++
Crohn disease (CD) and ulcerative colitis (UC),
collectively known as inflammatory bowel disease (IBD),
are idiopathic, lifelong, chronic inflammatory conditions of the
gastrointestinal (GI) tract which typically manifest during late
childhood to young adulthood. The physical and psychological burden
of these chronic relapsing diseases and their devastating effects
imposed on affected children and teenagers may be considerable.
Crohn disease and ulcerative colitis are grouped together in view
of many similarities in their epidemiologic, genetic, immunologic,
and clinical features. Diagnostic approaches are similar, but treatment
approaches and prognosis differ.
++
Inflammatory bowel disease (IBD) is unevenly distributed throughout
the world with the highest disease rates occurring in industrialized
countries of Europe, North America, and Australia.1,2However,
the incidence of IBD is rapidly increasing in other emerging industrialized
countries. European studies have suggested that the incidence of
IBD in children and adolescents has significantly increased over
the last 35 years.3Although population-based studies
are difficult to perform in North America, an epidemiological population-based
study in Wisconsin found the incidence of IBD to be 7 per 100,000
in children under 18 years of age.4 In children,
about two thirds of IBD cases are Crohn disease (CD), and one half
are ulcerative colitis (UC), and in the adult population the prevalence
CD and UC are equal.5 The geographical and chronological
variation of IBD since its description early in the 20th century
is represented in eFigure 410.1.
++
++
Onset of disease has a bimodal distribution, with the greatest
incidence being adolescents and young adults, with a second peak
in the fifth to sixth decade of life. Median age of onset of disease
is between 10 and 11 years and is not different from CD. However,
significant IBD cohorts have been described under 5 years of age.6 Population-based
studies have not demonstrated an altered risk of IBD associated
with gender, ethnicity, or urban versus rural setting.4In
adults, exposure to tobacco smoke is associated with a lower incidence
of UC, but the opposite effect has been seen in CD.7,8 A
prospective cohort study of childhood exposure to smoke (active
or passive) showed an increased risk with smoke exposure for both
CD and UC in adulthood.9 Appendectomy is associated
with a decreased incidence of UC but appears to increase the risk
for CD, especially for worsening of disease for the first year following
surgery.10,11 Controversy exists regarding the
clinical significance of this in UC and whether the risk associated
with CD represents diagnostic bias.12,13
+++
Pathophysiology
and Genetics
++
Inflammatory bowel disease was recognized as a disease entity
during the early 20th century, and the pathogenesis has been linked
to a combination of genetic, environmental, and microbial factors.14 Inflammatory
bowel disease (IBD) is a disease of chronic gut inflammation. The
most widely accepted theory of pathogenesis is that in genetically
susceptible individuals, an environmental trigger promotes a chronic,
dysregulated immune response. The environmental trigger may be an
infectious agent such as a commensal organism of the normal gut
flora or possibly a ubiquitous environmental agent.15 Following
activation of the response, it appears that the mechanisms that
attenuate the response may be defective in some individuals with
IBD. It is likely that IBD has several different, as yet unnamed, subtypes.
These subtypes would each have different genetic and environmental
triggers, but they all present with similar symptoms and signs.
++
Crohn disease is heritable with specific genes associated with
an increased risk of IBD.16 The comparative risk
for Crohn disease (CD) in first-degree relatives of patients with
CD is increased by up to 35 times, but the comparative risk for
those of first-degree relatives of ulcerative colitis patients is
approximately 3 times. Family history of IBD is present in less
than 15% of patients with ulcerative colitis (UC).4,17,18 Sib-pair-based
genome-wide linkage analyses showed a non-MHC association at the
NOD2 gene on chromosome 16.19 More recently, the
application of genome-wide association scanning (GWAS) has identified
30 confirmed loci to date.20 Notable findings are
that of IL23R susceptibility indicating involvement of the IL23/IL12
pathway and two separate autophagy genes ATG16L1 and IRGM that increase
the Crohn disease risk, strongly implicating involvement of innate
immune mechanism for sequestration and control of intracellular
bacteria in the pathogenic process.21
++
Several genetic susceptibility loci for UC have been identified,
some in common with CD and others unrelated to CD. Loci common to both
UC and CD include IL23R, IL12B, HLA, NKX2-3, MST1, CCNY,
and 3p21.31. However, ECM1, PTPN2, HERC2, and STAT3 are
associated with UC but not CD.22,23 Further identification
of susceptibility haplotypes, identifying the causal variant(s)
within these haplotypes and establishing their functional consequences
will be essential to unraveling the etiopathogenesis of IBD. By
understanding the functional consequences of disease-associated
alleles, new therapies can target the specific immunoregulatory
derangement. This may also help direct the search for environmental
factors whether they are pathogens, commensal bacteria, or other
environmental triggers.
++
The clinical features of inflammatory bowel disease (IBD) disease
vary widely and depend upon the anatomic location(s) of involvement,
extent of disease, and presence of extraintestinal manifestations.14,24 The
frequency of common clinical features in pediatric patients with
IBD is shown in Table 410-1. The diagnosis
of ulcerative colitis is classically based on a suggestive history
of bloody diarrhea and abdominal pain, which may be associated with
fever, whereas in Crohn disease the presentation is often more enigmatic.
Up to 50% of children and adolescents with IBD present
with mild symptoms, characterized by fewer than four stools per
day and only minimal intermittent hematochezia. Children may also
present without GI symptoms and only extraintestinal manifestations
of IBD.
++
++
Common symptoms and signs include abdominal pain, diarrhea, weight loss, rectal bleeding, growth
impairment, perirectal disease, and extraintestinal manifestations. Fulminant
colitis can occur at initial presentation or later. Patients
with fulminant colitis are extremely ill, and often present with
fever, chills, abdominal distention, nausea and vomiting, leukocytosis,
significant anemia, dehydration, and deranged electrolyte balance.
These patients are at risk for the development of toxic megacolon
or perforation and require prompt treatment and intervention as
detailed below.
++
Abdominal pain is the most common symptom at
presentation.25 The pain may not be localized,
so differentiating pain caused by IBD from other causes of abdominal
pain, such as functional abdominal pain, may be difficult. The pain
is more likely to be chronic in nature, with a persistant location
and severity. Terminal ileal or ileocecal Crohn disease is associated
with a chronic history of right lower quadrant discomfort or pain.
In contrast, the acute development of right lower quadrant pain
without a past history of pain would more likely suggest a diagnosis
of appendicitis.
