Inflammatory Bowel Disease

Abstract

After completing this article, readers should be able to: IBD is a complex, multifactorial disease characterized by chronic inflammation in the intestinal tract of a genetically predisposed host. The spectrum of IBD in children primarily includes ulcerative colitis (UC) and Crohn disease (CD). With pediatric patients now accounting for 20% to 25% of newly diagnosed cases, it is becoming increasingly important for pediatricians to recognize the symptoms of IBD. (1) In this review, we discuss the epidemiology, clinical presentation, diagnosis, and complications of IBD, with specific emphasis on growth failure and pubertal delay because these are unique manifestations in children. We also describe newer, less invasive diagnostic techniques and current trends in management and advances in the pharmacologic treatment of affected children.The epidemiologic patterns of pediatric IBD have evolved over the past few decades, with significant increases in both incidence and prevalence. The current incidence is 5 to 11 per 100,000 children, with a recent statewide survey from Wisconsin reporting the annual rate of diagnosis as 4.56 per 100,000 for CD and 2.14 per 100,000 for UC. (2) Canadian studies have reported an acceleration in new diagnoses from 9.5 per 100,000 in 1994 to 11.4 per 100,000 in 2005. The most significant increases were among the younger age groups, with the incidence rising 5% annually in children younger than 4 years of age and 7.6% annually in children ages 5 to 9 years. (3)The mean age at diagnosis of pediatric IBD in the United States is 12.5 years, (2) with 20% of children diagnosed before the age of 10 years and fewer than 5% diagnosed before age 5 years. Males seem overrepresented in new cases of pediatric CD, although an equal number of males and females receive a UC diagnosis. (4)Many risk factors have been associated with IBD, including family history, ethnicity, and tobacco use. Up to 25% of children who develop IBD have a positive family history of IBD. (5) Children who have a first-degree relative affected by either UC or CD have a 10 to 13 times higher risk for developing IBD. (5) Monozygotic twin concordance is approximately 50% for CD and nearly 20% for UC. (6)In the United States, population-based studies historically have shown a higher prevalence of IBD in patients of European or African descent than in patients of Hispanic or Asian descent. (7) Notably, Jewish ancestry (Ashkenazi more than Sephardic) is a significant risk factor for the development of IBD. However, more recent pediatric-specific population studies detected no differences in IBD frequency between ethnic groups. (2)The prevalence of IBD is highest in the industrialized world, including North America, northern Europe, and the United Kingdom. However, with progressive modernization, the prevalence is now increasing in the developing world. Tobacco use is linked closely with an increased risk of IBD. In smokers, the probability of developing CD is twice as high as for nonsmokers. (7) Passive exposure to smoking may be influential as well. (8)A genetic predisposition to IBD has been hypothesized for decades because of the strong familial pattern of disease. Linkage analyses and genome-wide association studies have identified numerous IBD candidate genes. Many share a connection to the immune, inflammatory, or bacterial recognition pathways, which are fundamental mechanisms in the pathogenesis of IBD.In 2001, the NOD2/CARD15 gene, located on chromosome 16q in the IBD1 susceptibility locus, was associated with CD. Three high-risk single nucleotide polymorphisms (SNPs) are suggested to alter recognition of bacterial peptidoglycans in monocytes, macrophages, gut epithelial cells, and Paneth cells. NOD2 mutations can impair the degradation of gut bacteria, leading to an accumulation of bacterial antigens and predisposing to mucosal T-cell activation.Nearly 40% of white patients who have CD carry one of these NOD2 SNPs compared with 20% of controls. (9) These allelic variants also have phenotypic implications for those who have CD, with earlier age of onset, stricturing disease, and ileal involvement occurring more frequently.The IBD5 locus on chromosome 5q31 is associated with a higher susceptibility toward CD. Patients who have CD and IBD5 locus polymorphisms may have more perianal disease, colonic disease, and importantly in pediatric patients, decreased weight and height at diagnosis. (10) There also has been a weak association of the IBD5 locus with UC.The IBD3 locus on chromosome 6 contains the major histocompatibility complex genes, which also may contribute toward IBD predisposition. The DRB1*1502 gene has been associated with UC, and the DRB1*07 gene has been associated with CD, particularly in patients who have ileal disease without a high-risk NOD2 polymorphism. The DRB1*0103 allele has been linked to UC and colonic CD. Patients who have UC and this variant seem to have a greater predisposition toward more extensive and severe colonic involvement. There also seems to be an association between IBD3 locus variants and the extraintestinal manifestations of uveitis and peripheral