Chapter17: INTESTINES:Inflammatory Bowel Disease

Question 1

What is IBD?

Answer 1

Inflammatory bowel disease (IBD) is a chronic condition resulting from inappropriate mucosal
immune activation.

Question 2

What are thee two disorders that comprise IBD?

Answer 2

1. Crohn disease and
2. ulcerative colitis.

Question 3

Descriptions of ulcerative colitis and Crohn disease date back to antiquity and at least the sixteenth century, respectively, but it took modern bacteriologic techniques to exclude conventional infectious etiologies for these diseases. [92]

As will be discussed below, however,

commensal bacteria normally present in the intestinal lumen are probably involved in IBD pathogenesis.

Question 4

What is the distinction between ulcerative colitis and Crohn disease?

Answer 4

The distinction between is based, in large part, on the
distribution of affected sites ( Fig. 17-32 ) and the morphologic expression of disease ( Table
17-8 ) at those sites. \

Question 5

What is Ulcerative colitis?

Answer 5

Ulcerative colitis is a severe ulcerating inflammatory disease that is limited to the colon and rectum and extends only into the mucosa and submucosa.

U-CRMS ( Colon,Rectum,Mucosa and Submucosa)

Question 6

What is Crohn disease?

Answer 6

In contrast, Crohn
disease, which has also been referred to as regional enteritis (because of frequent ileal
involvement)may involveany area of the GI tractand istypically transmural.

CT ( Crohn and Transmural)

Question 7

Answer 7

FIGURE 17-32 Distribution of lesions in inflammatory bowel disease.

The distinction
between Crohn disease and ulcerative colitis is primarily based on morphology

Question 8

TABLE 17-8 – Features That Differ between Crohn Disease and Ulcerative Colitis

MACROSCOPIC

Answer 8

Crohn Disease

• Bowel region: Ileum ± colon
• Distribution: Skip lesions
• Stricture :Yes
• Wall appearance :Thick

Ulcerative Colitis

• Bowel region: Colon only
• Distribution: Diffuse
• Stricture :Rare
• Wall appearance :Thin

Question 9

TABLE 17-8 – Features That Differ between Crohn Disease and Ulcerative Colitis

MICROSCOPIC

Answer 9

Crohn Disease

• Inflammation: Transmural
• Pseudopolyps: Moderate
• Ulcers: Deep, knife-like Superficial,
• Lymphoid reaction: Marked
• Fibrosis :Marked
• Serositis :Marked
• Granulomas: Yes (∼35%)
• Fistulae/sinuses: Yes

Ulcerative Colitis

• Inflammation: Limited to mucosa
• Pseudopolyps: Marked
• Ulcers: Superficial, broad-based
• Lymphoid reaction: Moderate
• Fibrosis :Mild to none
• Serositis :Mild to none
• Granulomas: No
• Fistulae/sinuses: No

Question 10

TABLE 17-8 – Features That Differ between Crohn Disease and Ulcerative Colitis

CLINICAL

Answer 10

Crohn Disease

• Perianal fistula :Yes (in colonic disease)
• Fat/vitamin malabsorption: Yes
• Malignant potential :With colonic involvement
• Recurrence after surgery: Common
• Toxic megacolon :No

Ulcerative Colitis

• Perianal fistula :No
• Fat/vitamin malabsorption: No
• Malignant potential :Yes
• Recurrence after surgery: No
• Toxic megacolon :Yes

Question 11

Both Crohn disease and ulcerative colitis are more common to what gender and age group?

Answer 11

Both Crohn disease and ulcerative colitis are more common in females and frequently present
in the teens and early 20s.

Question 12

What is the epidemiology of IBD?

Answer 12

In Western industrialized nations IBD is most common among Caucasians and, in the United States, occurs 3 to 5 times more often among eastern European
(Ashkenazi) Jews.

This is at least partly due to genetic factors, as discussed below.

The geographic distribution of IBD is highly variable, but it is most common in North America,
northern Europe, and Australia.

However, IBD incidence worldwide is on the rise, and it is becoming more common in regions such as Africa, South America, and Asia, where the
prevalence was historically low.