++
The majority of children with IBD also present with diarrhea.
Because the intestinal inflammation in ulcerative colitis (UC) is
limited to the colon, a change in stool pattern is the most common
presenting symptom for UC. Diarrhea in IBD is often nocturnal, and when
the distal colon is involved, it can be associated with urgency
and tenesmus. Rectal bleeding may vary in severity
at presentation. Although gross blood is seen in most of the cases
of UC, or in Crohn disease (CD) with colonic involvement, both UC
and CD can present with diarrhea alone. Adolescents with CD are
less likely to present with rectal bleeding than those with UC.
++
Weight loss, anorexia, and fatigue also herald
the onset of UC or CD. Classically, most children had weight loss
prior to the diagnosis of CD. However, more recent studies indicate
that most children with inflammatory bowel disease (IBD) have a
normal body mass index (BMI) at diagnosis.26 Less
than 10% of children with UC have a BMI less than the fifth
percentile at diagnosis compared to approximately 25% in
CD. Twenty percent to 34% of children with UC have a BMI
in the at-risk for overweight or overweight range at diagnosis (approximately
10% in CD). Thus, in an era of epidemic obesity, underweight
may not be as sensitive predictor in the evaluation of a child with
suspected IBD.27Growth failure is
seen in between 13% and 58% of children with IBD28. Deviations
from growth velocity curves and height-for-age curves are sometimes
the sole clinical feature at presentation in CD and may precede
clinical symptoms despite a lack of evidence of disease activity,
malabsorption, or reduced caloric intake. The impact of growth failure
is most significant if the disease onset occurs prior to puberty,
as the pubertal growth spurt accounts for about 16% of
the adult height. The exact mechanisms by which growth impairment
occurs are unclear but are presumably multifactorial.29 Undernutrition
is thought to be the major contributor to growth impairment in children
with IBD. Nutritional insufficiency results mainly from inadequate
caloric intake rather than increased losses or requirements. The
resting energy expenditure has been found to be normal in most studies
involving patients with CD. Inadequate intake is likely attributable
to active symptoms such as postprandial abdominal pain as well as
anorexia due to circulating proinflammatory cytokines, such as TNF-α.
Other potential causes that may play a significant role in growth
failure include active severe inflammation, growth hormone resistance,
and medication effects, in particular, corticosteroids.
++
Delayed onset of puberty is common in Crohn
disease (CD) and occurs less frequently in ulcerative colitis.30 This
may have a substantial effect on linear growth because inflammatory
bowel disease often presents in young adolescence. The pathophysiology
of delayed sexual maturation is likely multifactorial, but malnutrition
is thought to be the primary cause. The endocrinologic mechanisms
responsible for pubertal delay associated with inflammatory bowel
disease are incompletely understood.
++
Perirectal disease is common in CD and is not
seen in ulcerative colitis. It is not unusual for adolescents with
undiagnosed CD to be referred to other health professionals, including
surgeons, for perirectal disease labeled as hemorrhoids or perianal
condylomatas. Approximately 25% to 30% of affected
children with CD will have nonhealing deep anal fissures, fistulas,
perirectal abscesses, or large, multiple anal tags.31 Surprisingly,
perirectal pain is unusual unless there is actual abscess formation
that may require prompt drainage. Suspicion for an abscess should
be high when there is fever, although it may be difficult to differentiate
clinically between an abscess formation and an exacerbation of the
underlying disease involving an inflammatory reaction of the bowel.
When evaluating an adolescent with a perirectal abscess, in addition
to CD, chronic granulomatous disease32 and, although
rare, tuberculosis should be considered.33 Fistulization
in CD can occur between any two epithelialized surfaces. Enterocutaneous
fistulas, such as perianal and perirectal fistulization (see eFig. 410.2),
are the most common, compromising about 80% of the fistulas
seen in CD. Although a fistula may establish a communicating tract
with other intra-abdominal organs (eg, bladder, vagina, ureter),
it most often will end blindly and form an intraperitoneal or retroperitoneal
inflammatory mass or frank abscess. Cases of perianal CD, severe
enough to prompt an evaluation for child sexual abuse, have also
been reported.
++
++
A palpable abdominal mass (typically in the
right lower quadrant) is not uncommon in patients presenting with
CD. The mass may be inflamed intestine, or on occasion may represent
abscess.
++
Rheumatologic, dermatologic, ocular, and hepatobiliary extraintestinal
manifestations of inflammatory bowel disease (IBD) (listed in Table 410-2) are seen in up to 25% to 35% of
patients with long-standing IBD. These may also be the sole presenting
feature in pediatric IBD with no associated gastrointestinal symptoms. Axial
arthritis (ankylosing spondylitis or sacroilitis) and peripheral
arthropathy (knees, ankle, hips, wrists, and elbows) may precede
the development of intestinal inflammation in IBD. Joint disease
activity often corresponds with clinical bowel activity, but in
a minority of cases, the course of joint inflammation is independent
of any bowel disease. Finger clubbing, a form of hypertrophic osteoarthropathy,
can be seen in children with CD, particularly when the small intestine
is involved. Erythema nodosum lesions (eFig. 410.3) appear as raised, erythematous,
and painful nodules that occur over the tibia, lower leg ankle,
or extensor surfaces of the arm. Pyoderma gangrenosum (eFig.
410.4)
appears as a small, painful, sterile pustule that coalesces into
a larger abscess, ultimately forming a deep, necrotic ulcer. Extensive
small bowel involvement in CD may cause zinc deficiency with characteristic
rashes.
++
++
++
++
Oral ulcers may be seen in many patients with
IBD with varying severity (Fig. 410-1). Granulomatous
inflammation involving
the orofacial structures such as lips, gums, and face, have been
reported to occur in a minority of patients at presentation (eFig. 410.5).
Aphthous ulcerations involving the mouth and gums can be seen in
many adolescents if a careful systemic evaluation is undertaken.
Although rare, uveitis, episcleritis (eFig. 410.6),
and iritis may be seen either as an existing presentation or a sole
presenting manifestation of IBD in children. A slit lamp examination
by an ophthalmologist is necessary to make such a diagnosis. Liver
abnormalities including sclerosing cholangitis (see eFig. 410.7) or chronic
hepatitis occur in both ulcerative colitis (UC) and Crohn
disease (CD). Several reports of idiopathic pancreatitis in
patients with IBD, and as the presenting manifestation of CD, suggest
that pancreatitis could be an extraintestinal manifestation of IBD.