arthropathy. (9)The field of IBD genetics is continuously expanding, but genetic testing is currently limited to research. In the future, children who have IBD may undergo genetic testing to quantify disease risk in family members or to predict phenotypic expression.The precise causes of IBD remain unknown, but the current understanding involves a genetic predisposition combined with a dysregulation between the immune system and the antigenic environment in the gastrointestinal tract, leading to inflammation and damage. (11) The major pathogenic mechanism underlying CD is an excessive Th1 immune response, whereby CD4+ T cells become upregulated and markedly resistant to apoptosis. (12) An excessive Th2 immune response has been implicated in patients who have UC. (13)Defective gastrointestinal mucosal integrity may lead to enhanced uptake of luminal bacteria, causing the normally protective mucosal immune system to be overwhelmed. This derangement may be a result of tolerance to luminal antigens, a hyperreactive cell-mediated immune system, or specific gene mutations (such as NOD2).It has been postulated that the unchecked intestinal immune response to ubiquitous bacterial and enteric antigens could lead to the pathologic gross tissue injury characteristic of IBD. Activated immune cells secrete a variety of soluble mediators of inflammation, including cytokines (tumor necrosis factor [TNF]-alpha, interferon-gamma, transforming growth factor-beta, and interleukin-2, -5, -6, -12, and -18), arachidonic acid metabolites, reactive oxygen intermediates, streptolysins, and growth factors. (12) Activated neutrophils and macrophages may also release metalloproteinases, which digest collagen in the lamina propria and basement membrane and are markedly elevated in the fistulous tracts of those who have CD.The most persuasive argument for a pathogenic role of enteric flora comes from murine studies of IBD. (14)(15) The gut inflammation seen in mouse models of IBD depends on the presence of bacterial flora. No single infectious agent has been reproducibly associated with IBD, but several bacterial species, including Salmonella, Helicobacter, toxigenic Escherichia coli, Listeria, and Campylobacter, have been suggested to play a role in pathogenesis. Mycobacterium paratuberculosis has been strongly suspected in IBD development. (16) Viral theories have been proposed, including the potential for measles virus to cause a granulomatous vasculitis. (17) Another antigenic hypothesis in the development of IBD includes the phenomenon of dysbiosis, which is an altered balance between protective bacteria, such as Lactobacillus and Bifidobacterium, and aggressive organisms, including Bacteroides, Enterococcus, and invasive E coli. (18)UC and CD can have varied yet overlapping presentations. The cardinal symptoms of UC are diarrhea, rectal bleeding, and abdominal pain. Most children present with an insidious history of diarrhea without systemic signs of fever or weight loss. One third present with moderate symptoms, including hematochezia, abdominal cramping associated with fecal urgency, malaise, low-grade or intermittent fevers, anorexia with weight loss, mild anemia, and hypoalbuminemia. Only 10% of patients present with severe colitis, characterized by five or more bloody stools per day; more profound anemia and hypoalbuminemia; fever; tachycardia; and a diffusely tender or distended abdomen. (19)(20) Children who have UC may develop symptoms of reflux or dyspepsia associated with inflammation of the upper gastrointestinal tract. (21)The classic presentation of abdominal pain, diarrhea, and weight loss occurs in most children who have CD. Abdominal pain typically is crampy and can be diffuse or localized to the right lower quadrant. (22) Stools can appear nonbloody or melanotic or can contain frank red blood. Chronic perianal disease, including tags, fissures, fistulae, and abscesses, may be present. (23) Recurrent aphthous-stomatitis can also suggest the diagnosis. A decrease in height velocity may precede overt abdominal symptoms by 5 years, and growth failure may be the only sign of illness in 5% of children who receive the diagnosis of CD. (24) Poor appetite, fevers, and iron deficiency anemia are also commonly noted at initial presentation in children who have CD. Decreased bone density is seen in 25% of newly diagnosed children, even before initiation of corticosteroid therapy. (25)One third of patients who have IBD develop extraintestinal manifestations, which may predate the onset of intestinal symptoms (Table 1). (26) Arthralgias and arthritis are common extraintestinal manifestations of CD. (26) Arthropathy also occurs in 20% to 25% of patients who have UC and may be the presenting symptom. Large joints, such as the knee, ankle, hip, and wrist, typically are involved. A polyarticular arthropathy involves more than five joints; a pauciarticular form involves fewer joints and its disease course correlates with intestinal disease activity. (27) Ankylosing spondylitis associated with IBD runs a course independent of bowel disease activity and may progress to permanent deformity.Erythema nodosum (EN) and pyoderma gangrenosum (PG), although