The hygiene hypothesis suggests that this increasing incidence may be related to improved food storage conditions and decreased food contamination.

This hypothesis suggests that reduced frequency of enteric infections has resulted in inadequate
development of regulatory processes to limit mucosal immune responses, allowing pathogens
that should cause self-limited disease to trigger overwhelming immune responses and chronic
inflammatory disease in susceptible hosts.

Although many details to support this hypothesis are lacking, the observation that helminth infection, which is endemic in regions where IBD
incidence is low, can prevent IBD development in animal models and reduce disease in some
patients lends support to this idea. The observation that an episode of acute infectious
gastroenteritis may precede onset of IBD in some individuals is also consistent with the hygiene
hypothesis.

Question 13

What is the pathogenesis of IBD?

Answer 13

IBD is an idiopathic disorder and the responsible processes are only beginning to be understood.

Although there is limited epidemiologic association of IBD with autoimmunity, neither Crohn disease nor ulcerative colitis is thought to be an autoimmune disease.

Rather, most investigators believe that the two diseases result from a combination of defects in host
interactions with intestinal microbiota, intestinal epithelial dysfunction, and aberrant mucosal
immune responses. This view is supported by epidemiologic, genetic, and clinical studies as
well as data from laboratory models of IBD ( Fig. 17-33 ).

Question 14

What are the factors that contribute to IBD?

Answer 14

• Genetics
• Mucosal immune responses
• Epithelial defects.
• Microbiota

Question 15

What are the genetic factors that contribute to IBD?

Answer 15

Risk of disease is increased when
there is an affected family member and, in Crohn disease, the concordance rate for monozygotic twins is approximately 50%.

The same factors may also contribute to
disease phenotype, because twins affected by Crohn disease tend to present within 2 years of each other and develop disease in similar regions of the GI tract.

The concordance of monozygotic twins for ulcerative colitis is only 16%, suggesting that genetic factors are less dominant than in Crohn disease.

Concordance for dizygotic twins is less than 10% for both Crohn disease and ulcerative colitis.

Molecular linkage analyses of affected families have identified NOD2 (nucleotide oligomerization binding domain 2) as a susceptibility gene in Crohn disease.

Specific NOD2 polymorphisms confer at least a four-fold increase in Crohn disease risk among
Caucasians of European ancestry.

NOD2 encodes a protein that binds to intracellular
bacterial peptidoglycansand subsequently activatesNF-κB.

Question 16

What are the mechanism by which
NOD2 polymorphisms contribute to Crohn disease pathogenesis?

Answer 16

• It has been postulated that disease-associated NOD2 variants are less effective at recognizing and combating luminal microbes, which are then able to enter the lamina propria and triggerin flammatory reactions.
• Other data suggest that NOD2 may regulate immune responses to prevent excessive activation by luminal microbes.

Whatever the mechanism by which

NOD2 polymorphisms contribute to Crohn disease pathogenesis, it should be

remembered that fewer than 10% of individuals carrying NOD2 mutations develop disease.

Furthermore, NOD2 mutations are uncommon in African and Asian Crohn disease patients.

Thus, defective NOD2 signaling is only one of many genetic factors that contribute to Crohn disease pathogenesis.

Question 17

What is the mainstay of IBD therapy?

Answer 17

immunosuppression

Although the mechanisms by which mucosal immunity
contributes to ulcerative colitis and Crohn disease pathogenesis are still being
deciphered

Question 18

How does Mucosal immune responses contribute to the pathogenesis of IBD?

Answer 18

• Polarization of helper T cells to the TH1 type (see Chapter 6 ) is well-recognized in Crohn disease, and emerging data suggest that TH17 T cells also contribute to disease pathogenesis
• Consistent with this, certain polymorphisms of the IL 23 receptor confer protection from Crohn disease and ulcerative colitis. [95]
• IL-23 is involved in the development and suggesting that the protective IL-23 receptor polymorphisms may attenuate pro-inflammatory TH17 responses in Crohn disease and ulcerative colitis. maintenance of TH17 cells,
• Some data suggest that ulcerative colitis is a TH2-mediated disease, and this is consistent with observations of increased mucosal IL-13 in ulcerative colitis patients.
• However, the protection afforded by IL-23 receptor polymorphisms and effectiveness of anti-TNF therapy in some ulcerative colitis patients seems to support roles for TH1 and TH17 cells.
• A recent report linking polymorphisms near the IL-10 gene to ulcerative colitis, but not Crohn disease, further emphasizes the importance of immunoregulatory signals in IBD pathogenesis. [96]