Pancreatitis can also be seen as a result of duodenal disease in
CD. Urethral tract abnormalities or urinary obstruction may result
secondary to ileocecal inflammation or a mass that involves the
right ureter. Iron deficiency anemia secondary
to chronic blood loss (either occult or overt) is more common during
the initial presentation of CD than UC. When iron deficiency is
seen in an older child or in an adolescent without any obvious source of
blood loss such as menorrhagia, the suspicion for gastrointestinal
blood loss and underlying IBD should be high.
++
++
++
++
+++
Differential
Diagnosis and Diagnostic Evaluation
++
The diagnosis of inflammatory bowel disease (IBD) should be based
on clinical suspicion and subsequent screening laboratory workup
that can lead to the definitive endoscopic or radiologic procedures.25 A
detailed history and physical examination remain the most important
aspects in the evaluation of a child with abdominal pain or symptoms
suggestive of IBD. The indicators (“red flags”)
in the history and examination that make a clinician suspect IBD
in a child are listed in Table 410-3. Disorders
that may present similarly to IBD are listed in eTable 410.1.
Exclusion of intestinal infections that can cause rectal bleeding
such as enteric pathogens (Salmonella, Shigella, Campylobacter,
Yersinia, and E coli 0157/H7)
and C difficile is imperative. Other considerations
in children with abdominal pain and rectal bleeding include Henoch-Schonlein
purpura, Behcet disease, hemolytic-uremic syndrome, tuberculosis,
or vasculitis. When an abdominal abscess is found during the investigation
of abdominal pain, in addition to CD, a perforated appendix, trauma,
and gynecologic diseases must be considered.
++
++
++
The establishment of a firm diagnosis of IBD is essential before
establishing this chronic and lifelong diagnosis in any child. Laboratory,
endoscopic, and radiologic evaluation not only aid in the definitive diagnosis,
but also help to classify the type of IBD (UC or CD), localize the
region(s) involved, and determine the extent as well as the severity
of the IBD. These findings aid in determination of the best treatment
modalities. Table 410-4 describes the suggested
initial diagnostic evaluation in an adolescent suspected of having
IBD.
++
++
Patients with active inflammatory bowel disease (IBD) typically
have anemia that is microcytic (MCV below 78) and hypochromic, hypoalbuminemia
(serum albumin 2.0 to 3.5 g/dL), a mild thrombocytosis (above
400,000), and an elevated sedimentation rate (above 20 mm/hr)
and elevated C reactive protein (CRP). The absence of these signs
should not be used exclusively to rule out Crohn disease (CD) or ulcerative
colitis (UC).34 A recent multicenter prospective
study characterized a large pediatric IBD cohort at diagnosis. In
a subgroup of patients with mild disease activity,
over half of the newly diagnosed pediatric UC patients and one fifth
of CD patients’ ESR, CRP, and albumin were normal. However,
the presence of hematochezia was quite common. If hemoglobin, ESR,
platelet count, and albumin are included in analysis, only 6% of
patients with mild IBD would have been overlooked (sensitivity of
94%). However, findings of a normal hemoglobin, ESR, platelet
count, and albumin are found in only 6% of patients with
mild IBD (sensitivity of 94%). Recently, a commercial serologic
panel was added to the armamentarium of the laboratory evaluation
of patients with suspected IBD. Immunoglobulin A (IgA) and immunoglobulin
G (IgG) antibodies to anti-Saccharomyces cerevisiae (ASCA) have
been associated with CD, whereas perinuclear antineutrophil cytoplasmic
antibody (p-ANCA) has been associated with ulcerative colitis. Although
these tests might assist in differentiating between CD and UC, they
are not good screening tests. A retrospective review reported that
serologic screening that included ASCA, perinuclear antineutrophil
cytoplasmic antibody (pANCA), and antibody to Escherichia
coli outer-membrane porin (anti-OmpC) demonstrated a sensitivity
of 60%, a specificity of 91%, and a positive predictive
value of 60%.35 This panel may be a useful
adjunct to conventional laboratory tests, but it has not replaced
the need for definitive examinations such as endoscopy or radiologic
evaluations.
+++
Gastrointestinal
Endoscopy and Biopsy
++
Colonoscopy with intubation of the distal ileum and biopsy is
key for the accurate diagnosis of IBD. This approach has replaced radiographic
diagnostic methods due to superior sensitivity and specificity.
In most pediatric centers, an upper endoscopy is performed at the time
of the initial colonoscopy in children with suspected IBD to aid
in differentiating the type of IBD, if a diagnosis of IBD is confirmed.
++
Colonoscopic findings that suggest Crohn disease (CD) include
aphthous ulcers in the colon, a discontinuous colitis with intervening
areas of normal mucosa (skip areas), a relative decrease in the severity
of inflammation in the rectum (rectal sparing), or identification
of granulomas on biopsy (see Fig. 410-2).
In ulcerative colitis, the rectum is
always involved, and although the inflammation is continuous, it
may be limited to either the left colon or proximally extend to
the cecum (Fig. 410-3). Endoscopic findings in both disorders
can include friability, erythema, loss of vascularity, and haustrations,
and serpigenous ulcerations may be encountered depending on the
severity of inflammation. Pseudopolyps that represent heaped-up
granulation tissue or surviving patches of mucosa surrounded by
areas of denuded mucosa are more frequently seen with ulcerative
colitis (UC). Children with UC appear to have more extensive disease
at presentation than adults, with 80% to 90% having
pancolitis,4,36compared with 60% of adults.37
++
++
++
Histologic findings in CD include pathognomonic, well-formed
mucosal granulomas. These are not always present, and in these cases
diagnosis depends upon the distribution of inflammation which is often
patchy and often involves the submuscosa and deep layers of the
bowel wall in CD. In UC, superficial mucosal inflammation is continuous
and homogeneous, with extension proximally to a varying extent along
the colon. The inflammation involves the mucosa and superficially
the submucosa (deeper layers are only rarely involved, eg, toxic
megacolon). Chronicity, with derangement of the crypt architecture
(branching and atrophy) and crypt abscesses are typical of IBD.
