C h a p t e r 2 9
Disorders of Gastrointestinal Function
707
duct (i.e., sclerosing cholangitis). Occasionally, these
systemic manifestations may herald the recurrence of
intestinal disease. In children, growth retardation may
occur, particularly if the symptoms are prolonged and
nutrient intake has been poor.
Etiology and Pathogenesis
The causes of Crohn disease and ulcerative colitis are
largely uncertain. There is growing evidence that the two
diseases result from a combination of intestinal microor-
ganisms, intestinal epithelial dysfunction, and aberrant
immune responses in a genetically predisposed host.
6
The genetic basis for IBD has long been suspected.
The risk of disease is greater when there is an affected
family member, with a family history of IBD being more
common in Crohn disease than ulcerative colitis.
6,7,27
Molecular linkage analyses of affected families have
identified NOD2 (nucleotide oligomerization domain 2)
as a susceptibility gene in Crohn disease.
6,27,29
The NOD2
gene encodes a protein that is an intracellular recep-
tor for a component of the cell wall of many microbes
and is thought to play a role in host responses to these
pathogens. It has been postulated that disease-associated
NOD2 is less effective in recognizing and eliminating
luminal microbes.
6,27,28
The fact that fewer than 10%
of individuals carrying the NOD2 mutations develop
Crohn disease suggests that it is only one of many fac-
tors that contribute to the pathogenesis of the disease.
The intestinal microbiome consists of the microorgan-
isms that inhabit the gut.
6,27
These organisms play a key
role in development of the intestinal immune system and
supplying the body with key nutrients such as vitamin
B
12
. Although acquired shortly after birth, each person’s
microbiome changes rapidly during the first year of life.
Moreover, although each adult has a unique popula-
tion of microbiota that remains fairly stable over time,
changes occur in response to environmental and develop-
mental factors, and disease. Despite the growing evidence
that intestinal microorganisms contribute to IBD patho-
genesis, their precise role remains to be described and is
probably different in Crohn disease and ulcerative colitis.
A variety of epithelial defects have been described in
both Crohn disease and ulcerative colitis.
6,27
The intes-
tinal epithelium at the interface between the intestinal
microbiome and the wall of the gastrointestinal tract
plays a critical role in preventing the entry of bacteria
and shaping the mucosal immune response. An intact
mucosal barrier depends on tight epithelial cell junc-
tions that help to seal the space between the intesti-
nal contents and the underlying tissues of the intestinal
wall. Additional defenses against bacterial invasion con-
sist of specialized epithelial cells, including the goblet
cells, which regulate production of mucus and factors
that contribute to epithelial repair and regulation of
inflammation, and the Paneth cells, which secrete anti-
microbial peptides (see Chapter 28, Fig. 28-11).
A variety of other factors are associated with IBD for
unknown reasons.
6,7
For example, an episode of appen-
dicitis is associated with a decreased risk of developing
ulcerative colitis. Also, smoking tobacco has opposite
effects on the two forms of inflammatory bowel disease.
It predisposes to development of Crohn disease, yet is
associated with a reduced incidence of ulcerative colitis.
Crohn Disease
Crohn disease is a recurrent, granulomatous type of
inflammatory response that can affect any area of the
gastrointestinal tract. In half the cases, the disease affects
mainly the ileum and cecum, only the small intestine in
15%, only the colon in 20%, and mainly the anorec-
tal region in 15%.
7
It is a slowly progressive, relentless,
and often disabling disease. The disease usually strikes
people in their twenties or thirties, with women being
affected slightly more often than men.
Clinical Manifestations.
A characteristic feature of
Crohn disease is the sharply demarcated, granuloma-
tous lesions that are surrounded by normal-appearing
mucosal tissue. When the lesions are multiple, they often
are referred to as
skip lesions
because they are inter-
spersed between what appear to be normal segments of
the bowel. All the layers of the bowel are involved, with
the submucosal layer affected to the greatest extent. The
surface of the inflamed bowel usually has a character-
istic “cobblestone” appearance resulting from the fis-
sures and crevices that develop, surrounded by areas of
submucosal edema
6,7
(Fig. 29-6). There usually is a rela-
tive sparing of the smooth muscle layers of the bowel,
with marked inflammatory and fibrotic changes of the
submucosal layer. After a time, the bowel wall often
becomes thickened and inflexible; its appearance has
TABLE 29-1
Differentiating Characteristics of Crohn Disease and Ulcerative Colitis
Characteristic
Crohn Disease
Ulcerative Colitis
Types of inflammation
Granulomatous
Ulcerative and exudative
Level of involvement
Primarily submucosal
Primarily mucosal
Extent of involvement
Skip lesions
Continuous
Areas of involvement
Primarily ileum, secondarily colon
Primarily rectum and left colon
Diarrhea
Common
Common
Rectal bleeding
Rare
Common
Fistulas
Common
Rare
Strictures
Common
Rare
Perianal abscesses
Common
Rare
Development of cancer
Uncommon
Relatively common
