Article gastrointestinal

Inflammatory Bowel Disease

Sarah R. Glick, MD,*
Objectives After completing this article, readers should be able to:
Ryan S. Carvalho, MD
1. Develop a differential diagnosis and plan an initial evaluation for the child or
adolescent who presents with bloody diarrhea and abdominal pain.
Author Disclosure 2. Recognize that growth failure and pubertal delay may be an initial presentation of
Drs Glick and Crohn disease.
Carvalho have 3. List the extraintestinal manifestations of inflammatory bowel disease (IBD).
disclosed no financial 4. Discuss the genetic advances in understanding the pathogenesis of IBD.
relationships relevant 5. Describe the current treatments for IBD and the common adverse effects.
to this article. This
commentary does
contain a discussion
Introduction
IBD is a complex, multifactorial disease characterized by chronic inflammation in the
of an unapproved/
intestinal tract of a genetically predisposed host. The spectrum of IBD in children primarily
investigative use of a includes ulcerative colitis (UC) and Crohn disease (CD). With pediatric patients now
commercial accounting for 20% to 25% of newly diagnosed cases, it is becoming increasingly important
product/device. 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.

Epidemiology and Demographics

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
Abbreviations groups, with the incidence rising 5% annually in children
5-ASA: 5-aminosalicylates younger than 4 years of age and 7.6% annually in children
CD: Crohn disease ages 5 to 9 years. (3)
EN: erythema nodosum The mean age at diagnosis of pediatric IBD in the United
ESR: erythrocyte sedimentation rate States is 12.5 years, (2) with 20% of children diagnosed
FC: calprotectin before the age of 10 years and fewer than 5% diagnosed
FL: lactoferrin before age 5 years. Males seem overrepresented in new cases
IBD: inflammatory bowel disease of pediatric CD, although an equal number of males and
IGF-1: insulin-like growth factor-1 females receive a UC diagnosis. (4)
MRI: magnetic resonance imaging Many risk factors have been associated with IBD, includ-
PG: pyoderma gangrenosum ing family history, ethnicity, and tobacco use. Up to 25% of
PSC: primary sclerosing cholangitis children who develop IBD have a positive family history of
SNP: single-nucleotide polymorphism IBD. (5) Children who have a first-degree relative affected
TNF: tumor necrosis factor by either UC or CD have a 10 to 13 times higher risk for
UC: ulcerative colitis developing IBD. (5) Monozygotic twin concordance is ap-
VCE: video capsule endoscopy proximately 50% for CD and nearly 20% for UC. (6)
In the United States, population-based studies histori-

*Wright State University Boonshoft School of Medicine, Childrens Medical Center of Dayton, Dayton OH.

The Ohio State University College of Medicine, Nationwide Childrens Hospital, Columbus, OH.

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 gastrointestinal inflammatory bowel disease

cally have shown a higher prevalence of IBD in patients who have ileal disease without a high-risk NOD2 poly-
of European or African descent than in patients of His- morphism. The DRB1*0103 allele has been linked to
panic or Asian descent. (7) Notably, Jewish ancestry UC and colonic CD. Patients who have UC and this
(Ashkenazi more than Sephardic) is a significant risk variant seem to have a greater predisposition toward
factor for the development of IBD. However, more more extensive and severe colonic involvement. There
recent pediatric-specific population studies detected no also seems to be an association between IBD3 locus
differences in IBD frequency between ethnic groups. (2) variants and the extraintestinal manifestations of uveitis
The prevalence of IBD is highest in the industrialized and peripheral arthropathy. (9)
world, including North America, northern Europe, and The field of IBD genetics is continuously expanding,
the United Kingdom. However, with progressive mod- but genetic testing is currently limited to research. In the
ernization, the prevalence is now increasing in the devel- future, children who have IBD may undergo genetic
oping world. Tobacco use is linked closely with an in- testing to quantify disease risk in family members or to
creased risk of IBD. In smokers, the probability of predict phenotypic expression.
developing CD is twice as high as for nonsmokers. (7)
Passive exposure to smoking may be influential as well. (8) Causes
The precise causes of IBD remain unknown, but the
Genetics current understanding involves a genetic predisposition
A genetic predisposition to IBD has been hypothesized combined with a dysregulation between the immune
for decades because of the strong familial pattern of system and the antigenic environment in the gastrointes-
disease. Linkage analyses and genome-wide association tinal tract, leading to inflammation and damage. (11)
studies have identified numerous IBD candidate genes. The major pathogenic mechanism underlying CD is an
Many share a connection to the immune, inflammatory, excessive Th1 immune response, whereby CD4 T cells
or bacterial recognition pathways, which are fundamen- become upregulated and markedly resistant to apoptosis.
tal mechanisms in the pathogenesis of IBD. (12) An excessive Th2 immune response has been impli-
In 2001, the NOD2/CARD15 gene, located on chro- cated in patients who have UC. (13)
mosome 16q in the IBD1 susceptibility locus, was asso- Defective gastrointestinal mucosal integrity may lead
ciated with CD. Three high-risk single nucleotide poly- to enhanced uptake of luminal bacteria, causing the
morphisms (SNPs) are suggested to alter recognition normally protective mucosal immune system to be over-
of bacterial peptidoglycans in monocytes, macrophages, whelmed. This derangement may be a result of toler-
gut epithelial cells, and Paneth cells. NOD2 mutations ance to luminal antigens, a hyperreactive cell-mediated
can impair the degradation of gut bacteria, leading to an immune system, or specific gene mutations (such as
accumulation of bacterial antigens and predisposing to NOD2).
mucosal T-cell activation. It has been postulated that the unchecked intestinal
Nearly 40% of white patients who have CD carry one immune response to ubiquitous bacterial and enteric
of these NOD2 SNPs compared with 20% of controls. (9) antigens could lead to the pathologic gross tissue injury
These allelic variants also have phenotypic implications characteristic of IBD. Activated immune cells secrete
for those who have CD, with earlier age of onset, stric- a variety of soluble mediators of inflammation, includ-
turing disease, and ileal involvement occurring more ing cytokines (tumor necrosis factor [TNF]-alpha,
frequently. interferon-gamma, transforming growth factor-beta, and
The IBD5 locus on chromosome 5q31 is associated interleukin-2, -5, -6, -12, and -18), arachidonic acid
with a higher susceptibility toward CD. Patients who metabolites, reactive oxygen intermediates, streptolysins,
have CD and IBD5 locus polymorphisms may have more and growth factors. (12) Activated neutrophils and mac-
perianal disease, colonic disease, and importantly in pe- rophages may also release metalloproteinases, which di-
diatric patients, decreased weight and height at diagno- gest collagen in the lamina propria and basement mem-
sis. (10) There also has been a weak association of the brane and are markedly elevated in the fistulous tracts of
IBD5 locus with UC. those who have CD.
The IBD3 locus on chromosome 6 contains the The most persuasive argument for a pathogenic role
major histocompatibility complex genes, which also may of enteric flora comes from murine studies of IBD.
contribute toward IBD predisposition. The DRB1*1502 (14)(15) The gut inflammation seen in mouse models of
gene has been associated with UC, and the DRB1*07 IBD depends on the presence of bacterial flora. No single
gene has been associated with CD, particularly in patients infectious agent has been reproducibly associated with