NOTE:

Overall it is likely that some combination of derangements that activate mucosal immunity and suppress immunoregulation contribute to the development of ulcerative colitis and Crohn disease. The relative roles of innate and adaptive arms of the immune system are presently the subject of intense scrutiny.

Question 19

How does the epithelial defects contribute to IBD pathogenesis?

Answer 19

A variety of epithelial defects have been described in both Crohn disease and ulcerative colitis.

• For example, defects in intestinal epithelial tight junction barrier function are present in Crohn disease patients and a subset of their healthy firstdegree relatives. [97]
• In patients with Crohn disease and their relatives, this barrier dysfunction is associated with NOD2 polymorphisms, [98] and experimental models demonstrate that barrier dysfunction can activate innate and adaptive mucosal immunity and sensitize subjects to disease. [99]
• Moreover, mutation of the organic cation transporter SLC22A4 in Crohn disease suggests that defective transepithelial transport may also be related to IBD pathogenesis.
• Defects in the extracellular barrier formed by secreted mucin may also contribute. [100] Interestingly, polymorphismsin ECM1 (extracellular matrix protein 1), which inhibits matrix metalloproteinase 9, are associated with ulcerative colitis but not Crohn disease. [101] While the pathogenic relevance of ECM1 mutations is not understood, it is notable that inhibition of matrix metalloproteinase 9 reduces the severity of colitis in experimental models.
• Finally, the Paneth cell granules, which contain antibacterial peptides termed defensins, are abnormal in Crohn disease patients carrying ATG16L1 mutations, [102] suggesting that defective epithelial anti-microbial function contributes to IBD.

NOTE: Thus, while the details are incompletely defined and probably differ between Crohn disease and ulcerative colitis, deranged epithelial function is a critical component of IBD pathogenesis.

Question 20

The abundance of microbiota in the GI lumen is overwhelming, amounting to as much as

Answer 20

10 ¹² organisms per milliliter in the colon and 50% of fecal mass.

In total,
these organisms greatly outnumber human cells in our bodies, meaning that, at a cellular level, we are only about 10% human.

Although the composition of this dense
microbial population tends to be stable within individuals over at least several years, it
can be modified by diet and there is significant variation between individuals.

In addition
to the luminal microbiota, the more limited microbial population that inhabits the intestinal mucous layer may have the greatest impact on health.

Question 21

How does the microbiota contribute to the pathogenesis of IBD?

Answer 21

Despite growing evidence that intestinal microbiota contribute to IBD pathogenesis, [103] their precise
role remains to be defined and is probably different in ulcerative colitis and Crohn
disease.

For example, antibodies against the bacterial protein flagellin are associated with NOD2 polymorphisms as well as stricture formation, perforation, and small-bowel involvement in patients with Crohn disease, but are uncommon in ulcerative colitis patients.

In addition, some antibiotics, e.g. metronidazole, can be helpful in management of Crohn disease, and broad-spectrum antibiotics can prevent disease in some experimental models of IBD. [104]

Ongoing studies suggest that ill-defined mixtures
containing probiotic, or beneficial, bacteria may combat disease in experimental models
as well as some IBD patients, although the mechanisms responsible are not well
understood.

Question 22

Answer 22

FIGURE 17-33 One model of IBD pathogenesis. Aspects of both Crohn disease and
ulcerative colitis are shown.

Question 23

Explain the model that unifies the roles of intestinal microbiota, epithelial function, and mucosal
immunity.

Answer 23

suggests a cycle by which transepithelial flux of luminal bacterial components activates innate and adaptive immune responses. [106]

In a genetically susceptible host, the subsequent
release of TNFandother immune-mediated signals direct epithelia to increase tight junction permeability, which causes further increases in the flux of luminal material.