++
Assessment for small bowel inflammation is a key component to
differentiate between UC and CD when small bowel disease or granuloma
is not present. The terminal ileum is the site most frequently involved
in older children with CD, but in children under 10 years of age,
the colon is the most commonly affected site.38 Thus,
inflammation in the ileum strongly supports a diagnosis of CD versus
UC, but mild inflammation in the ileum can be seen in UC patients
if there is active inflammation in the cecum (termed backwash
ileitis). However, the presence of chronic small bowel
inflammation usually suggests CD. Wireless capsule endoscopy (WCE)
is increasingly used to search for occult small intestinal inflammation
and may be useful for initial evaluation in patients with suspected
IBD, or for follow-up evaluation of disease activity. Excluding
evidence of partial obstruction is required (usually with small
bowel follow through) prior to use of WCE. In smaller children who
cannot swallow large capsules, the WCE device can be placed endoscopically.
++
Following diagnosis, differentiation of UC and CD guides treatment
strategies and discussions of prognosis. The most helpful findings
that differentiate CD from UC are the presence of small bowel involvement,
perirectal disease, or granulomas in the histological biopsy findings.
The presence of aphthous oral ulcerations or perianal lesions is
much more suggestive of the diagnosis of CD. In CD the inflammatory
process is asymmetric and segmental, with transmural involvment
of any segment of the bowel, from the oral cavity to the anus. In
UC only the colon is involved. Approximately two thirds of pediatric
patients with CD have some degree of colonic involvement. In the
20% to 30% of patients whose disease is restricted
to the large bowel, precise classification of the colitis may be
difficult if no skip areas or pathognomonic well-formed mucosal
granulomas are found. Hence, even with an expert IBD clinician and
an experienced gastrointestinal pathologist, in about 10% to
15% of cases, differentiating CD from UC is not possible
despite a full diagnostic evaluation. These patients carry a provisional
diagnosis of indeterminate colitis.39
+++
Radiographic
Evaluation
++
Historically, an upper gastrointestinal series with small bowel
follow-though (SBFT) has been the primary modality to evaluate for
inflammation, manifesting as areas of mucosal ulceration, narrowing, obstruction,
or fistula of the small intestine (eFig. 410.8), or obstruction or even
an enteroenteric fistula. Abdominal and pelvic CT scans are now
often used to identify small bowel inflammation (eFig.
410.9), or an abdominal
or pelvic abscess. Radio-labeled white blood cell (WBC) scan has
been proven useful in patients where the mid-small bowel was involved
and conventional evaluation failed to demonstrate the pathology.
More recently, ultrasound, CT, and MRI enterography have augmented
(and in some centers replaced) the SBFT.40,41 The
utility of these approaches at present is dependent on the expertise
of the radiologist.
++
++
+++
Treatment Principles in
Inflammatory Bowel Disease
++
The primary goal of treatment of both Crohn disease (CD) and
ulcerative colitis (UC) is to induce and maintain remission of the
disease in order to minimize the impact on lifestyle, growth, and
development. There are established short-term and long-term goals
for managing these chronic relapsing conditions.25,38 In
the short term, inducing and maintaining remission, improving the
quality of life, and treating complications take priority. The long-term
goals should be aimed at prevention of relapses and complications,
the optimization of growth and pubertal development, the prevention
of bone loss, and limiting the need for surgical interventions. The
management of IBD in children requires a team approach that includes
the primary physician, pediatric gastroenterologist, surgeon, nutrition
specialist, psychologist, or social worker. Adjunctive pediatric
subspecialists such as rheumatologists, ophthalmologists, dermatologists,
and endocrinologists may be needed as IBD is a systemic disease
with potentially multisystem involvement (extraintestinal manifestations)
being fairly common. The response to therapy is determined by reduction
of symptoms, growth parameters, as well as improvement in laboratory
studies and rarely endoscopic findings. Although nutritional and
probiotic therapy for IBD seems attractive, the mainstay of treatment
of IBD is still via pharmacologic agents. When the disease is active,
quick-acting potent medications are used to induce remission. Once
the disease activity is under control, the goal is to use medications
with fewer side effects.
++
The strategies used for treatment of CD and UC are similar, but
the response to specific medical therapies, and the potential for
surgical “cure” with UC alter the management approach
in individual patients. Outpatient medical therapy achieves remission
following diagnosis and during disease exacerbations in many pediatric
patients. In others with a more severe presentation or severe disease
exacerbation, hospitalization may be necessary. Some present with
fulminant colitis, a life-threatening disorder that manifests with
tachycardia, orthostatic hypotension, and diffuse abdominal tenderness.
It can occur in both UC and CD. Aggressive resuscitation with fluid,
electrolyes, and blood product replacement is needed. In those with
fever and possible toxic megacolon, broad-spectrum
antibiotics should be administered and oral feedings should be discontinued.
Generally, corticosteroids should be administered intravenously.
Emergent surgical intervention may be required for toxic megacolon
or for management of complications of CD or UC. Elective colectomy
may be indicated for management of UC that is poorly controlled
with medical therapies.
++
Many children with the diagnosis of inflammatory bowel disease
(IBD) require psychological support during the course of the disease because
it is a chronic, lifelong disease, and it can have profound effects
on body image and appearance due to drugs and surgery. The psychological
and social aspects of chronic inflammatory bowel disease may be
intensified during adolescence, and psychological dysfunction associated
with delayed puberty may be particularly disconcerting in males.
Short stature and delayed puberty often leave children much shorter
than their classmates. The quality of life is obviously impaired
in teenagers who may need to take multiple pills per day, sometimes
as many as 15 or more. In particular, the cosmetic side effects
of corticosteroids, the presence of nasogastric or gastrostomy tubes,
and ostomies all lead to a sense of being different. Conflicts are
common between parents and children with IBD particularly concerning
eating habits and compliance with medications. Psychological counseling
by a professional who is familiar with IBD and the chronic nature
of the disease is essential for some patients. Many parents and teenagers
are either too busy or reluctant to go to counseling due to the
stigmata of having mental illness. The primary care provider and
the gastroenterologist should address these issues openly during
the initial diagnosis as well as during subsequent visits. Additionally,
the benefit of joining support groups for parents and patients,
as well as online “chat groups” for teenagers
cannot be underestimated.
+++
Treatment of
Crohn Disease
++
Pharmacologic agents used for treatment of Crohn disease (CD)
are detailed in Table 410-5. Therapy usually
begins with treatment with corticosteroids, followed by treatment
with azathioprine or 6-mercaptopurine to maintain remission. When
these agents are either ineffective or have intolerable side effects,
methotrexate or a biologic agent may be substituted. CD severity
and response to therapy are generally monitored by use of clinical
judgment and compendium measures such as the Pediatric Crohn Disease
Activity Index.