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gastrointestinal inflammatory bowel disease

IBD, but several bacterial species, including Salmonella, tial presentation in children who have CD. Decreased bone
Helicobacter, toxigenic Escherichia coli, Listeria, and density is seen in 25% of newly diagnosed children, even
Campylobacter, have been suggested to play a role in before initiation of corticosteroid therapy. (25)
pathogenesis. Mycobacterium paratuberculosis has been
strongly suspected in IBD development. (16) Viral the- Extraintestinal Manifestations
ories have been proposed, including the potential for One third of patients who have IBD develop extra-
measles virus to cause a granulomatous vasculitis. (17) intestinal manifestations, which may predate the onset
Another antigenic hypothesis in the development of IBD of intestinal symptoms (Table 1). (26) Arthralgias and
includes the phenomenon of dysbiosis, which is an al- arthritis are common extraintestinal manifestations of
tered balance between protective bacteria, such as Lacto- CD. (26) Arthropathy also occurs in 20% to 25% of
bacillus and Bifidobacterium, and aggressive organisms, patients who have UC and may be the presenting symp-
including Bacteroides, Enterococcus, and invasive E coli. tom. Large joints, such as the knee, ankle, hip, and wrist,
(18) typically are involved. A polyarticular arthropathy in-
volves more than five joints; a pauciarticular form in-
Clinical Presentation volves fewer joints and its disease course correlates with
UC and CD can have varied yet overlapping presenta- intestinal disease activity. (27) Ankylosing spondylitis
tions. The cardinal symptoms of UC are diarrhea, rectal associated with IBD runs a course independent of
bleeding, and abdominal pain. Most children present bowel disease activity and may progress to permanent
with an insidious history of diarrhea without systemic deformity.
signs of fever or weight loss. One third present with Erythema nodosum (EN) and pyoderma gangreno-
moderate symptoms, including hematochezia, abdomi- sum (PG), although rare, are the most frequent cutane-
nal cramping associated with fecal urgency, malaise, low- ous manifestations in IBD. EN occurs more commonly
grade or intermittent fevers, anorexia with weight loss, with CD; is characterized by tender, warm, red nodules
mild anemia, and hypoalbuminemia. Only 10% of pa- or plaques; and typically is localized to the extensor
tients present with severe colitis, characterized by five or surfaces of the lower extremities. PG occurs in fewer than
more bloody stools per day; more profound anemia and 5% of UC patients and often is associated with more
hypoalbuminemia; fever; tachycardia; and a diffusely ten- extensive colonic involvement. The lesions may appear
der or distended abdomen. (19)(20) Children who have initially as discrete pustules with surrounding erythema
UC may develop symptoms of reflux or dyspepsia asso- and subsequently extend peripherally, developing into an
ciated with inflammation of the upper gastrointestinal ulceration that has a well-defined border and a deep
tract. (21) erythematous-to-violaceous color. PG tends to develop
The classic presentation of ab-
dominal pain, diarrhea, and weight Table 1. Extraintestinal Manifestations of
loss occurs in most children who
have CD. Abdominal pain typically Inflammatory Bowel Disease
is crampy and can be diffuse or lo- System Extraintestinal manifestations
calized to the right lower quadrant.
(22) Stools can appear nonbloody Skeletal Arthritis, arthralgia, ankylosing spondylitis, digital clubbing
(hypertrophic osteoarthropathy), osteopenia, osteoporosis,
or melanotic or can contain frank
aseptic necrosis
red blood. Chronic perianal disease, Cutaneous Erythema nodosum, pyoderma gangrenosum, aphthous ulcers,
including tags, fissures, fistulae, and vesiculopustular eruption, necrotizing vasculitis, metastatic
abscesses, may be present. (23) Re- Crohn disease
current aphthous-stomatitis can also Ocular Uveitis, episcleritis, corneal ulceration, retinal vascular disease
Hepatic Primary sclerosing cholangitis, bile duct carcinoma, autoimmune
suggest the diagnosis. A decrease in
chronic active hepatitis, fatty liver disease, cholelithiasis
height velocity may precede overt ab- Endocrine Growth failure, pubertal delay
dominal symptoms by 5 years, and Hematologic Autoimmune hemolytic anemia, thrombocytopenic purpura,
growth failure may be the only sign of thrombocytosis, thrombophlebitis, thromboembolism, arteritis
illness in 5% of children who receive Renal Nephrolithiasis (classically oxalate stones)
Cardiac Pericarditis, myocarditis, heart block
the diagnosis of CD. (24) Poor appe-
Pancreatic Acute pancreatitis (Crohn disease > ulcerative colitis)
tite, fevers, and iron deficiency ane- Neurologic Peripheral neuropathy, myelopathy, myasthenia gravis
mia are also commonly noted at ini-