These events may establish a self-amplifying cycle in which a stimulus at any site may be sufficient to initiate
IBD. [107]

Although this model is helpful in advancing our understanding of IBD pathogenesis, it is important to recognize that a variety of factors are associated with disease for unknown reasons.

For example, an episode of appendicitis is associated with reduced risk of developing ulcerative colitis. Tobacco also modifies IBD epidemiology, but, paradoxically, the risk of Crohn
disease is increased by smoking while that of ulcerative colitis is reduced.

Question 24

What is Crohn disease?

Answer 24

Crohn disease, an eponym based on the 1932 description by Crohn, Ginzburg, and Oppenheimer, has existed for centuries.

Louis XIII of France (1601–1643) suffered relapsing
bloody diarrhea, fever, rectal abscess, small intestinal and colonic ulcers, and fistulae beginning
at age 20 years, most likely due to Crohn disease.

Question 25

Crohn disease may occur in any area of the GI tract, but the most commonsites involved at presentation are what?

Answer 25

• terminal ileum,
• ileocecal valve, and
• cecum.

Disease is limited to the small intestine alone in about 40% of cases;

the small intestine and
colon are both involved in 30% of patients;

and the remainder have only colonic
involvement.

Question 26

What is the characteristic of Crohn disease that may help in the differentiation from ulcerative colitis?

Answer 26

The presence of multiple, separate, sharply delineated areas of disease,
resulting in skip lesions, is characteristic of Crohn disease and may help in the
differentiation from ulcerative colitis.

Strictures are common ( Fig. 17-34A ).

Question 27

What is the earliest Crohn disease lesion?

Answer 27

the aphthous ulcer, may progress, and multiple lesions often coalesce into elongated, serpentine ulcers oriented along the axis of the bowel.

Question 28

In Crohn’s disease Edema and loss of the normal mucosal texture are common.

Sparing of interspersed mucosa, a
result of the patchy distribution of Crohn disease, results in what appearance?

Answer 28

results in a coarsely textured,
cobblestone appearance in which diseased tissue is depressed below the level of normal
mucosa ( Fig. 17-34B ).

Question 29

In Crohn’s disease, what frequently develop between mucosal folds and may extend deeply to become fistula tract or sites of perforation?

Answer 29

Fissures

Question 30

What is the creeping fat apperance in Crohn disease?

Answer 30

The intestinal wall is thickened and rubbery as a consequence of transmural edema, inflammation,
submucosal fibrosis, and hypertrophy of the muscularis propria, all of which contribute to
stricture formation.

In cases with extensive transmural disease, mesenteric fat frequently extends around the serosal surface (creeping fat) ( Fig. 17-34D ).

Question 31

What are the microscopic features of active Crohn disease?

Answer 31

The microscopic features of active Crohn disease include abundant neutrophils that infiltrate
and damage crypt epithelium.

Clusters of neutrophils within a crypt are referred to as crypt abscesses and are often associated with crypt destruction.

Ulceration is common in Crohn
disease, and there may be an abrupt transition between ulcerated and adjacent normal
mucosa. Even in areas where gross examination suggests diffuse disease, microscopic
pathology can appear patchy.

Question 32

What happens when there is Repeated cycles of crypt destruction and regeneration in Crohn disease?

Answer 32

distortion of mucosal architecture;

the normally straight and parallel crypts take on
bizarre branching shapes and unusual orientations to one another ( Fig. 17-35A ).

Epithelial
metaplasia, another consequence of chronic relapsing injury, often takes the form of gastric
antral-appearing glands, and is called pseudopyloric metaplasia.

Question 33

What is Paneth cell metaplasia in Crohn disease?

Answer 33

Paneth cell metaplasia
may also occur in the left colon, where Paneth cells are normally absent.

These architectural
and metaplastic changes may persist even when active inflammation has resolved.

Mucosal
atrophy, with loss of crypts, may occur after years of disease.

Question 34

What is the hallmark of Crohn disease, are found in approximately 35% of cases and
may occur in areas of active disease or uninvolved regions in any layer of the intestinal wall

Answer 34

Noncaseating granulomas ( Fig. 17-35B ), (Fig. 17-35C ).

