Epidemiology

IBD presents in a bimodal manner as pertains to age, first in late adolescence or early adulthood and a smaller peak in the fifth decade of life. The sexes are equally affected by ulcerative colitis; in adults, the incidence of Crohn's disease is 20-30% higher in women.

In terms of trends in disease over time, the incidence of ulcerative colitis remained stable during the second half of the twentieth century; Crohn's disease has demonstrated a marked increase across all age groups since 1950. Although IBD can affect all races, Caucasians are affected significantly more than Africans or people of African origin.

Table 4 Hamartomatous intestinal polyps

Syndrome Location of polyps Pathology Extraintestinal Cancer risk abnormalities

Juvenile polyposis

Peutz-Jeghers

Cowden's syndrome

Colon; some small intestinal

Mostly small intestinal; some gastric and colonic

Colon and stomach

Up to 3 cm Mucus retention and inflammatory cells in the lamina propria cysts Mostly pedunculated 1-3 cm

Either sessile or pedunculated Glandular epithelium and smooth muscle branching Multiple polyps Hamartomatous

Macular pigmentation on hands, lips, and mouth

Lipomas Papillomas Orocutaneous hamartomas

Colonic; low risk

Up to 18 times versus the general population; lower than other polyposis syndromes Fibrocystic or fibroademomatous, ductal breast cancer Nodular thyroid hyperplasia or follicular adenoma

Table 5 Polyposis syndromes

Type/syndrome Location(s)

Histology

Clinical features

Cancer risk

Familial polyposis coli

Gardner's syndrome

Turcot's syndrome

Cronkhite-Canada syndrome

Inflammatory polyposis

Colonic; fundic gland hyperplasia (stomach)

Colon, stomach, duodenum, small intestine

Colonic

Throughout gastrointestinal tract

Colonic; pseudopolyps

Thousands of adenomas Elevated ornithine decarboxylase levels APC gene

2-5 mm Sessile mostly Adenomas in the antrum and periampular regions More than 1000 over time

Adenomatous polyps

Adenomatous lesions within adenomatous polyps

Pleiomorphic Regenerative tissue

Apparent after puberty Diarrhea most common symptom Abdominal pain Hypertrophic retinal lesions Triad of: Polyps Osteomas Soft tissue tumors Also dental abnormalities

Presents in adolescents with cancer; family history Autosomal recessive Alopecia Nail dystrophy Brown macular skin lesions Edema related to protein-

losing enteropathy Systemic signs and symptoms of inflammation

Thyroid cancer Pancreatic cancer Risk of colon cancer 100% by 55 years of age

Duodenal tumors at highest risk Associated risk of Pancreatic carcinoma Ampullary cancer Hepatoblastoma Associated neural tumors Medulloblastmas Gliomas

5% of cases evolve into gastrointestinal carcinomas

Colonic; risk of cancer from inflammatory bowel disease (Crohn's disease and ulcerative colitis)

Ashkenazi Jews have a markedly increased risk of IBD compared to other Jewish groups. The incidence in the Ashkenazi Jewish population roughly parallels that of the respective geographical community in which they reside, albeit at a level that can be three or four times that of the general population, suggesting a genetic predisposition. The majority of individuals affected by these disorders reside in North America and northern Europe. The remainder of Europe, Latin America, and Australia have lower incidence rates, and rare cases occur in Africa and Asia.

Etiology

The exact etiology of IBD is unclear and an area of active research. A multifactorial interaction between genetic predisposition, environmental stimuli, endogenous triggers, immunological dysregulation, and modifying factors is postulated.

Figure 3 Polyp histology: tubullovillous adenoma. (Reproduced with permission from Wheater PR, Burkitt HG, Stevens A, and Lowe JS (1991) Basic Histopathology, 2nd edn. Churchill Livingston, UK.)

Genetics

A positive family history confers significant risk (10-20%) of disease occurrence of either disease type in a first-degree relative. The roles of race and ethnicity were discussed previously, with northern European and North American populations, particularly the Ashkenazi Jewish population globally, having the highest risk of disease.

A high rate of concordance among Swedish mono-zygotic twins versus dizygotic twins has been reported for Crohn's disease (44 vs 3.8%). In the same study, the incidence rate observed in monozy-gotic twins for ulcerative colitis was 6.3%. These data, although supportive of a genetic role, show less than 100% penetrence, suggesting that although genetics are more important in Crohn's disease than in ulcerative colitis, environmental influences play a significant role. Simple Mendelian models of inheritance are inadequate to address the complex inheritance patterns of IBD. Candidate gene studies have suggested modest HLA associations that differ in different populations. Systemic genome searches performed on families with several members with IBD have employed linkage analyses. Evidence that the NOD-2 gene on chromosome 16 is involved in Crohn's disease has led to it being labeled the IBD1 gene locus. This gene is involved with the encoding of a protein associated with monocytic nuclear factor-^B; this protein and pathway are involved in the interaction of monocytes with bacterial peptidoglycans. Note that only approximately 30% of individuals with Crohn's disease are positive for this particular gene mutation.