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 gastrointestinal inflammatory bowel disease

around sites of trauma and surgical scars. Although the colitis, lymphocytic colitis, eosinophilic enterocolitis,
emergence of EN usually follows intestinal disease activ- Henoch-Schonlein purpura, and hemolytic-uremic syn-
ity, PG runs an independent course, often necessitating drome should be considered in addition to IBD. Intesti-
potent therapy. nal malignancies such as non-Hodgkin lymphoma also
Transient transaminase elevation occurs in some chil- should be considered. The periodic fevers syndromes,
dren who have IBD and may be related to medications including TRAPS (TNF receptor-associated periodic
or disease activity. Persistent elevations suggest the pres- syndrome) and PFAPA (periodic fever, aphthous stoma-
ence of primary sclerosing cholangitis (PSC) or auto- titis, pharyngitis, and cervical adenitis), are rare but have
immune hepatitis. PSC is more commonly associated some clinical overlap with IBD. Rheumatologic disor-
with UC and can predate the onset of intestinal symp- ders, such as juvenile idiopathic arthritis, ankylosing
toms in 50% of patients. (28) Typical symptoms in- spondylitis, and systemic lupus erythematosus, share
clude chronic fatigue, anorexia, pruritus, and jaundice, many characteristics with pediatric IBD, specifically,
although children may be asymptomatic. Elevated gamma- weight loss, malaise, recurrent fevers, and joint involve-
glutamyltranspeptidase and alkaline phosphatase values ment. Finally, intestinal tuberculosis and CD have similar
along with results of cholangiography and liver biopsy clinical, radiographic, and endoscopic features and can
help confirm the diagnosis. (29) be remarkably hard to differentiate. Intestinal tuberculo-
sis typically involves the ileocolonic region, and the ul-
Nutritional Considerations cerative form is most common. A patient who has risk
Growth failure occurs in 15% to 40% of children who factors for tuberculosis should have a tuberculin skin test
have IBD and is more frequent in CD than UC. The placed.
Z-score (or standard deviation score) is used as an objec-
tive measurement of growth. The mean height Z-score Diagnosis
at diagnosis of pediatric CD is 0.54, and a delay in A new diagnosis of IBD often is suggested by the clinical
diagnosis or presence of jejunal disease is negatively history and findings on physical examination (Fig. 1).
correlated with the Z-score. (4) Poor weight gain also The history should focus on the nature and duration of
may precede a diagnosis of IBD. Mean weight Z-score at symptoms; location and quality of abdominal symptoms;
diagnosis of pediatric CD is 1.06, with almost 30% frequency and consistency of bowel movements; pres-
of patients having weight Z-scores below the 3rd per- ence of blood in stools; urgency, tenesmus, and night-
centile. In comparison, mean weight Z-score at diagnosis time awakening for bowel movements; and perianal,
of UC is 0.32, with only 9% of patients falling below systemic (weight loss, fevers, fatigue), and extraintestinal
the 3rd percentile for age. (4) symptoms (aphthous ulcers, skin lesions, joint pains, eye
The cause of growth failure in IBD is multifactorial. symptoms). A family history of IBD is of critical impor-
Patients often experience abdominal pain and diarrhea tance.
related to eating, leading to food avoidance behaviors The physical examination should include measure-
and a decrease in total energy intake. Elevated concen- ments of height and weight as well as Sexual Maturity
trations of proinflammatory cytokines contribute to an- Rating staging. A complete evaluation includes examin-
orexia and can cause growth hormone resistance, with ing the mouth for aphthous lesions and performing a
inhibition of insulin-like growth factor-1 (IGF-1) pro- thorough abdominal examination. Physical findings may
duction. (30) In CD, active inflammation in the small include abdominal tenderness, right lower quadrant mass
intestine can decrease the absorptive surface area, result- or fullness, pallor, and digital clubbing. A benign abdom-
ing in a protein-losing enteropathy. Fat malabsorption inal examination does not exclude the diagnosis of IBD.
contributes to the general energy-deficient state and may A rectal examination is mandatory, and the perianal area
cause deficiencies in fat-soluble vitamins. Disease com- must be checked for skin tags, fistulae, and fissures.
plications such as the presence of internal fistulae, surgi- Nutritional assessment should include measurements
cal bowel resections, or diverting ostomies can decrease of growth velocity, height and weight Z-scores, and a
nutrient absorption further. comparison of absolute height with predicted mid-
parental height. A bone age radiograph can be obtained
Differential Diagnosis if there is concern for significant growth delay. A dietary
The differential diagnosis for a child or adolescent pre- history should be obtained, with calculation of protein,
senting with abdominal pain and bloody diarrhea is carbohydrate, fat, vitamin, and mineral intake and com-
broad. Infectious enterocolitis, pseudomembranous parison to recommended daily values. Serum concentra-

