Transcript Document 7193188

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Two chronic inflammatory disorders of
unknown etiology are Crohn’s disease (CD) and
ulcerative colitis (UC).
CD is a granulomatous disease that may affect
any portion of the gastrointestinal tract from
mouth to anus but most often involves the small
intestine and colon.
UC is a nongranulomatous disease limited to
colonic involvement.
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Crohn disease and ulcerative colitis differ in
many respects, including the natural history of
the disease, pathological aspects, and in the
types of therapies and responses to treatment.
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The normal intestine is in a steady state of
"physiologic" inflammation, representing a
dynamic balance between :
(1) factors that activate the host immune system,
such as luminal microbes, dietary antigens, and
endogenous inflammatory stimuli
 (2) host defenses that down-regulate inflammation
and maintain the integrity of the mucosa.
The search for the causes of loss of this balance in
Crohn disease and ulcerative colitis has revealed
many parallels, but the origins of both diseases remain
unexplained (thus their designation as idiopathic).
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The pathogenesis of IBD involves genetic
susceptibility, failure of immune regulation,
and triggering by microbial flora
1] Genetic predisposition.
- Familial aggregations in IBD.
- First-degree relatives are 3 to 20 times more likely to
develop the disease, and 15% of persons with IBD have
affected first-degree relatives
- CD-HLA--DR7 and DQ4 alleles are associated with
approximately 30% of Crohn disease cases in North American
white males
- UC – HLA-DRB1
- IBD 1 locus on chromosome 16, NOD 2 gene (NFkB)
- A gene in CD and UC is a mutant form of the IL-23 receptor
(IL-23R) gene. IL-23 is a cytokine that promotes the
production of IL-17 by T cells, and IL-17 has been implicated
in inflammatory reactions in IBD
2] Infectious causes.
- Mycobacterium paratuberculosis and measles virus.
3] Abnormal host immunoreactivity:
- Stimulated immune system.
- In IBD: cytokine IL-17 a recently discovered subset of
CD4+ T cells that is being called the "TH17" subset is
secreted
- cytokine TNF may play an important pathogenic role
in Crohn disease
- Induction of cytotoxic antiepithelial AB or natural
killer cells
- ANCA are present in about 75% of persons with
ulcerative colitis and only 11% of individuals with
Crohn disease. .
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To summarize, IBD is a heterogeneous group
of diseases characterized by an exaggerated
and destructive mucosal immune response.
The tissue injury in IBD is likely to be initiated
by diverse genetic and immunologic pathways
that are modified by environmental influences,
including microbes and their products
Inflammation is the final common pathway for
the pathogenesis of IBD.
Idiopathic inflammatory bowel disease
Etiology and Pathogenesis
The normal intestine is in a steady state of physiologic
Inflammation, representing a dynamic balance
Factors that activate the
host immune system
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Luminal microbes
Dietary antigens
Endogenous inflammatory
stimuli
Host defenses that downregulate inflammation and
maintain the integrity of the
mucosa
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Crohn’s disease is a chronic inflammatory disorder that
most commonly affects the ileum and colon but has the
potential to involve any part of the gastrointestinal tract
from the mouth to the anus.
Crohn disease must be viewed as a systemic inflammatory
disease
Active cases of the disease are often accompanied by
extra-intestinal complications of immune origin, such as
uveitis, sacroiliitis, migratory polyarthritis, erythema
nodosum, bile duct inflammatory disorders, and
obstructive uropathy with attendant nephrolithiasis.
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CD is characterized by:
a. Skip areas – regional entities.
b. Non-caseating epitheliod cell granulomas.
c. Transmural (full-thickness) inflammation of
affected parts.
d. Fissuring and fistula formation.
e. Systemic manifestations
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Worldwide in distribution, Crohn disease is much
more prevalent in the United States, Great Britain, and
Scandinavia than in Central Europe, and is rare in Asia
and Africa.
It occurs at any age, from young childhood to
advanced age, but the peak incidence is between the
second and third decades of life, with a minor peak in
the sixth and seventh decades.
Females are affected slightly more often than males.
Whites appear to develop the disease two to five times
more often than do nonwhites.