Granulomas may also be present in mesenteric lymph nodes. Cutaneous granulomas form nodules that are referred to as metastatic Crohn disease.

The absence
of granulomas does not preclude a diagnosis of Crohn disease.

Question 35

Answer 35

FIGURE 17-34 Gross pathology of Crohn disease

• A, Small-intestinal stricture
• . B, Linear mucosal ulcers and thickened intestinal wall.
• C, Perforation and associated serositis.
• D, Creeping fat.

Question 36

Answer 36

FIGURE 17-35 Microscopic pathology of Crohn disease

• . A, Haphazard crypt organization results from repeated injury and regeneration.
• B, Noncaseating granuloma.
• C, Transmural Crohn disease with submucosal and serosal granulomas (arrows).

Question 37

What are the cinical manifestation of Crohn disease?

Answer 37

The clinical manifestations of Crohn disease are extremely variable.

In most patients disease begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain.

Approximately 20% of patients present acutely with right lower quadrant pain, fever, and bloody
diarrhea that may mimic acute appendicitis or bowel perforation.

Iron-deficiency anemia may develop in individuals with colonic disease, while extensive small bowel disease may result in serum protein loss and hypoalbuminemia, generalized nutrient malabsorption, or malabsorption of vitamin B12 and bile salts.

Fibrosing strictures, particularly
of the terminal ileum, are common and require surgical resection.

Disease often recurs at the
site of anastamosis,and as many as40% of patients require additional resections within 10
years.

Fistulae develop between loops of bowel and may also involve the urinary bladder,
vagina, and abdominal or perianal skin

. Perforations and peritoneal abscesses are common

Periods of active disease are
typically interrupted by asymptomatic periods that last for weeks to many months.

Question 38

Disease reactivation of Crohn disease can be associated with a variety of external triggers such as what?

Answer 38

• including physical or emotional stress,
• specific dietary items, and
• cigarette smoking.

The latter is a strong exogenous risk factor

for development of Crohn disease and, in some cases, disease onset is associated with
initiation of smoking.

Unfortunately, smoking cessation does not result in disease remission

Question 39

What are the extra-intestinal manifestations of Crohn disease?

Answer 39

• uveitis
• migratory polyarthritis,
• sacroiliitis,
• ankylosing spondylitis,
• erythema nodosum, and
• clubbing of the fingertips,

any of which may develop before intestinal disease is recognized.

Pericholangitis and primary
sclerosing cholangitis occur in Crohn disease but are more common in ulcerative colitis (see
Chapter 18 ).

As discussed below, risk of colonic adenocarcinoma is increased in patients with
long-standing colonic disease.

Question 40

What is Ulcerative colitis?

Answer 40

Ulcerative colitis is closely related to Crohn disease.

However, _intestinal disease in ulcerative
colitis is limited to the colon and rectum._

Question 41

Common extra-intestinal manifestations of ulcerative
colitis overlap with those of Crohn disease and include what?

Answer 41

• migratory polyarthritis,
• sacroiliitis,
• ankylosing spondylitis,
• uveitis,
• skin lesions,
• pericholangitis, and
• primary sclerosing cholangitis (Chapter 18 ).

Approximately 2.5% to 7.5% of individuals with ulcerative colitis also have primary
sclerosis cholangitis.

The long-term outlook for ulcerative colitis patients depends on the severity of active disease and disease duration.

Question 42

What is the gross appearance of ulcerative colitis?

Answer 42

Grossly, ulcerative colitis always involves the rectum and extends proximally in a continuous fashion to involve part or all of the colon.

Skip lesions are not seen (although focal appendiceal or cecal inflammation may occasionally be present in ulcerative colitis).

Question 43

What is pancolitis?

Answer 43

In ulcerative colitis disease of the entire colon is termed pancolitis ( Fig. 17-36A ), while left-sided disease
extends no farther than the transverse colon.

Question 44

What is ulcerative proctitis or ulcerative proctosigmoiditis.