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gastrointestinal inflammatory bowel disease

used as noninvasive markers of gut inflammation. Al-

though conditions other than IBD, such as infections,
can cause inflammation and thus elevate these markers,
measurement of FC and FL has a role in differentiating
children who have IBD from those who have non-
inflammatory gastrointestinal conditions, such as irrita-
ble bowel syndrome. (33)
The use of IBD serologic panels for population
screening or as an isolated diagnostic tool is not recom-
mended. False-positive results can create unwarranted
anxiety and lead to excessive invasive testing. It should be
noted that nearly one third of patients who have a posi-
tive serologic panel do not have IBD. Serologic panels
are most useful in children who have indeterminate coli-
tis to differentiate CD from UC (Table 2). (34) Higher
serologic antibody titers and a greater number of positive
markers are associated with a more aggressive disease
course. (35)(36) Notably, anti-Saccharomyces cerevisiae-
positive CD patients are more likely to have perianal disease
Figure 1. Evaluation of a patient suspected of having inflam- and ileal stricturing disease requiring resection. (37)
matory bowel disease (IBD). ESRerythrocyte sedimentation Imaging studies play an important role in the diag-
rate, UGIupper gastrointestinal, VCEvideo capsule nosis of IBD. With CD, a barium upper gastrointestinal
endoscopy radiographic series may demonstrate stenosis, abnormal
separation of bowel loops, and fistula formation. Com-
tions of total protein, albumin, vitamin D, and iron puted tomography scan can assess for intestinal wall
should be measured. Depending on disease location, thickening and is important in the assessment of urgent
vitamin B12, folic acid, and micronutrients such as zinc complications of IBD, such as abscess formation and
also should be assessed. fistulizing or stricturing disease. Magnetic resonance im-
Measurements of hemoglobin, platelet count, eryth- aging (MRI) is beginning to play a larger role in children
rocyte sedimentation rate (ESR), and albumin classically who have IBD because there is no radiation exposure.
show abnormalities in children who have new-onset MRI has greater than 90% sensitivity and specificity for
IBD. Anemia is present in approximately 70% of patients, detecting CD of the small intestine and has the potential
and ESR is elevated in nearly 75% of children who have to distinguish colonic CD from UC because mucosal
moderate-to-severe disease. Only 4% of children who and full-thickness bowel wall inflammation enhance dif-
have moderate or severe IBD have normal test results at ferently. (38)(39)
the time of diagnosis compared with 21% of patients who Endoscopy, including esophagogastroduodenoscopy
have mild CD and about 50% of those who have mild and colonoscopy with biopsy sampling, is the gold stan-
UC. (31) Thus, normal values in these domains should dard for diagnosing IBD. Inflammation of the upper
not delay further diagnostic evaluation if a high degree of gastrointestinal tract can be seen in both UC and CD,
suspicion for IBD exists. although the presence of noncaseating granulomas in
An infectious cause should be excluded before diag- the stomach (versus nonspecific gastritis) is diagnostic
nosing IBD. Screening stool studies should include: of CD.
culture for Salmonella, Shigella, E coli, Campylobacter, Endoscopic features of UC include the characteristic
and Yersinia; examination for Giardia and Cryptospo- continuous inflammation beginning in the rectum and
ridium; and an assay for Clostridium difficile cytotoxin. extending a variable distance proximally into the large
If there is a history of immigration or overseas travel, intestine. A sharp demarcation may exist between normal
stool should be checked for Entamoeba histolytica. and diseased colon. The mucosal surface may be ery-
Fecal markers, such as calprotectin (FC) and lacto- thematous and granular, and there can be a loss of the
ferrin (FL), are released by neutrophils that have mi- normal vascular pattern with remarkable friability in areas
grated into the intestinal wall and can be measured of endoscope contact (Fig. 2). There may be small ero-
quantitatively in stool samples. (32) These markers are sions, patches of exudates, and pseudopolyps. Patchy

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 gastrointestinal inflammatory bowel disease

