Transcript Inflammatory Bowel Disease

Inflammatory Bowel
Disease
Dr. Mohammad Shaikhani
CABM, FRCP
Pretest 1:
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What % of IBD is regarded to be intederminate:
A.90%
B. 70%
C.10%.
D.25%.
E.0%.
Pretest 2:
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Appendisectomy in crease the risk of:
A.UC
B. CD
C. Both.
D. Neither.
Pretest 3:
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Smoking:
A. Increase the risk of UC.
B. Protect against UC.
C. Protect against CD.
D. ALL.
E. None..
Pretest 4:
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Proctitis in UC leads to:
A. Constipation > diarrhea.
B. Diarrhea> constipation.
C. Both.
D. Neither.
Pretest 5:
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CD can cause the following except:
A. GOO.
B. Mouth ulcer.
C. Perianal fistulas.
D. diverticuli.
E. RIF mass
Pretest 6:
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CD can cause the following except:
A. GOO.
B. Mouth ulcer.
C. Perianal fistulas.
D. diverticuli.
E. RIF mass
Pretest 7:
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Granulomas, characteristic of CD, occur in:
A. Nearly all.
B. Nearly none.
C. Around 1/3.
D. Most of them.
E. None of the above.
Pretest 8:
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Primary sclerosing cholangitis:
A. Occurs in CD > UC.
B. Occurs in most patients with UC.
C. Most patients with PSC have UC.
D. All of the above.
E. None of the above.
Pretest 9:
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IBD with Primary sclerosing cholangitis have
increases risk of:
A. CRC.
B. Cholangiocarcinoma.
C. Both.
D. Neither.
Pretest 10:
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The most serious acute complications of IBD is:
A. Pyoderma gangrenosa.
B. Toxic megacolon.
C. PSC.
D. EN.
E. Peripheral arthritis.
Introduction
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IBD: an idiopathic chronic inflammatory disease of the GIT
consistsing of 2 distinct clinical entities: ulcerative colitis & Crohn
disease (regional enteritis),both cause macroscopic inflammation.
Microscopic colitis is less common& does not cause significant
macroscopic abnormalities.
The pathogenesis not fully understood but likely involves a genetic
predisposition& a dysregulated immunologic response to the local
microenvironment of luminal bacteria.
Both are usually differentiated on the basis of differences in the
distribution of pathology in the bowel & histopathologic
appearance of the lesion.
10% of patients cannot be shown to have either Crohn disease or
ulcerative colitis ( indeterminate colitis).
Risk factors:
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The peak incidence :second, third& fourth decades of life
A second peak in the seventh&eighth decades.
There are no sex differences.
Ashkenazi Jewish descent have a higher risk.
A 5-10% risk for first-degree relatives of affected patients.
Many candidate genes:
1.Established link between Crohn disease &variants of the
CARD15 (also known as NOD2) gene, in only some patients &
does not affect the risk for colitis.
2. IL-23 receptor affects the risk for both Crohn disease & colitis.,
as monoclonal antibody against the p40 subunit have
demonstrated benefit in the treatment of Crohn disease.
Less common colitis forms are:
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Microscopic colitis (collagenous& lynphocytic)
Others
Diversion colitis after clostomies.
 Radiation colitis
 Drug induced colitis
 Infectious colitis
 Ischemic colitis
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Clinical features: UC
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Generally present with bloody diarrhea with rectal urgency,
discomfort& cramps.
They have profound tenesmus (feelings of urgency& incomplete
evacuation), secondary to proctitis, this can cause constipation to
be a more common manifestation than diarrhea; in such patients,
determining the activity of the disease& treating it can be
challenging.
UC extends proximally from the anal verge&can progress to
pancolitis involving the cecum.
Fever is infrequent, but weight loss secondary to the
inflammatory disease itself or to the chronic diarrhea is common.
Physical examination findings can range from mild lower
abdominal tenderness to abdominal distention with rebound
tenderness& hypoactive bowel sounds, suggestive of toxic
megacolon.
Clinical features: Crohn disease
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More protean in its manifestations than ulcerative colitis, as the
disease can affect any portion of the GIT& frequently has socalled “skip lesions” with areas of normal mucosa juxtaposed with
severe inflammation.
The transmural nature of the disease results in three distinct
manifestations: inflammatory, fistulizing& fibrostenotic.
Large-volume diarrhea can occur; diarrhea is associated with
both small& large-bowel Crohn disease, whereas hematochezia is
almost always a sign of colonic disease.
The inflamed tissue causes a secretory diarrhea& a protein-losing
enteropathy, steatorrhea from fat malabsorption (with patients
who have ileal or ilealocolic disease frequently being vitamin B12& vitamin D-deficient)& other types of malabsorption.
Patients who have had their terminal ileum resected are also at
risk for a choleretic diarrhea secondary to bile salt wasting.
Clinical features: Crohn disease
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Fistulae are abnormal connections between the bowel&
adjacent organs.