Environmental Influences

Because of the rapid increase in Crohn's disease during the past 50 years, increasing trends in immigrant populations, as well as incomplete genotype-pheno-type associations, attention has focused on environmental factors. In particular, the search to identify an antigenic trigger for the enteric immune system has been pursued by several investigators. Postulated microbial intraluminal triggers include mycobacter-ium and viruses. Dietary antigens or toxins have not been identified; Westernized diet has been explored and remains an active area of research. Exposures early in the life cycle (birth environment) and nutritive factors (breast vs formula feeing; the former confers protective effects) have also been considered. Additional modulating factors include smoking and the use of oral contraceptives.

Pathogenesis

The interactions between the enteric immune system and the intestinal lumen are dynamic; some degree of inflammation in response is always present in the normal mucosal lamina propria of the colon and small intestine, which handle a very large antigenic load daily. An intact mucosal barrier, in addition to normally functioning immunoregulatory mechanisms, prevents this interaction from progressing to the level at which tissue injury occurs.

Current chronic, inflammatory relapsing disease processes may represent an inappropriate persistent immune response to a luminal antigen/stimulus versus an appropriate immune response to a persistent, abnormal stimulus or perhaps a prolonged immune response to a ubiquitous stimulus.

Enteric flora may play a role in this process, although no evidence strongly indicates a single pathogen. Defective mucosal barrier function and increased intestinal permeability may also be involved, with the latter being documented in patients with IBD and in up to 10% of nonaffected first-degree relatives.

The immune response is primarily T cell mediated and of a Th-1 nature—interleukin-12, interferon-gamma, and tumor necrosis factor-alpha (TNF-a). White blood cells respond to these inflammatory mediators and proliferate the immune response. These recruited cells synthesize agents such as arachidonic acid metabolites, platelet activating factor, proteases, and free radicals such as reactive oxygen species—all of which cause direct injury to cells and the mucosa.

Pathology

Pathology differs between these two disorders in terms of anatomical distribution and tissue involvement. Ulcerative colitis is limited to the colon and rectum, usually beginning distally in the rectum and extending to varying lengths proximally in a continuous manner (Figure 4). Usually, a clear distinction

Figure 4 Continuous distribution of ulcerative colitis.

can be made where disease ends and normal mucosa can be appreciated grossly or endoscopically. The gross appearance of the mucosa is dependent on the severity of the disease process. Mild disease presents with a diffuse erythema and loss of the characteristic appearance of the vasculature. Numerous small, superficial ulcerations, exudates, and bleeding are seen in moderate disease; larger, deeper ulcerations, increased exudates, and the development of pseudopolyps are seen in severe disease, with loss of normal gross architectural landmarks such as the folds. Microscopically, ulcerative colitis is limited to the mucosa; with more severe disease, deeper layers may show a degree of involvement, with inflammatory cell infiltrates, shortening, branching, and decreases in the number of crypts as well as crypt abscesses (Figure 5).

Crohn's disease may involve any part of the alimentary tract from the mouth to the anus, and it frequently does so in a discontinuous manner, leaving 'skip areas'—regions that are grossly and histologically normal; in the colon, this lends a cobblestone appearance. Macroscopically, wall thickening is evident in longstanding disease. By definition, this disease is a transmural process (Figure 6). With chronic disease, fibros-tenosis occurs, narrowing the intestinal lumen. Stricturizing disease may follow fibrosis of superficial and deeper layers of the intestinal wall, evident on radiographic studies (Figure 7).

The mesentery may also demonstrate inflammation, with resutant adhesion and fixation of the colon. Adjacent loops of bowel may become matted

Crypt Mainly mucosal Goblet cell/

abscesses disease mucin depletion

Crypt Mainly mucosal Goblet cell/

abscesses disease mucin depletion

Figure 5 Illustration of ulcerative colitis. (Reproduced with permission from Kelly DA and Booth IW (1996) Pediatric Gastroenterology & Hepatology. London: Mosby-Wolfe.)

together. As luminal diameter narrows, intraluminal pressure may increase; in the case of nonabating inflammation, this transmural process may lead to fistula formation. Enteroenteric fistulas are limited to the bowel; enterovaginal, enterovesicular, and enterocutaneous fistulization may occur. Inflammatory intraabdominal masses called phlegmons may also form by this fistulization process.

