Available at: http://www.medscape.com/viewarticle/434522.] Accessed 6/26/2002.
10. Ahmad T, Satsangi J, McGovern D, et al. Review article: the genetics of inflammatory bowel disease. Aliment Pharmacol Ther. 2001;15(6):731-748.
11. Cho JH. The Nod2 gene in Crohn's disease: implications for future research into the genetics and immunology of Crohn's disease. Inflamm Bowel Dis. 2001;7(3)271-275.
12. Bagnoli S, Ortolani C, Papi L, et al. Refractory ulcerative colitis is associated with the hMLH1 mismatch repair gene. Am J Gastroenterol. 2001;96:S309.
13. Sartor RB. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol. 1997;92(12 Suppl):5S-11S.
14. Lampinen M, Carlson M, Sangfelt P, et al. IL-5 and TNF-alpha participate in recruitment of eosinophils to intestinal mucosal in ulcerative colitis. Dig Dis Sci. 2001;46(9):2004-2009.
15. Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999;5(4):285-294.

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