++
++
Corticosteroids remain the initial treatment choice for acute
therapy in moderate to severe CD. In adolescents with active mucosal
inflammation, oral prednisone, prednisolone, or medrol, or intravenous
solumedrol or hydrocortisone permit rapid improvement in most patients
by potent anti-inflammatory activity.42 There is
no evidence to suggest that corticosteroids heal the inflamed mucosa
or are useful as a maintenance therapy. Therefore, the common strategy
is to use corticosteroids in the acute setting as a short-term induction
therapy to bridge the gap while slower-acting, more effective maintenance
therapy takes effect. Long-term use is associated with bone demineralization
and adrenal insufficiency. Other side effects include fluid retention,
weight gain, striae, acne, fat redistribution, hirsutism, hypertension,
hyperglycemia, cataracts, osteonecrosis, myopathy, emotional disturbances,
and benign intracranial hypertension. An alternative to traditional
corticosteroids are newer steroids that maintain efficacy but have
fewer side effects. The first such agent became available in the
United States in late 2001. Budesonide (Entocort-EC™) is
a highly potent steroid that is released in the small intestine
and right colon in patients with CD. Most of the drug is metabolized
on first passage through the liver such that only about 10% to
30% is distributed systemically. It is effective for inducing
remission in some patients with terminal ileal and cecal CD but
is less effective than conventional corticosteroid therapy, and
long-term steroid side effects still occur.43
++
The term aminosalicylates encompasses a wide
variety of medications, each with a 5-aminosalicylate (5-ASA) moiety.
These medications have proven efficacy in the treatment of ulcerative
colitis (see below), but their role as a therapy for CD remains
controversial. Controlled studies have found only marginal benefits
such that they are rarely used for treatment of CD.44
++
Azathioprine and its metabolite, 6-mercaptopurine (6-MP) are
a mainstay for treatment of steroid refractory Crohn disease (CD).
Following initiation of therapy, clinical remission is common, but
these agents may take from 3 to 6 months to achieve their maximal
efficacy. 6-MP and azathioprine have many toxic side effects, but
their short-term safety has been proven in children with CD.45 As
immunomodulators, the mechanism of action is through the blockade
of CD-28–dependent T-cell activation.46Three
to six months of therapy may be required to achieve full effect.
Up to 30% of patients fail therapy, either from toxicity
or lack of efficacy. Side effects include myelosuppresion, hepatotoxicity, pancreatitis,
flu-like symptoms, and rash. Genetic polymorphisms in thiopurine
methyltransferase identify a small subset of patients that are at
high risk for myelosuppression. Genotyping (or measuring enzyme
activity) before starting therapy has become standard at most pediatric
inflammatory bowel disease (IBD) centers. This does not identify
all patients at risk, and monitoring is still required (usually CBC
and liver-associated enzymes). Typical doses are 1 to 1.5 mg/kg/day
for 6-mercaptopurine and 2 to 3 mg/kg/day for
azathioprine. Serum levels are highly variable, but measurement
of intracellular metabolites (thioguanine nucleotides) can help
direct treatment decisions in patients who are not responding.47Patients
should not receive live vaccines while on immunomodulators. Opportunistic
infections have been reported in IBD patients taking thiopurines,48 as
have malignancies and lymphoproliferative disorders.49,50
++
Limited data are available for the use of this agent in children
with inflammatory bowel disease, although a substantial amount of
data exists documenting its long-term safety in pediatric patients
with juvenile rheumatoid arthritis. Adverse effects include myelosuppression, oral
ulcers (mucositis), infections, pneumonitis, and hepatitis.
++
Although there is no controlled data available that antibiotics
are efficacious, they are commonly used in IBD management in clinical
practice. They have a limited role in treating intestinal inflammation and
should be used primarily to treat complications such as abdominal
or perianal abscesses. Agents such as ciprofloxacin and metronidazole
are the two most commonly used antibiotics in IBD.
+++
Biological Treatments
++
Proinflammatory cytokines such as tumor necrosis factor alpha
(TNF-α) are involved in the pathogenesis of Crohn
disease (CD). This has led to the use of new anti-TNF-α monoclonal
antibodies; Infliximab (Remicade), Adalilumab (Humira), and a pegylated
Certolizumab pegol (Cymzia).51 Several studies
have shown infliximab’s excellent beneficial effect in
children with treatment-unresponsive (refractory) CD. Side effects
of infliximab include infusion reactions, development of anti-infliximab
antibodies, delayed hypersensitivity reactions, formation of autoantibodies
and Lupus-like reactions. Unusual and aggressive infections have
been reported with infliximab.41 Reactivation of
quiescent tuberculosis, or histoplasmosis following infliximab therapy
can be lethal. Hepatosplenic T-cell lymphoma has been reported in
several adolescent and younger adult patients treated with combination
infliximab and thiopurines, leading to a now common practice of
discontinuing thiopurine therapy prior to initiating biologic therapy.52Biologic
agents have proven to be highly effective in achieving clinical
improvement and remission in significantly more patients than conventional
therapy. In addition, these biologic agents show superior efficacy
in healing perianal and other fistulas. Studies of newer biologicals
such as adalilumab and certalizumab in children are yet to be performed.
++
Nutritional therapy has been used in pediatric inflammatory bowel
disease53,54 to induce remission (primary therapy)
in small bowel CD, as supplemental therapy to improve weight gain
and growth, and to replenish micronutrient deficiencies. Primary
therapy requires that almost all the caloric needs are met by giving
elemental or polymeric formula as a whole source of nutrition. Although
the supplements can be taken by mouth, due to poor palatability
they are often administrated by nasogastric tube or gastrostomy
tube. Because adolescents tend to oppose the use of nasogastric
tubes on a daily basis, this avenue of treatment has never gained
popularity in the United States, but this approach is often used
successfully in Canada and Europe with initial remission rates of
50% to 80% in CD.
++
Supplemental nutritional therapy is used when a patient cannot
take the recommended 100% to 150% of daily allowances
for energy (85–90 kcal/kg/day and protein
2.5–3 g/kg/day). Children who are unable
to increase their enteral intake may require supplemental nocturnal
nasogastric feedings. This strategy is used most frequently for
children with growth failure that usually is associated with small bowel
disease.