In the United States, Crohn disease occurs three to five
times more often among Jews than among non-Jews.
Pathology
 Combine ileal and colonic disease (30%). The ileum alone
in 40% and the colon in 30%.
 Perianal lesions such as abscesses, fistulas and skin tags –
75%.
 Segmental with skip areas.
 Acute phases: swollen and reddened with ulceration.
 Chronic phase: thickened and rigid (lead pipe or garden
hose appearance).
 Mesenteric fat creeps from the mesentery to the bowel
wall (creeping fat).
 The mucosal surface: longitudinal serpiginous ulcers
(cobblestone effect).
 Fissures and fistulas.
Crohn’s Disease
Microscopic features
 Distortion of mucosal crypt architecture.
 Transmural inflammation.
 Presence of epitheliod granulomas.
 Fissure-ulcers.
 Fibrosis.
 The regional mesenteric
lymph nodes are enlarged
and may contain
non-caseating granulomas.
Crohn’s Disease
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is highly variable and unpredictable.
The dominant manifestations are recurrent
episodes of diarrhea, crampy abdominal pain, and
fever lasting days to weeks.
These manifestations usually begin insidiously but
may be acute
melena is present in about 50% of cases with
colon involvement
In most patients, after an initial attack, the
manifestations remit either spontaneously or with
therapy, but characteristically they are followed by
relapses, and intervals between successive attacks
grow shorter.
malabsorption
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(2)
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fistula formation to other loops of bowel, the
urinary bladder, vagina, or perianal skin
abdominal abscesses or peritonitis
intestinal stricture
Bleeding
toxic dilation of the colon
carcinoma of the colon or small intestine
Ulcerative colitis is an inflammatory disease of colon
of uncertain cause.
 Limited to the mucosa and submucosa
 begins in the rectum and extends proximally in a
continuous fashion, sometimes involving the entire colon
 UC is a systemic disorder associated in some persons
with migratory polyarthritis, sacroiliitis, ankylosing
spondylitis, uveitis, erythema nodosum, and hepatic
involvement (pericholangitis and primary sclerosing
cholangitis
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In USA, incidence = 4-12/100,000.
the incidence of this condition has risen in recent
decades
Age: 20-25 years, any age.
Slightly higher in females than in males.
Whites are more often affected than blacks.
Jews more often than non-Jews.
Prevalent in North America and Western Europe and
less prevalent in Asia, Africa and South America.
about 20% of persons with the disorder have affected
relatives
Individuals with ulcerative colitis and ankylosing
spondylitis have an increased frequency of the HLA-B27
allele
Pathology
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UC is a disease of the rectum.
The disease extends proximally from the rectum in a
continuous manner without skip areas.
The appendix is involved in about 30% of cases.
UC involves mainly the mucosa.
The mucosal surface shows diffuse hyperemia with
numerous superficial ulcerations in the acute phase.
Chronic: mucosa flat, atrophic, inflammatory
pseudopolyp.
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Well-formed granulomas are absent.
There are no skip lesions.
The mucosal ulcers rarely extend below the
submucosa, and there is surprisingly little
fibrosis.
Mural thickening does not occur, and the
serosal surface is usually completely normal.
There appears to be a high risk of carcinoma
development.
Microscopic appearance
Acute phase:
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Mucous marked inflammation with neutrophils,
lymphocytes, and plasma cells.
Crypt abscesses and active cryptitis.
Chronic phase:
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Crypt atrophy, distorted architecture and chronic
inflammatory cells in the lamina propria.
Active inflammation correlates well with the severity of
symptoms.
The inflammation is usually restricted to the mucosa.
Dysplasia and high grade adenocarcinoma.
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UC is chronic relapsing and remitting disorder
Attacks of bloody mucoid diarrhea
Abdominal cramps and colicky pain relieved by
defecation
Extra-intestinal manifestations particularly
migratory polyarthritis.
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Sever diarrhea
Rupture
Massive hemorrhage
perforation
Toxic megacolon
colon carcinoma: Two factors govern the
risk:
duration of the disease, at 20 years the risk is on
the order of 2%.
2. With pancolitis, the risk of carcinoma is 10% at 20
years and 15% to 25% by 30 years.
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Toxic megacolon