Granulomata Lymphoid Fissures Aphthoid aggregates / ulcers

Granulomata Lymphoid Fissures Aphthoid aggregates / ulcers

Figure 6 Illustration of Crohn's disease. (Reproduced with permission From Kelly DA and Booth IW (1996) Pediatric Gastroenterology & Hepatology. London: Mosby-Wolfe.)
Figure 7 Barium enema in a patient with colonic Crohn's disease. Note the bowel wall ulcerations, structuring, and asymmetric bowel wall edema. (Reproduced with permission from Kelly DA and Booth IW (1996) Pediatric Gastroenterology & Hepatology. London: Mosby-Wolfe.)

The endoscopic appearance of Crohn's disease varies by location and time relative to disease evolution. Intestinal Crohn's disease may initially present with apthous ulceration overlying Peyer's patches in the colon. Ulcerations eventually grow, with frankly friable, exudative lesions.

Histological findings of affected areas include intense inflammatory cell infiltrates extending into the crypts, with shortening and forking of these structures, and associated abscesses. The inflammation is transmural; fibrosis and histiocyte proliferation are also seen. Noncaseating granulomatous submucosal and mucosal lesions, which are a hallmark of this disease, are not found in a majority of biopsy specimens. Granulomas can also be seen in intestinal infections, such as in intestinal tuberculosis and sacoidosis. Even macroscopically appearing normal tissue may yield histological findings of inflammation compatible with Crohn's disease, thus indicating that examination of the entire alimentary canal and surveillance biopsies are required prior to arriving at a diagnosis.

IBD and the Terminal Ileum

The terminal ileum is one of the most commonly involved sites in the intestine in Crohn's disease, often originating at the lymphoid follicle; strictures may form. A phenomenon of ileal involvement has been postulated in cases of apparent ulcerative colitis that involve the ileum, in which cecal inflammation is postulated to 'backwash' into the ileum; this finding being consistent with ulcerative colitis is controversial.

Extraintestinal manifestations are common in both Crohn's disease and ulcerative colitis, including ophthalmologic manifestations (uveitis), joint involvement (arthralgias and arthritis of the large joints), and manifestations of the skin, hepatobiliary system, pancreas, renal system, and vascular system. Anemia and weight loss are common at the time of presentation. Growth and pubertal delay are very common at the time of presentation in children; short stature occurs in up to 50% of children. Some of these findings relate to the inflammatory process; others are linked to malnutrition associated with IBD. Perianal disease with fistulization and/or skin tags is perhaps the most common extraintestinal abnormality associated with Crohn's disease.

Nutritional Consequences of IBD

Malnutrition includes weight loss acutely, partly attributable to anorexia associated with inflammation and partly to the disease process (i.e., inadequate intake as well as excessive (malabsorptive) losses). These deficiencies can evolve from frank losses as well as be malabsorptive in nature. An example delineating all of these mechanisms is anemia, which can result from frank blood loss from associated gastrointestinal bleeding, anemia of chronic disease mediated by the inflammatory mediators, anorexia with decreased dietary iron intake, and, as in the case of duodenal and jejunal disease activity (as can occur in Crohn's disease), anorexia with decreased absorption.

Intestinal disease can result in both decreased nutrient absorption and disruption of the mucosal barrier, resulting in exudation of proteins, a process known as protein-losing enteropathy (PLE). The latter can result in hypoalbuminemia; third spacing of fluids as a result of decreased intravascular oncotic pressure can occur. Increased energy expenditure as a consequence of inflammation is noted, particularly in the febrile state or with sepsis. Inflammation and discomfort also contribute to decreased enteral intake—factors contributory to a catabolic state.

In addition to iron, other mineral and trace element deficiencies are noted in IBD. Iron deficiency was discussed previously. Zinc is closely associated with gut mucosa and is susceptible to deficiency; low albumin levels resulting from PLE and increased intestinal epithelial cell turnover probably represent a significant source of zinc depletion. Vitamin B12 and folic acid deficiency has also been documented among the water-soluble vitamins, particularly when the terminal ileal disease is noted. Vitamin D deficiency is the most common among the fat-soluble vitamins.

Treatment of IBD

Several antiinflammatory treatment modalities have been employed in the treatment of IBD. Their use is dictated by disease type, location, extent, and severity. Steroids provide the cornerstone of initial therapy for acute inflammation. Five aminosalicylate derivatives, antimetabolites such as azothioprine and 6-mercapto-purine methotrexate, and newer biological agents including anti-TNF-a are currently employed.