Answer 44

Limited distal disease may be referred to
descriptively as ulcerative proctitis or ulcerative proctosigmoiditis.

The small intestine
is normal, although mild mucosal inflammation of the distal ileum, backwash ileitis, may be
present in severe cases of pancolitis.

Question 45

What is the appearance of Ulcerative colitis?

Answer 45

Grossly, involved colonic mucosa may be slightly red and granular or have extensive, broadbased
ulcers,and there can be anabrupt transition between diseased and uninvolved colon
( Fig. 17-36B ).

Ulcers are aligned along the long axis of the colon but do not typically replicate the serpentine ulcers of Crohn disease.

Isolated islands of regenerating mucosa
often bulge into the lumen to create pseudopolyps ( Fig. 17-36C ), and the tips of these
polyps may fuse to create mucosal bridges ( Fig. 17-36D ).

Chronic disease may lead to
mucosal atrophy with a flat and smooth mucosal surface that lacks normal folds. Unlike
Crohn disease, mural thickening is not present, the serosal surface is normal, and
strictures do not occur.

However, inflammation and inflammatory mediators can damage
the muscularis propria and disturb neuromuscular function leading to colonic dilation and
toxic megacolon, which carries a significant risk of perforation.

Question 46

What are the histologic feature of Ulcerative colitis?

Answer 46

Histologic features of mucosal disease in ulcerative colitis are similar to colonic Crohn disease
and include inflammatory infiltrates, crypt abscesses( Fig. 17-37A ),architectural crypt distortion, and epithelial metaplasia ( Fig. 17-37B ).

However, the inflammatory process is
diffuse and generally limited to the mucosaandsuperficial submucosa ( Fig. 17-37C ).

In
severe cases, extensive mucosal destruction may be accompanied by ulcers that extend more
deeply into the submucosa, but the muscularis propria is rarely involved.

Submucosal fibrosis, mucosal atrophy, and distorted mucosal architecture remain as residua of healed disease but
histology may also revert to near normal after prolonged remission.

_Granulomas are not
present in ulcerative colitis._

Question 47

Answer 47

FIGURE 17-36 Gross pathology of ulcerative colitis.

• A, Total colectomy with pancolitis showing active disease, with red, granular mucosa in the cecum (left) and smooth, atrophic mucosa distally (right).
• B, Sharp demarcation between active ulcerative colitis (right) and normal (left).
• C, Inflammatory polyps.
• D, Mucosal bridges

Question 48

Answer 48

• FIGURE 17-37 Microscopic pathology of ulcerative colitis. A, Crypt abscess.
• B, Pseudopyloric metaplasia (bottom).
• C, Disease is limited to the mucosa. Compare to
• Figure 17-35C .

Question 49

What is the clinical feature of ulcerative colitis?

Answer 49

Ulcerative colitis is a relapsing disorder characterized by attacks of bloody diarrhea with stringy, mucoid material, lower abdominal pain, and cramps that are temporarily relieved by defecation.

These symptoms may persist for days, weeks, or months before they subside, and, occasionally, the initial attack may be severe enough to constitute a medical or surgical emergency.

More than half of patients have clinically mild disease, although almost all experience at least one relapse during a 10-year period, and up to 30% require colectomy within the first 3 years after presentation because of uncontrollable symptoms.

Colectomy effectively cures intestinal disease in ulcerative colitis, but extra-intestinal manifestations may persist

Question 50

What are the factors that trigger ulcerative colitis?

Answer 50

The factors that trigger ulcerative colitis are not known, but, as noted above, infectious enteritis
precedes disease onset in some cases.

In other cases the first attack is preceded by
psychologic stress,whichmay also be linked to relapse during remission.

The initial onset of symptoms has also been reported to occur shortly after smoking cessation in some patients, and smoking may partially relieve symptoms.

Unfortunately, studies of nicotine as a therapeutic
agent have been disappointing.

Question 51

What is Intermediate Colitis?

Answer 51

There is extensive pathologic and clinical overlap between ulcerative colitis and Crohn disease
( Table 17-8 ); definitive diagnosis is not possible in approximately 10% of IBD patients.