+++
Future Medical
Therapies
++
Despite the use of anti-inflammatory and immunomodulatory therapies,
investigators continue to look for the ideal inflammatory bowel
disease therapy that is very effective in both the treatment as
well as the prevention of relapses, while exerting minimal toxicity.
Newer therapies are aimed at either selectively blocking detrimental
mucosal immune responses or decreasing the levels of luminal antigens. New
humanized agents that are being designed to target and interfere
with the production or action of various cytokines, adhesion molecules,
and the modulation of tissue architecture are in development. As
in multiple sclerosis, bone marrow ablation and stem cell transplantation
for severe Crohn disease is being studied.
+++
Surgical Management
of Crohn Disease
++
The major indication for operative management of Crohn disease
(CD) is the inability to control disease activity despite optimal
medical management. Additionally, operative intervention is indicated when
complications of the disease such as intestinal perforation, abscess,
bowel obstruction from inflammation or stricture, enterocutaneous
fistula, or hemorrhage occur. Growth failure, delayed puberty, and
quality of life issues such as subjective pain, school attendance,
and self-esteem are relative indications for operation.
++
Children and their families should be counseled that there is
currently no medical or surgical cure for CD. Therefore, surgical management
of CD is aimed at providing relief from symptoms or treating disease
complications while preserving as much intestinal length as possible.
Successful operations for CD require accurate localization of active
disease with endoscopic and directed diagnostic imaging studies
coupled with focused intervention. Helical CT scan imaging of the
abdomen and pelvis is extremely useful in preoperative identification
of anatomic relationships between the involved intestine and adjacent
structures such as the ureters or iliac vessels.
++
The most commonly performed operation for CD is ileocecal resection,
and this reflects anatomic disease distribution. Resection of involved bowel
is limited to grossly involved disease, as frozen section analysis
to clear microscopic margins does not improve outcome.55 Either
open or laparoscopic segmental intestinal resection with primary
anastomosis is preferred when feasible.56 In the
setting of established intra-abdominal infection, large inflammatory
phlegmon with fistula, or abscess, resection of the grossly diseased
intestine with temporary diverting enterostomy may be required.
For a chronically inflamed, fibrotic stricture, site-directed stricturoplasty
without resection and anastomosis is an alternative to resection.
++
Persistent inflammatory symptoms of CD colitis despite optimal
medical management are well treated by segmental or total abdominal
colectomy. Current data support the concept of performing segmental
or total abdominal colectomy with primary anastomosis, avoiding
diverting colostomy or ileostomy when possible.57 Although
ileoanal pouch reconstruction is the procedure of choice for children
with ulcerative colitis, results for pouch procedures with CD have
been discouraging secondary to recurrent disease and a higher reoperation
and complication rate.58 Perianal disease is observed
in approximately 13% of pediatric patients with CD and
fissures, fistulas, and tracts may be anatomically complex. Severe,
intractable perianal CD generally occurs with established colorectal
disease and may require proctocolectomy to control the disease.
++
Postoperative complications following operations for CD are unfortunately
common and include small bowel obstruction and intra-abdominal infection.59 Clinically
significant, recurrent disease and future operative intervention
should be anticipated, particularly in children with colonic disease
or severe, aggressive disease at the time of operation. Recurrence
rates of symptomatic disease following an initial operation were
reported to be 17% at 1 year, 38% at 3 years,
and 60% at 5 years,60 whether contemporary
recurrence rates are lowered by the use of maintenance therapy and
biological modifiers remains to be determined.
+++
Treatment of Ulcerative
Colitis
++
Pharmacologic agents used for treatment of ulcerative colitis
(UC) are similar to those for Crohn disease (CD) but because 5-ASA
agents are far more effective, the approach to therapy differs.
Therapy usually begins either with treatment with corticosteroids
for moderate to severe disease, followed by treatment a 5-ASA agent
to maintain remission, or may be initiated with only 5-ASA therapy
in mild disease. Thiopurines are the front-line immunomodulator
for UC. As in CD, when these agents are not either ineffective or
have intolerable side effects, methotrexate or a biologic agent
may be substituted. However, surgical therapy is a real option in
UC, so the risk and benefits of long-term immunosuppressive therapy
need to be considered.
++
Corticosteroids are frequently used to control the symptoms of
UC at the time of initial diagnosis and during acute exacerbations.
The initial treatment dose is the prednisone equivalent of 2 mg/kg/day
followed with a rapid taper, usually over 1 to 2 months. In pediatric
UC, steroids are typically used to help stabilize patients who are
threatening to develop fulminant colitis, or to control symptoms
in patients with acute exacerbations during chronic therapy with
other agents. Side effects and lack of long-term efficacy in maintaining
remission make corticosteroids undesirable for long-term management
of UC. Side effects are described in the section above pertaining
to use of corticosteroids in CD. The alternative use of rectally administered
budesonide appears to be less efficacious then rectal 5-ASA.
++
The efficacy of intravenous corticosteroid treatment for severe
exacerbations was reviewed in a retrospective longitudinal cohort
study.61 Half of the patients hospitalized responded
to steroids in the short term. Predictors of treatment failure determined
by multivariable modeling at days 3 and 5 were C reactive protein, number
of nocturnal stools, and three disease activity indices.
++
5-Aminosalicylates (5-ASA) include 5-aminosalicylic acid, mesalamine,
mesalazine, and sulfasalazine. These medications act as anti-inflammatory
agents at the level of the mucosa rather than by systemic absorption,
possibly by blocking the production of prostaglandin E2 and leukotrienes. Other
proposed mechanisms of action include inhibition of antigen presentation,
inhibition of T-cell proliferation, and antibody production by B
cells, antioxidant properties, inhibition of NK cells, mast cells,
neutrophils, mucosal lymphocytes, and macrophages, and blocking
expression of adhesion molecules and nuclear factor kappa B.62-64
++
Sulfasalazine was the first such agent employed
to treat ulcerative colitis. It contains 5-ASA linked to sulfapyridine
by an azo bond, that when cleaved by the colonic bacteria releases
5-ASA. The sulfa moiety is absorbed systemically and is responsible
for the many of the side effects of sulfasalazine. Newer formulations
do not have the sulfa moiety and have different time release formulations
to target specific regions of the alimentary canal. Adherence has
been a challenge historically, because the preparations required
multiple doses per day with multiple large pills. The most recent
formulations allow once or twice daily dosing. In younger patients,
capsules can be opened and mixed with soft food, and sulfasalazine
can be administered as a suspension. These agents can also be given
rectally as suppositories or enemas. The side effects of 5-ASA drugs
are listed in Table 410-6 and occur in 10% to
45% of patients. Agranulocytosis, oligospermia, hemolytic
anemia, and folate deficiency are unique to sulfasalazine. Monitoring
renal function is recommended because of the long-term risk of interstitial
nephritis.65,66
++
++
Despite a large body of literature demonstrating efficacy in
adults both for inducing and maintaining remission,67there
is a dearth of pediatric data. In adults with mild to moderate ulcerative
colitis, response rates are as high as 75%. One pediatric
multicenter randomized double-blind study compared 30 mg/kg/d olsalazine
to 60 mg/kg/d sulfasalazine for induction of remission
and showed improved response in the sulfasalazine group (79% versus
39%).68Doses typically employed in children
are 50 to 100 mg/kg/d.66,67 There
may be a role for 5-ASA drugs in the chemoprevention of colorectal
cancer in UC (discussed below).