Table 2. Detection of Commercially Available Serologic Markers

Serologic Marker Crohn Disease Ulcerative Colitis Controls
ASCA (anti-Saccharomyces cerevisiae antibody) 40% to 56% 0% to 7% <5%
immunoglobulin A and G
ANCA (anti-neutrophil cytoplasmic antibody) 18% to 24% 60% to 80% <5%
histamine 1 protein, DNAase-specific
Anti Omp C (outer membrane protein of 25% 6% 3%
Escherichia coli )

colitis and relative rectal sparing can be consistent with and stricturing may be present anywhere from the mouth
early disease or partially treated UC. Biopsies may reveal to the anus, but the rectum typically is spared from gross
crypt distortion with branching, shortening, or atrophy; inflammation. The terminal ileum is classically abnormal
there may also be crypt abscesses. Inflammatory changes on gross inspection, and the ileocecal valve may be
are limited to the mucosal layer. stenotic. The characteristic finding on biopsy is noncase-
Endoscopic features of CD include the characteristic ating granulomas. Inflammation can extend through the
skip lesions, in which areas of inflamed mucosa are in- full thickness of the bowel wall.
terspersed with normal-appearing gut. Cobblestoning Wireless video capsule endoscopy (VCE) is an excit-
involves linear ulceration, with adjacent swelling giving ing modality that can detect small bowel lesions in areas
tissue a cobblestone pattern (Fig. 3). Aphthae, exudates, not accessible to traditional endoscopy. VCE is also

Figure 2. A. Normal colonic mucosa and vascularity. B. Colon Figure 3. A. Normal terminal ileum with lymphoid nodularity.
in a child who has ulcerative colitis, showing continuous B. Terminal ileum in a child who has Crohn disease, showing
inflammation, swelling, loss of vascular markings, and bleeding. inflammation, cobblestoning, exudates, and bleeding.

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gastrointestinal inflammatory bowel disease

helpful in identifying disease recurrence, evaluating anas-

tomotic sites, and detecting luminal complications such
as malignancy. The drawbacks of VCE are difficulty with
capsule ingestion in young children and risk of capsule
retention.

Treatment
Medical Management
Immense progress has been made in the medical man-
agement of pediatric IBD over the past decade. The
primary goals of therapy are induction and maintenance Figure 4. Treatment pyramid for ulcerative colitis (UC)
of remission, prevention of disease complications (such and Crohn disease (CD) in children. TPNtotal parenteral
as fistula, stricture, abscess, and cancer), control of post- nutrition, TNF-tumor necrosis factor-alpha, 6-MP6-
operative disease recurrence, maintenance of normal mercaptopurine, 5-ASA5-aminosalicylates, IVintravenous
growth and development, and maximization of quality
of life. who have CD are given immunomodulators within 2
Medications are selected based on the disease loca- years of diagnosis. Immunomodulators such as azathio-
tion and severity, the potential for adverse effects, and prine and 6-mercaptopurine, which interfere with purine
anticipated compliance. Current IBD medications in- biosynthesis, have demonstrated good tolerance and
clude corticosteroids, 5-aminosalicylates (5-ASA), im- can maintain remission in 75% of patients after discon-
munomodulators, biologic agents, antibiotics, and pro- tinuation of corticosteroids. (44)(45) Because azathio-
biotics (Fig. 4). prine (which is metabolized to 6-mercaptopurine) and
Moderate-to-severe symptoms initially are addressed 6-mercaptopurine require 3 to 6 months to take effect,
most commonly with oral or intravenous corticosteroids, these medications often are started soon after diagnosis.
which inhibit the inflammatory cascade. The goal is to Methotrexate is used in children who have CD and
use corticosteroids for as short a period as possible, then may be particularly useful when remission is not achieved
change to nonsteroidal maintenance therapy. Budes- with azathioprine or 6-mercaptopurine or in patients
onide, an oral corticosteroid, is frequently employed in who experience intolerable adverse effects from those
the treatment of mild-to-moderate CD because it is medications. (46) Methotrexate inhibits dihydrofolate
released in the distal small bowel and proximal colon, reductase, an enzyme necessary for folic acid metabolism
common sites of inflammation. Acute response to corti- and thymidine synthesis. The drug is effective at provid-
costeroids is excellent, with 80% of IBD patients show- ing short-term symptom control, long-term remission,
ing improvement, although corticosteroid dependency and steroid withdrawal. (47) Methotrexate usually is
occurs in up to 50% of UC patients and 30% of CD delivered as a weekly subcutaneous injection, and folic
patients. (40)(41) acid supplementation is recommended. Other immuno-
For adult patients who have mild-to-moderate UC, modulators used infrequently in IBD treatment include
5-ASA medications (sulfasalazine, mesalamine, balsala- tacrolimus and mycophenolate mofetil.
zide) are effective in inducing and maintaining remission For moderate-to-severe disease, biologic therapy is
in 90% of cases. (42) Experience in children suggests useful for induction and maintenance of remission. In-
similar response rates. The exact mechanism of action fliximab is a chimeric monoclonal antibody directed
remains unknown but may involve decreased leukotriene against the cytokine TNF-alpha that acts by inducing
production or scavenging of reactive oxygen species. apoptosis of active T lymphocytes. A response rate of up
A new, once-daily 5-ASA medication, mesalamine to 90% is achieved in patients who have moderate-to-
delayed-release tablets, has shown comparable efficacy severe CD, even when disease is refractory to corticoste-
with the benefit of better compliance. However, the use roids and immunomodulators. (48) Those children who
of 5-ASA medications in CD has become controversial have refractory UC previously were treated with cyclo-
because a meta-analysis demonstrated no superiority to sporine, but infliximab has become the treatment of
placebo in maintaining remission. (43) choice because cyclosporine therapy has a high likelihood
The use of immunomodulators in children who have of eventual treatment failure and the need for colectomy
IBD has become the standard of care. Fifty percent of in children.
newly diagnosed children who have UC and 75% of those For patients who respond to infliximab, scheduled