Abscesses may form& the fistula acts as a natural drainage
mechanism, causing pus to emerge from the fistulae.
The fistulae become symptomatic with drainage of fecal
material around the anus (perianal fistulae), seepage of
bowel contents through the skin (enterocutaneous fistulae),
passage of feces through the vagina (rectovaginal
fistulae)& pneumaturia or recurrent urinary tract
infections (enterovesical fistulae).
The intestinal inflammation may extend to adjacent
musculature &result in neuromuscular sequelae; for
example, a patient with Crohn disease&a new limp likely
has a psoas muscle abscess.
Clinical features: Crohn disease
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Patients with intestinal strictures present with signs of
obstruction: fever, abdominal distention, pain, nausea, vomiting.
Strictures may be secondary to severe inflammation or to fibrosis
of the bowel& can be relieved only by surgical resection.
The most common site of strictures is in the terminal ileum where
they result in partial or complete small-bowel obstruction.
Patients with duodenal Crohn disease may develop gastric outlet
obstruction.
In patients with ileal disease, the abdominal examination
commonly shows right lower quadrant tenderness; a
phlegmonous mass may be present.
A detailed anorectal examination is important in patients with
suspected Crohn disease: the presence of skin tags suggests the
diagnosis& the examination may also show fistulae.
Environmental Precipitants
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Factors:
Early appendectomy (increase UC incidence)
 Smoking (protects against UC but increases the
risk of CD).
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UC
Distinguishing characteristics of CD and UC
Feature
Location
CD
SB or colon
Rectal spare
UC
Only colon (rarely
“backwash ileitis”
Continuous,
begins distally
Involved in >90%
Anatomic
distribution
Rectal
involvement
Gross bleeding
Peri-anal disease
Fistulization
Granulomas
Skip lesions
Only 25%
75%
Yes
10-30%
Universal
Rare
No
No
Endoscopic features of CD and UC
Feature
Mucosal
involvement
Aphthous ulcers
CD
Discontinuous
UC
Continuous
Common
Rare
Surrounding
mucosa
Longitudinal ulcer
Cobble stoning
Mucosal friability
Vascular pattern
Relatively
normal
Common
In severe cases
Uncommon
Normal
Abnormal
Rare
No
Common
distorted
Pathologic features of CD and UC
Feature
Transmural inflammation
CD
Yes
UC
Uncommon
Granulomas
50-75%
No
Fissures
Fibrosis
Submucosal inflammation
Common
Common
Common
Rare
No
Uncommon
Radiologic features of CD and UC
Feature
CD
UC
Nodularity
granularity
cobble stoning
string sign of SB
Collar button
ulcers
Comparison of Features in Ulcerative Colitis and Crohn's Disease
Feature
Ulcerative Colitis
Crohn's Disease
Depth of inflammation
Mucosal
Transmural
Pattern of disease
Contiguous
Skip areas
Location
Colorectum
Mouth to anus
Rectal involvement
Usual
Less common
Ileal disease
Backwash ileitis (15%–
20% of patients)
Common
Fistulas
Rare
Common
Perianal disease
Rare
Common
Granulomas
Unlikely
%30–%10of patients
Overt bleeding
Usual
Less common
Malnutrition
Unlikely
More common
Cancer risk
Colorectal cancer,
cholangiocarcinoma (if
primary sclerosing
cholangitis is present)
Colorectal cancer, small
bowel cancer (depending
on disease location)
Tobacco use
Protective
Harmful
UC
CD
DDX of UC
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Infectious
Drug induced
Microscopic colitis
CD
Anatomic
distribution
 CD activity index
 DDx (lymphoma,
Yersinea
Enterocolitis, TB)
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CD ilitis: DDx
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Lymphoma
 Yersinea
 TB
Enterocolitis
Extra-intestinal manifestations of IBD
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Arthritis:
Peripheral arthritis, usu paralels the disease activity
 Ankylosing Spondylitis, 1-6%, sacroiliitis
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Ocular lesions:
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Iritis (uvietis) (0.5-3%), episcleritis, keratitis,
Skin and oral cavity:
Erythema nodosum 1-3%
 Pyoderma Gangrenosum 0.6%
 Aphthus stomatitis, metastatic CD.
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Extra-intestinal manifestations of IBD
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Occur in 10-20% at some time in the course of their disease.
Arthritis, the most common, can either be related to the intestinal
inflammation itself or be part of an overlap syndrome with
rheumatoid arthritis.
Sacroiliitis &ankylosing spondylitis, in association with HLA
B27, occur in 5-10%.
Uveitis & episcleritis may also occur.
Erythema nodosum, which manifests as small exquisitely tender
nodules on the anterior tibial surface, occurs more commonly in
Crohn disease, whereas pyoderma gangrenosum is more common
in ulcerative colitis& can range from small lesions to large ulcers.
Even small amounts of trauma to the skin can activate this
inflammatory process.
Extra-intestinal manifestations of IBD
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Primary sclerosing cholangitis: occurs in 5% of patients with UC
& may occur in Crohn disease as well.