Nutritional therapies including semielemental ent-eral feedings or parenteral therapy have a role in the management of IBD. Although enteral therapy is not considered a first-line therapy for ulcerative colitis in the United States, its use as such is popular in Europe and Canada and allows for steroid sparing/ avoidance. The time to onset of remission using enteral therapy in Crohn's disease is much less with steroids than with enteral therapy, however, with the former occurring typically within 2 weeks and the latter taking usually 6-8 weeks to achieve similar clinical remission. Smaller studies have been conducted employing low-fat diets and less processed sugar foods. The latter has shown promise in studies of Crohn's disease, thought to be secondary to the immunomodulatory effects of these fatty acids. Another approach under investigation is enteral therapy containing TGF-0, which is thought to modulate the enteric immune response. Also under investigation are dietary fiber, short-chain fatty acids, and influencing the colonic flora with the use of prebiotics and probiotics.

Surgical treatment is indicated in ulcerative colitis when acute, fulminant disease does not respond to medical therapy or when persistent chronic disease is refractory to medical (steroid) therapy and the diagnosis has been confirmed (i.e., Crohn's disease has been ruled out). Colectomy is curative in this instance.

Crohn's disease is more complex, and surgical intervention, limited to involved segments only, is not curative. Failure of medical therapy to reduce inflammation, critical stenosis of the involved segments with fibrosis leading to obstruction, perforation, fistulization, and/or abscess formation not amenable to medical therapy, and frank gastrointestinal hemorrhage are indications for surgical intervention. Reactivation of disease can occur postoperatively at the site of anastomoses or elsewhere.

The natural history of IBD is such that long-standing disease increases the risk of colonic dysplasia, particularly in the case of ulcerative colitis, even though it is a curative intervention, making colect-omy more attractive in the older patient. Ileoanal continuity can be achieved by means of surgical anastomoses. Pouchitis secondary to bacterial overgrowth, smoldering pockets of disease activity that may not have been resected or become evident after resection, and loss of continence are common complications of these procedures.

See also: Colon: Structure and Function; Nutritional Management of Disorders. Diarrheal Diseases. Dietary Fiber: Physiological Effects and Effects on Absorption; Potential Role in Etiology of Disease; Role in Nutritional Management of Disease. Small Intestine: Structure and Function; Disorders.

Further Reading

Balfour R (2002) Mucosal immunology & mechanisms of gastrointestinal inflammation. In: Feldman M, Friedman LS, and Sleisenger MH (eds.) Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis Management, 7th edn, pp. 21-54. Philadelphia: WB Saunders.

Bayless TM and Hanauer S (eds.) (2001) Advanced Therapy of Inflammatory Bowel Disease. Hamilton, Ontario, Canada: BC Decker.

Griffiths AM and Bueller HB (2000) Inflammatory bowel disease. In: Waker WA, Durie P, Hamilton R, Watkins J, and Walker-Smith J (eds.) Pediatric Gastroenterology: Pathophysiology, Diagnosis, Management, 3rd edn, pp. 28-38. Hamilton, Ontario, Canada: BC Decker.

Guandalini S (2000) Acute diarrhea. In: Waker WA, Durie P, Hamilton R, Watkins J, and Walker-Smith J (eds.) Pediatric Gastroenterology: Pathophysiology, Diagnosis, Management, 3rd edn. Hamilton, Ontario, Canada: BC Decker.

Homer DH and Gorbach SL (2002) Infectious diarrhea and bacterial food poisoning. In: Feldman M, Friedman LS, and Sleisenger MH (eds.) Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis Management, 7th edn, pp. 1864-1932. Philadelphia: Saunders.

Pickering LK and Cleary TG (1998) Approach to patients with gastrointestinal tract infections and food poisoning. In: Feigin RD and Cherry JD (eds.) Textbook of Pediatric Infectious Diseases, 4th edn, pp. 567-600. Philadelphia: WB Saunders.

Shashidhar S and Mobassaleh M (1998) Bacterial infections. In: Altshuler S and Liacouras C (eds.) Clinical Pediatric Gastroenterology, pp. 131-142. Philadelphia: Churchill Livingstone.

Steffen R and Loering-Burke V (1999) Constipation and encopresis. In: Willie R and Hyams J (eds.) Pediatric Gastroenterology, 2nd edn, pp. 43-50. Philadelphia: WB Saunders. Yamada F, Alpers DH, Laine L, Owyang C, and Powell DW (eds.) (1999) Textbook of Gastroenterology, 3rd edn. Philadelphia: Lippincott, Williams & Wilkins.

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