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 gastrointestinal inflammatory bowel disease

maintenance infusions are continued every 6 to 12 weeks. scribed for treatment of pouchitis following colectomy
Gut mucosal healing has been demonstrated following or ileoanal pouch procedures in UC patients. (53) Rifaxi-
infliximab therapy. Infliximab also plays an important min, a nonabsorbed oral antibiotic, has shown benefit in
role in treating fistulizing CD, which typically is more symptom reduction of abdominal pain and diarrhea in
resistant to conventional therapies, and extraintestinal children who have IBD. (54)
manifestations of IBD. PG, vasculitis, uveitis, EN, and Probiotics have not been shown reproducibly to alter
arthritis have responded to this therapy. the natural history of CD, but for children who have
Infliximab is the only immunomodulator approved newly diagnosed UC, probiotics are beneficial for main-
by the United States Food and Drug Administration for taining remission when added to standard treatment
children who have CD. However, two other anti-TNF regimens. (55) Probiotics are also helpful in the preven-
agents, adalimumab and certolizumab, appear effica- tion and treatment of pouchitis. (56)(57) Safety in IBD
cious. Response rates are similar to infliximab, but be- patients is well established.
cause these antibodies are more fully humanized, allergic Significant adverse effects exist for all of the previously
reactions may be less common. Adalimumab has shown described medications (Table 3). A favorable risk-benefit
efficacy in children who are intolerant or become unre- ratio is the goal when considering any therapy. Infliximab
sponsive to infliximab. (49) is contraindicated in patients who have active tuberculo-
Natalizumab (anti-alpha 4 integrin) inhibits the ad- sis, opportunistic infection, history of demyelinating dis-
hesion, migration, and activation of monocytes, macro- ease, malignancy, congestive heart failure, or concurrent
phages, and lymphocytes in a variety of tissues and has serious infection. Immunity to varicella should be as-
demonstrated clinical efficacy in treating children who certained before use of anti-TNF therapy. Recently, an
have CD. (50) Three cases of progressive multifocal aggressive malignancy, hepatosplenic T-cell lymphoma,
leukoencephalopathy associated with the human JC virus has been described in young patients (mostly male) who
were described following trials in adults, which has cre- were treated with a combination of infliximab and either
ated concern about its routine use. azathioprine or 6-mercaptopurine. (58)
Nutritional therapy may be a primary or adjunctive
treatment in CD. Exclusive enteral nutrition from ele- Surgical Management
mental or polymeric formulas has been associated with Despite improvements in medical strategies, surgery
short-term remission in up to 80% of children, equal to maintains an important therapeutic role. Indications for
the response rate from corticosteroids. (51) The mecha- surgery include uncontrolled gastrointestinal bleeding,
nism involves adequate suppression of bowel inflamma- bowel perforation, obstruction, intractable disease de-
tion and the induction of mucosal
healing. (51) Improved growth and
development, without the adverse Table 3. Adverse Effects of Medications Commonly
effects of corticosteroids, makes en-
teral nutrition an excellent choice Used to Treat Inflammatory Bowel Disease
for first-line therapy in children Medication Class Important Adverse Effects
who have active CD. However,
after induction, long-term medica- Corticosteroids Cushingoid facies, growth suppression, osteopenia,
hypertension, hyperglycemia, acne, cataracts,
tions, such as immunomodulators,
hypothalamic-pituitary-adrenal axis suppression
are necessary to maintain remis- 5-Aminosalicylates Hypersensitivity reaction, disease exacerbation,
sion. Supplements such as iron, fo- headache, diarrhea, rash, pneumonitis, interstitial
lic acid, calcium, and vitamin D are nephritis
required in certain situations. 6-Mercaptopurine, Bone marrow suppression, pancreatitis, hepatitis, rash,
azathioprine vasculitis; increased risk of lymphoma
Antibiotics have specific indica-
Methotrexate Hepatitis, liver fibrosis, rash, folic acid deficiency,
tions in IBD treatment. Metronida- nausea, vomiting, hair loss
zole is used to treat perirectal fistu- Anti-tumor necrosis Resurgence of tuberculosis, histoplasmosis, varicella,
las, although recurrence rates are factor malignancies (including lymphoma), fatal
high and toxicity (eg, paresthesias) lymphoproliferative syndromes, anaphylaxis, serum
sickness syndrome, lupuslike syndrome, increased risk
often limit long-term use. (52) Cip-
of serious infections
rofloxacin is also useful in fistula Anti-integrin Progressive multifocal leukomalacia
treatment. Both antibiotics are pre-

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gastrointestinal inflammatory bowel disease