++
There are no published studies on the efficacy of thiopurines
6-mercaptopurine and azathioprine) for ulcerative colitis (UC) in
pediatric patients. In adults, thiopurines are clearly beneficial
for UC, but the evidence is less convincing than for Crohn disease
(CD). Retrospective data suggest that thiopurines will maintain
remission in 75% of pediatric patients with UC69 and
are generally the immunomodulator used for maintenance therapy in
UC patients who cannot maintain remission with only 5-ASA.70 As in
CD, 3 to 6 months of therapy may be required to achieve full effect.
Side effects, monitoring, precautions, and dosing are the same as
for CD, discussed above.
++
Because of toxicity, cyclosporine A (CSA) and tacrolimus are
typically reserved for rescue therapy, serving as a bridge to other
maintenance medications (such as a thiopurine) or to surgery. CSA
is a calcinurin inhibitor and works by inhibiting cytokine production
by T-helper cells. Side effects are renal toxicity, hypertension,
hyperkalemia, seizures, paresthesias, gingival hyperplasia, headache,
tremor, elevated liver function tests, infection, and lymphoma and
other neoplasms. The typical scenario for use of CSA is the hospitalized
patient with subfulminant colitis, who is steroid refractory (not responding
after 5 to 7 days of IV corticosteroids. In children, remission
is induced in up to 80% of patients, but most require colectomy
within 1 year.71 Because of the side effects, careful
monitoring of CSA levels and renal function is required when initiating
treatment. Tacrolimus has also been used in adults72 and
children with UC, typically under the same circumstances as CSA.
Pediatric response rates in the short term have been reported near
70%, but long-term benefit is similarly disappointing to
CSA therapy.73 Given the significant toxicities
associated with calcinurin inhibitors and the poor long-term outcome,
many pediatric IBD centers are using infliximab, particularly in
patients already failing thiopurines, for rescue therapy.
+++
Biological Treatments
++
Infliximab is a monoclonal antibody that binds tumor necrosis
factor alpha (TNF-α). Initially used in CD, it
is now approved by the Food and Drug Administration (FDA) for use
in adults with UC. Pediatric case series show short-term response
rates of between 77% and 88%, with 66% in
remission beyond 9 months.74,75 Side effects and
risks are similar to those described above for treatment of CD.
+++
Future Medical
Therapies
++
Development of novel and improved therapies for UC remains an
active area for investigation.76,77 Adalimumab,
another TNF monoclonal antibody, is currently in adult trials for
UC treatment. New agents with potential benefit include anti-CD3
antibodies (visiluzumab), anti-IL2 receptor antibody (daclizumab),
and molecules that block leukocyte migration and recruitment (MLN02).
New targets include phosphodiesterase 4, an enzyme involved with
cell homeostasis and inflammation.78 A pilot study
using phosphatidylcholine (important in mucosal barrier function)
has recently been reported with improved results over placebo.79 Removal
of activated leukocytes by extracorporal leucocytopharesis has been
explored but is yet to be proven efficacious in adults.80 Newer
probiotics continue to be developed such as Esherichia coli
Nisile 1917, and chemicals with innate anti-inflammatory
activity (cumarin) may be effective.
+++
Surgical Management
of Ulcerative Colitis
++
Operative intervention for ulcerative colitis (UC) is often viewed
as a treatment of last resort in a hospitalized, ill child or adolescent.
In part, this may reflect the acute and relatively severe course
in symptomatic pediatric patients with UC. However, it is important
to recognize that UC may be effectively cured by a well-designed
operation with complete cessation of immunosuppressive or anti-inflammatory
medications. In contrast to operations for Crohn disease (CD), UC
can be surgically cured with acceptable morbidity and demonstrated
excellent long-term outcome.81 Therefore, timing
of operative intervention for pediatric UC should account for symptom
severity, quality of life issues, surgical experience, and patient/parent
preferences.
++
Approximately 25% of children and adolescents with UC
will require urgent or emergent operation for failure of optimal
medical management, gastrointestinal bleeding, intestinal perforation,
toxic megacolon, or systemic sepsis from severe colitis. In an emergent
setting in a child on high-dose corticosteroids and immunosuppressive
agents, most surgeons prefer removal of the colon with retention
of the distal rectal stump (Hartmann pouch) and diverting end ileostomy.
Restoration of gastrointestinal continuity and reconstructive procedures
are electively performed following metabolic recovery several weeks
to months later.
++
Definitive management of pediatric ulcerative colitis includes
removal of the rectal mucosa—this can be performed using
an endorectal technique that excises the distal rectal mucosa and
preserves the rectal musculature, making injury to the adjacent
nerves and structures responsible for urinary and sexual function
less likely. The most commonly performed operations for pediatric
ulcerative colitis include total abdominal proctocolectomy with
either a direct (straight) ileoanal anastomosis or construction
of an ileoanal pouch (J-pouch) anastomosis (IPPA).82These
procedures are currently being performed using minimally invasive
surgical techniques with similar excellent outcome.83
++
The concept of creating a small pouch or reservoir with the terminal
ileum was driven, in part, by the desire to reduce stool frequency
in the absence of a colon. A J-pouch is constructed by reflecting
the terminal ileum upon itself for a distance of 8 to 12 cm and
creating a common channel or pouch prior to performing ileoanal
anastomosis. Data support this concept as stool frequency and rates
of urgency and nocturnal incontinence tend to be initially higher
in the first postoperative year following straight ileoanal reconstruction
compared to ileoanal pouch procedures. This difference tends to
diminish over time, and therefore, decisions between these two approaches
should reflect consideration of the patient’s age, lifestyle,
preference, and surgeon experience. Excellent outcomes have been
reported using total abdominal proctocolectomy with ileoanal pouch
reconstructive procedures in children and adolescents.