These cases, termed indeterminate colitis, do not involve the small bowel and have colonic disease in
a continuous pattern that would typically indicate ulcerative colitis.

However, patchy histologic
disease, fissures, a family history of Crohn disease, perianal lesions, onset after initiating use of
cigarettes, or other features that are not typical of ulcerative colitis may prompt more detailed
endoscopic, radiographic, and histologic examination.

Serologic studies can be useful in these
cases, because perinuclear anti-neutrophil cytoplasmic antibodies are positive in 75% of
individuals with ulcerative colitis but only 11% with Crohn disease.

In contrast, ulcerative colitis
patients tend to lack antibodies to Saccharomyces cerevisiae, which areoften present in those
with Crohn disease.

Even after extensive evaluation, IBD in approximately 10% of patients defies classification.

In some of these cases features that develop over time (e.g., strictures or fistulae) ultimately establish the diagnosis; classification remains impossible in other patients.

Because of extensive overlap in medical management of ulcerative colitis and Crohn disease,
patients carrying a diagnosis of indeterminate colitis can be treated effectively.

However, it is
preferable to definitively categorize patients, when possible, as evolving medical therapies and
surgical management differ in ulcerative colitis and Crohn disease.

Question 52

One of the most feared long-term complications of ulcerative colitis and colonic Crohn disease
is the development of what?

Answer 52

neoplasia.

Question 53

One of the most feared long-term complications of ulcerative colitis and colonic Crohn disease
is the development of neoplasia. This begins as dysplasia, which, just as in Barrett esophagus
and chronic gastritis, represents in situ transformation. The risk of dysplasia is related to
several factors:

Answer 53

• Risk increases sharply 8 to 10 years after disease initiation.
• • Patients with pancolitis are at greater risk than those with only left-sided disease.
• • Greater frequency and severity of active inflammation (characterized by the presence of neutrophils) may increase risk.

Question 54

What promotes dysplasia in Colitis-Associated Neoplasia?

Answer 54

The role of inflammation in promoting dysplasia is emphasized by the observation that anti-TNF
antibody treatment can suppress the development of colitis-associated cancers in experimental
animals

Question 55

To facilitate early detection of neoplasia, patients are typically enrolled in surveillance programs
approximately 8 years after diagnosis of IBD.

What is the major exceptio to this?

Answer 55

The major exception to this is patients with _primary
sclerosing cholangitis_, who have an evengreater risk of dysplasia and are generally enrolled
for surveillance at the time of diagnosis.

Surveillance requires regular and extensive mucosal
biopsy, making it a costly practice.

Research efforts have therefore included a search for
molecular markers of dysplasia in nondysplastic mucosa.

Genomic instability in rectal mucosa
has the potential to be such a marker, but biopsy surveillance remains the best tool currently
available.

Question 56

In many cases dysplasia occurs in flat areas of mucosa that are not grossly recognized as abnormal.

Thus, advanced endoscopic imaging techniques including chromoendoscopy and
confocal endoscopy are beginning to be used experimentally to increase sensitivity of
detection.

IBD-associated dysplasia is classified histologically as low grade or high grade ( Fig.
17-38A , B) and may be multifocal.

High-grade dysplasia may be associated with invasive
carcinoma at the same site ( Fig. 17-38C ) or elsewhere in the colon and, therefore typically prompts colectomy.

Low-grade dysplasia may be treated with colectomy or followed closely,
depending on a variety of factors including patient age and the number of dysplastic foci
present.

Colonic adenomas (discussed below) also occur in IBD patients, and in some cases
these may be difficult to differentiate from a polypoid focus of IBD-associated dysplasia.

Question 57

Answer 57

FIGURE 17-38 Colitis-associated dysplasia.

• A, Dysplasia with extensive nuclear stratification and marked nuclear hyperchromasia.
• B, Cribriform glandular arrangement in high-grade dysplasia.
• C, Colectomy specimen with high-grade dysplasia on the surface and underlying invasive adenocarcinoma. A large cystic, neutrophil-filled space lined by invasive adenocarcinoma is apparent at the bottom right (arrow) beneath the muscularis mucosa, and is surrounded by small invasive glands (arrowhead).