spite standard therapy, and dysplasia. At times, surgical dependent after 1 year, and 5% may require colectomy.
resection is used to treat growth failure, especially if it (40)
allows the discontinuation of corticosteroids. Toxic megacolon, although rare in children, occurs in
The surgical procedure of choice in UC is resection of approximately 5% of adults who have severe UC and may
the entire colon with ileal pouch-anal anastomosis. This be triggered by hypokalemia or opiate use. Colonic per-
curative procedure can be performed either as a primary foration may occur and colectomy may become neces-
operation or in a staged approach, depending on the sary. (65) Patients who have severe colitis (more than five
condition of the patient. Long-term results are excellent, bloody stools per day, fever, hypoalbuminemia, anemia)
and continence can be achieved in 89% of patients after require hospitalization, bowel rest with parenteral nutri-
2 years with creation of a J-pouch reservoir. (59) The tion support, intravenous corticosteroids, and very care-
major complication occurring after ileoanal pull-through ful monitoring. Anecdotal experience supports the use of
is inflammation of the pouch (pouchitis), which occurs in infliximab in reducing colectomy rates among patients
10% to 40% of children. (60)(61) who have severe colitis.
In CD, segmental bowel resection is the most com- The risk of colorectal cancer depends on the extent
mon surgery and typically involves removing the diseased and duration of the disease. (66) The cumulative inci-
terminal ileum and adjacent inflamed colon. Short seg- dence of colorectal cancer in patients who have pancolitis
ments of bowel that are narrowed from fibrosis can be is 5% to 10% after 20 years and 12% to 20% after 30 years
treated with stricturoplasty. Perirectal disease also may of disease. Screening is recommended beginning 8 years
necessitate surgery. after diagnosis.
Patients who experience early-onset CD have a lower
Adjunctive Therapies final adult height compared with predicted mid-parental
Oral nutrition supplements and either nasogastric or height, with an average height reduction of 2.4 cm.
gastrostomy feedings may be critically important in ad- Population studies have not shown a difference in final
dressing chronic undernutrition in children who have adult height in pediatric patients who have UC. (67)
IBD. The administration of adequate calories with the Osteopenia and osteoporosis can occur because of vita-
addition of these supplements can help to reverse growth min D deficiency, corticosteroid use, and high concen-
failure. trations of circulating inflammatory cytokines, which
Complementary and alternative medicine approaches inhibit IGF-1. Abnormally low bone mineral density is
are used by up to 40% of patients who have IBD. To found in nearly 50% of patients who have IBD. Maintain-
prevent medication interactions and limit undue adverse ing disease remission, avoiding corticosteroids, exercis-
effects, these therapies are not routinely recommended ing, and ensuring adequate calcium and vitamin D in-
without physician consultation. take are imperative to optimize bone development and
The need for family education and reassurance cannot mineralization in the growing child, particularly during
be overemphasized. Adolescents who have IBD may puberty. Dual-energy radiograph absorptiometry scans
have a particularly difficult time because of issues related should be performed in children who experience growth
to growth failure, body image (eg, cushingoid features failure and prolonged steroid use. (25)(68)(69)
and acne from corticosteroids), and social invalidism
from abdominal pain and diarrhea. Pubertal delay may Issues for the General Pediatrician
also cause significant anxiety. Recent trials with growth Children and adolescents who have IBD should avoid
hormone and IGF-1 have shown some promise in im- the use of nonsteroidal anti-inflammatory drugs (includ-
proving growth. ing ibuprofen) because their routine use can trigger a
In general, patient and family counseling and peer disease flare, enteropathy, or gastritis. Cautious use of
support groups are very helpful. acetaminophen is suggested for treatment of minor pain
and fever. The casual use of antibiotics should be limited
Prognosis and Disease Complications in children who have IBD to prevent the risk of C difficile
Disease symptoms recur in up to one third of patients at colitis, which has been associated with increased morbid-
1 year and more than one half at 2 years after initiation ity. Children taking immunosuppressive medications and
of therapy. Factors that predispose to a relapse of CD biologic therapy should be restricted from live vaccine
include the number of previous strictures and the pres- administration. With administration of inactivated vac-
ence of FC or FL in the stool. (62)(63)(64) In UC, a cines, seroconversion is not always obtained if immuno-
significant number of patients remain corticosteroid- suppressive therapy is being used concomitantly. Mea-

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 gastrointestinal inflammatory bowel disease