++
Most symptomatic children and adolescents report good to excellent
quality of life following colectomy and ileoanal reconstruction.84 A
reasonable long-term functional goal is normal fecal continence,
stool frequency of 3 to 6 bowel movements per 24 hours, with normal
urinary and sexual function. Given the absence of a colon, children
and adolescents will require modification of eating behavior for
optimal outcome, and initially, antidiarrheal medications such as
loperamide or diphenoxylate and supplemental bulk fiber agents are
commonly used.
++
Immediate postoperative complications are common and include
anastomotic leak or stenosis, infection, and small bowel obstruction.
Other complications include bladder dysfunction, impotence, dyspareunia,
infertility, and ileovesical or ileovaginal fistula. Intractable
diarrhea is more common following straight ileoanal reconstruction.
Children with ileoanal pouch reconstruction may develop pouchitis
which is discussed below.
++
Pouchitis describes the presence of idiopathic inflammation in
the ileal reservoir following ilealanal pouch anastomosis (IPAA).
In adults who underwent IPAA for UC, 15% to 53% of
adults develop pouchitis, compared with a much lower rate in adults
who undergo the same procedure for familial polyposis syndromes
(3% to 14%).85 Pouchitis can
occur at any time following IPAA, but it occurs most often within
the first 6 months.
++
The cause of pouchitis is unknown. Undiagnosed Crohn disease
(CD) is frequently considered. This represents a minority of
patients, affecting only 6% to 15% of pediatric
patients who develop pouchitis.86,87 In the remaining
patients, the cause of pouchitis is likely multifactorial.88 Proposed
contributing factors include alterations in proinflammatory cytokines,
mucosal ischemia, fecal stasis, and bacterial overgrowth. A history
of extraintestinal manifestations and the presence of perinuclear
antineutrophil cytoplasmic antibody appear to be related to the
development of pouchitis Pouchitis is classified as acute or chronic
(greater than 4 weeks) and by responsiveness to antibiotics (responsive,
dependent, or resistant).
++
Symptoms of pouchitis are increased stool frequency, hematochezia,
abdominal pain, the development or worsening of incontinence, and low-grade
fever. Endoscopically, inflammation is seen in the pouch, especially
the distal and posterior portions. There is a wide spectrum of severity
from hyperemia, edema and friability, to ulceration, and pseudomembrane
formation. Significant inflammation in the neoterminal ileum suggests
undiagnosed CD, but differentiating pouchitis from CD is difficult because
there is an overlap between the acute and chronic inflammatory changes
seen histologically in both. In healthy ileal pouches, the ileal
mucosa frequently develops histologic features that resemble colonic
mucosa. This is suspected to be stimulated by changes in bacterial
population, bile salts, and short-chain fatty acids. In pouchitis,
villous blunting, crypt hyperplasia, and increased inflammatory
cells in the lamina propria are seen. Also, crytitis, crypt abscesses,
and mucin or foreign body granulomas may be present. Some of the
histologic features of pouchitis bear similarity to histologic features
of CD,89 but mild inflammation in the neoterminal
ileum does not confirm the diagnosis of CD.90
++
Other causes of pouchitis symtoms include infections (particularly Clostridium
difficile and cytomegalovirus), irritable pouch syndrome,
cuffitis, and stenosis of the pouch. In newer pouches, one must
also consider anastomotic leak.
++
The vast majority of acute episodes of pouchitis respond to antibiotic
therapy.88 The front-line therapy remains ciprofloxacin
or metronidazole for 7 to 14 days. Therapies for chronic pouchitis
include prolonged antibiotics, combination antibiotics, and probiotics
such as VSL-3.91 For patients who remain refractory,
anti-inflammatory or immunomodulator therapy is considered. Takedown
and creation of an ileostomy is only rarely required.
++
Irritiable pouch syndrome (IPS) is indistinguishable
from pouchitis based on symptoms. In contrast to pouchitis, patients
with IPS do not have active inflammation. Over 40% of symptomatic
patients have IPS.92 IPS has an equivalent impact
on patient function and quality of life when compared to pouchitis.93 Current
therapies for IPS are similar to symptomatic therapies for irritable
bowel syndrome, including antidiarrheal, anticholenergic, or antidepressant
medications.
+++
Cancer Risk
in Inflammatory Bowel Disease
++
It is well recognized that patients with ulcerative colitis (UC)
have an increased risk of colorectal cancer (CRC).94,95 The
risk is related to extent and duration of disease, increasing with
both. Other risk factors are family history of CRC, primary sclerosing
cholangitis (PSC), and age at diagnosis (early age increases risk). The
extent of this risk has been the source of some controversy. Early
studies have been criticized for overestimating this risk, primarily
due to referral bias. Later studies may underestimate the risk by
including patients with colectomies in the denominator. The estimated
risk of developing CRC after 8 to 10 years of disease is 0.5% to
1%. A meta-analysis including 116 studies determined the
overall prevalence of CRC to be 3.7% (incidence 3 cases
per 1000 person-years duration).96 Colon cancer
is rare in the pediatric population, but following 8 years of disease,
colonoscopic surveillance is indicated.
++
Adult guidelines for the management of UC include cancer prevention
strategies.97,98 Surveillance colonoscopies are
recommended beginning 8 to 10 years after diagnosis. These guidelines
have been applied to pediatrics, but there are no data supporting
this approach. Random biopsies are usually obtained in 4 quadrants
every 10 cm. Augmentation of examinations using “chromoendoscopy” with
dye stains or confocal endomicroscopy to identify and highlight
dysplastic lesions in early studies suggest improved detection rates.
The precise role of these modalities in the management of UC is
yet to be determined. Colectomy is required if dysplasia or more
aggressive lesions are identified.
++
Chemoprevention of CRC is an area of intense interest. A meta-analysis
of the impact of 5-ASA medications demonstrated a protective effect
(OR 0.51; 95% confidence interval 0.37 to 0.69).99 Ursodeoxycholic
acid has been shown to reduce the risk of CRC in patients who have
both UC and PSC.100 Population-based studies show
that extraintestinal cancers are uncommon, but specific types (lymphomas,
biliary tract cancers, and squamous cell skin cancers) may be increased
in IBD patients.