rare, are the most frequent cutaneous manifestations in IBD. EN occurs more commonly with CD; is characterized by tender, warm, red nodules or plaques; and typically is localized to the extensor surfaces of the lower extremities. PG occurs in fewer than 5% of UC patients and often is associated with more extensive colonic involvement. The lesions may appear initially as discrete pustules with surrounding erythema and subsequently extend peripherally, developing into an ulceration that has a well-defined border and a deep erythematous-to-violaceous color. PG tends to develop around sites of trauma and surgical scars. Although the emergence of EN usually follows intestinal disease activity, PG runs an independent course, often necessitating potent therapy.Transient transaminase elevation occurs in some children who have IBD and may be related to medications or disease activity. Persistent elevations suggest the presence of primary sclerosing cholangitis (PSC) or autoimmune hepatitis. PSC is more commonly associated with UC and can predate the onset of intestinal symptoms in 50% of patients. (28) Typical symptoms include chronic fatigue, anorexia, pruritus, and jaundice, although children may be asymptomatic. Elevated gamma-glutamyltranspeptidase and alkaline phosphatase values along with results of cholangiography and liver biopsy help confirm the diagnosis. (29)Growth failure occurs in 15% to 40% of children who have IBD and is more frequent in CD than UC. The Z-score (or standard deviation score) is used as an objective measurement of growth. The mean height Z-score at diagnosis of pediatric CD is −0.54, and a delay in diagnosis or presence of jejunal disease is negatively correlated with the Z-score. (4) Poor weight gain also may precede a diagnosis of IBD. Mean weight Z-score at diagnosis of pediatric CD is −1.06, with almost 30% of patients having weight Z-scores below the 3rd percentile. In comparison, mean weight Z-score at diagnosis of UC is −0.32, with only 9% of patients falling below the 3rd percentile for age. (4)The cause of growth failure in IBD is multifactorial. Patients often experience abdominal pain and diarrhea related to eating, leading to food avoidance behaviors and a decrease in total energy intake. Elevated concentrations of proinflammatory cytokines contribute to anorexia and can cause growth hormone resistance, with inhibition of insulin-like growth factor-1 (IGF-1) production. (30) In CD, active inflammation in the small intestine can decrease the absorptive surface area, resulting in a protein-losing enteropathy. Fat malabsorption contributes to the general energy-deficient state and may cause deficiencies in fat-soluble vitamins. Disease complications such as the presence of internal fistulae, surgical bowel resections, or can decrease diagnosis for a or presenting with abdominal pain and bloody diarrhea is colitis, colitis, and should be in to IBD. such as also should be The including and and are but have some clinical with IBD. such as and systemic share with pediatric IBD, weight loss, malaise, fevers, and involvement. intestinal and CD have and and can be to typically involves the and the ulcerative form is most A who has risk factors for should have a new diagnosis of IBD often is suggested by the clinical history and on 1). 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CD, bowel is the most common and typically involves the and of bowel that are from can be with disease also may and either or may be important in chronic in children who have IBD. The of with the of these can help to growth and are used by to 40% of patients who have IBD. and these are without for family and be who have IBD may have a particularly because of related to growth and from and from abdominal pain and delay may also cause significant with growth hormone and have shown some in and family and are symptoms in to one third of patients at and more than one at years initiation of therapy. that to a of CD include the number of and the presence of or in the In UC, a significant number of patients remain and 5% may although in children, occurs in approximately 5% of who have severe UC and may be by or use. may and may become Patients who have severe colitis than five bloody stools per bowel with and experience the use of in among patients who have severe risk of depends on the and of the disease. The incidence of in patients who have is 5% to 10% years and to 20% years of disease. is years who experience CD have a lower height compared with with an height of studies have shown a in height in pediatric patients who have UC. and can because of corticosteroid and high concentrations of which bone density is in nearly 50% of patients who have IBD. disease and and are to bone development and in the particularly should be in children who experience growth failure and use. and who have IBD should the use of because use can a disease or use of is suggested for treatment of pain and The use of should be limited in children who have IBD to the risk of colitis, which has been associated with increased Children medications and should be from With of is is used of growth of pubertal and are even for children who have IBD.