surement of growth velocity, evaluation of pubertal 12. Bouma G, Strober W. The immunological and genetic basis of
Sexual Maturity Rating staging, and annual-to-biannual inflammatory bowel disease. Nat Rev Immunol. 2003;3:521533
13. Saxon A, Shanahan F, Landers C, Ganz T, Targan S. A distinct
eye examinations are recommended, even for asymptom-
subset of antineutrophil cytoplasmic antibodies is associated with
atic children who have IBD. inflammatory bowel disease. J Allergy Clin Immunol. 1990;86:
202210
14. Ehrhardt RO, Ludviksson BR, Gray B, Neurath M, Strober W.
Induction and prevention of colonic inflammation in IL-2-deficient
Summary mice. J Immunol. 1997;158:566 573
15. Fiocchi C. Inflammatory bowel disease: etiology and patho-
Recent major advances have been made in the genesis. Gastroenterology. 1998;115:182205
diagnosis and treatment of pediatric IBD, and 16. Sanderson JD, Moss MT, Tizard ML, Hermon-Taylor J. My-
understanding of its pathophysiology continues to cobacterium paratuberculosis DNA in Crohns disease tissue. Gut.
evolve. 1992;33:890 896
The long-term outcome for children who have IBD 17. Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent
continues to improve with better appreciation of measles virus infection in Crohns disease. J Med Virol. 1993;39:
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and more effective treatments. 18. Farrell RJ, LaMont JT. Microbial factors in inflammatory
Although the incidence of pediatric IBD appears to bowel disease. Gastroenterol Clin North Am. 2002;31:41 62
be rising, the future for affected children and 19. Grand RJ, Homer DR. Approaches to inflammatory bowel
adolescents appears promising. disease in childhood and adolescence. Pediatr Clin North Am.
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20. Motil KJ, Grand RJ. Ulcerative colitis and Crohn disease in
children. Pediatr Rev. 1987;9:109 120
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3. Benchimol EI, Guttmann A, Griffiths AM, et al. Increasing 1991;26:513515
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Levine JJ. Age and family history at presentation of pediatric 26. Hyams JS. Extraintestinal manifestations of inflammatory
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6. Halfvarson J, Bodin L, Tysk C, Lindberg E, Jarnerot G. Inflam- 27. Passo MH, Fitzgerald JF, Brandt KD. Arthritis associated with
matory bowel disease in a Swedish twin cohort: a long-term inflammatory bowel disease in children. Relationship of joint dis-
follow-up of concordance and clinical characteristics. Gastroenter- ease to activity and severity of bowel lesion. Dig Dis Sci. 1986;31:
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7. Cho JH. Inflammatory bowel disease: genetic and epidemio- 28. Hyams JMJ, Treem W. Characterization of hepatic abnormal-
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356 359 30. Kirschner BS, Sutton MM. Somatomedin-C levels in growth-
9. Walters TD, Silverberg MS. Genetics of inflammatory bowel impaired children and adolescents with chronic inflammatory bowel
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influence of OCTN1/2 variants within the IBD5 locus on disease Pediatrics. 2007;119:11131119
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33. Joishy M, Davies I, Ahmed M, et al. Fecal calprotectin and for moderate to severe Crohn disease in adolescents. J Pediatr
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34. Sabery N, Bass D. Use of serologic markers as a screening tool analysis of enteral nutrition as a primary treatment of active Crohns
in inflammatory bowel disease compared with elevated erythrocyte disease. Gastroenterology. 1995;108:1056 1067
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A. Serologic testing with ANCA, ASCA, and anti-OmpC in chil- RN, Staiano A. Effect of a probiotic preparation (VSL#3) on
dren and young adults with Crohns disease and ulcerative colitis: induction and maintenance of remission in children with ulcerative
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Gastroenterol. 2004;99:22352241 56. Gionchetti P, Amadini C, Rizzello F, Venturi A, Poggioli G,
38. Darbari A, Sena L, Argani P, Oliva-Hemker JM, Thompson R, Campieri M. Diagnosis and treatment of pouchitis. Best Pract Res
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Dis. 2004;10:6772 pouch dysfunction or pouchitis with an ileoanal pouch. Best Pract
39. Paolantonio P, Ferrari R, Vecchietti F, Cucchiara S, Laghi A. Res Clin Gastroenterol. 2004;18:9931006
Current status of MR imaging in the evaluation of IBD in a 58. Thayu M, Markowitz JE, Mamula P, Russo PA, Muinos WI,
pediatric population of patients. Eur J Radiol. 2009;69:418 424 Baldassano RN. Hepatosplenic T-cell lymphoma in an adolescent
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corticosteroid therapy for ulcerative colitis in children. Clin Gastro- disease. J Pediatr Gastroenterol Nutr. 2005;40:220 222
enterol Hepatol. 2006;4:1118 1123 59. Koivusalo A, Pakarinen MP, Rintala RJ. Surgical complications
41. Markowitz J, Hyams J, Mack D, et al. Corticosteroid therapy in relation to functional outcomes after ileoanal anastomosis in
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 gastrointestinal inflammatory bowel disease

PIR Quiz
Quiz also available online at http://pedsinreview.aappublications.org.

6. Which of the following symptoms or signs is seen in children who have Crohn disease, but not in children
who have ulcerative colitis?
A. Anemia.
B. Arthritis.
C. Loose stools.
D. Perianal fistula.
E. Weight loss.

7. Which of the following infections can mimic the intestinal inflammation of Crohn disease?
A. Epstein-Barr virus.
B. Herpes simplex virus-1.
C. Measles virus.
D. Rotavirus.
E. Tuberculosis.

8. Which of the following tests is the gold standard for diagnosis of IBD?
A. Abdominal computed tomography scan.
B. Endoscopy and colonoscopy with biopsy.
C. Fecal lactoferrin.
D. Serologic panel.
E. Wireless capsule endoscopy.

9. A 15-year-old boy received the diagnosis of Crohn disease of the colon 6 months ago. He has had active
disease despite 5 months of 6-mercaptopurine therapy and two courses of corticosteroid therapy. Of the
following, which medication is most likely to induce remission?
A. Azathioprine.
B. Infliximab.
C. Mesalamine.
D. Metronidazole.
E. Rifaximin.

10. An adolescent girl who has ulcerative colitis has been successfully maintained on 6-mercaptopurine for
2 years and presents today for a health supervision visit. She asks which immunizations she can have in
the future. Which of the following vaccines is contraindicated?
A. Human papillomavirus vaccine.
B. Influenza vaccine.
C. Measles, mumps, and rubella vaccine.
D. Pneumococcal vaccine.
E. Tetanus toxoid.

Pediatrics in Review Vol.32 No.1 January 2011 25

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 Inflammatory Bowel Disease
Sarah R. Glick and Ryan S. Carvalho
Pediatrics in Review 2011;32;14
DOI: 10.1542/pir.32-1-14

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 Inflammatory Bowel Disease
Sarah R. Glick and Ryan S. Carvalho
Pediatrics in Review 2011;32;14
DOI: 10.1542/pir.32-1-14

The online version of this article, along with updated information and services, is
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