Up to 80% of patients with PSC have underlying IBD.
May present with only an isolated elevation in SAP or with
jaundice, biliary obstruction, & evidence of portal hypertension.
These patients may have recurrent episodes of cholangitis as well
as a malignant transformation to cholangiocarcinoma& a much
higher than normal incidence of colorectal cancer.
Therapy with ursodeoxycholic acid has been shown to be
chemoprotective against colon cancer.
Extra-intestinal manifestations of IBD
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Increased risk for CRC; the risk is associated with the age of
onset; duration, extent, severity of disease& whether the patient
has a family history of CRC.
Annual CRC rate in extensive colitis is at least 0.5% /year after
the first decade of colitis.
Screening recommendations include colonoscopy every 1 to 2
years beginning 8 years after diagnosis.
Unlike sporadic colorectal cancer that develops primarily from
colon polyps, inflammatory bowel disease-associated colon cancer
can arise from flat dysplastic mucosa which is not readily
detectable from underlying inflammatory tissue.
Extra-intestinal manifestations of IBD
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50% with IBD have osteopenia, with a substantially increased risk
of osteoporosis & fracture.
The risk is present in patients with ulcerative colitis / Crohn
disease, in both sexes&in patients who are taking corticosteroids
& those who have never taken them.
Patients with prolonged IBD, malabsorption, a history of using
corticosteroids for >3 months, cigarette smoking, older age,
history of fractures, or a family history of osteoporosis should be
evaluated for the presence of metabolic bone disease.
Kidney stones / gallstones are other extraintestinal manifestations
of inflammatory bowel disease.
Complications of IBD
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Bleeding
Stricture
Fistula
Toxic megacolon
Cancer: Patients with either UC or CD have an increased risk of
intestinal dysplasia & CRC that is related to the duration,
extent& severity of the inflammation,so those with
extensive/longstanding disease should undergo regular
colonoscopic examinations with mucosal biopsies to detect these
complications.
Complications of IBD
Dignosis/assessing severity & extent:
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Should be considered in any young patient with chronic
diarrhea or hematochezia.
Infection should be excluded by stool culture for ova/
parasites, Giardia& Clostridium difficile.
Laboratory findings suggestive of IBD include anemia,
hypoalbuminemia, leukocytosis, vitamin deficiencies (more
likely in small-intestinal Crohn disease than ulcerative
colitis).
Dignosis/assessing severity & extent:
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2/3 with ulcerative colitis, but only 15- 20% with Crohn disease
&< 5% of persons without IBD have p-ANCA, a serum antibody
directed against a particular histone H1 antigen& detectable by
immunofluorescence or specific enzyme immunoassay.
Approximately 50% with Crohn disease have anti-Saccharomyces
cerevisiae antibodies (ASCA), as opposed to < 5% of patients with
ulcerative colitis &control subjects.
So measuring both serum p-ANCA & ASCA is reasonably
reliable for the diagnosis of Crohn disease or ulcerative colitis.
Newer antibody tests, directed against the outer membrane porin
of Escherichia coli (Omp-C)& against the flagellum of pathogenic
polyflagellated organisms (Cbir1), are also predictive of classic
Crohn disease,but not differentiating atypical presentations or
diagnosing indeterminate colitis.
Dignosis/assessing severity & extent:
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50% with ulcerative colitis have proctosigmoiditis only
15-20% have left-sided disease.
1/3 present with pancolitis.
Patients with proctitis generally have a benign course, but
11% develop more extensive disease by 5 years&19% by
10 years.
Endoscopic findings range from a decreased vascular
pattern& minimal friability in patients with mild disease to
spontaneous bleeding&deep ulcerations in severe disease.
Histopathology typically consists of crypt abscesses with
branching&architecture distortion& acute/ chronic
inflammation.
Dignosis/assessing severity & extent:
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Crohn disease has a different pattern of distribution than
ulcerative colitis
30% having isolated small-bowel disease
25% colonic disease
40% ileocolonic disease.
A few patients have upper GIT or isolated perianal
disease in the absence of colonic inflammation.
The mildest endoscopic lesions are aphthous ulcers, which
can, however, coalesce to form deep
ulcerations&cobblestone appearance.
Affected areas are commonly separated by normal mucosa,
the so-called “skip lesions” that are the hallmark of Crohn
disease.
Granulomas are almost pathognomonic of Crohn disease
but are rarely seen on endoscopic mucosal biopsies.
Dignosis/assessing severity & extent:
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Radiographic studies establish the location, extent&
severity of inflammatory bowel disease.
The plain abd radiograph can show a dilated colon&
small-bowel obstruction.
A barium-contrast small-bowel series or enteroclysis
provides information about location& amount of
inflammatory or stricturing small-bowel disease.
Separation of loops of bowel, thumbprinting,spiculation
(formation of needle-like projections) are all indicators of
jejunoileitis.
CT enterography is the most comprehensive study,
highlights the areas of bowel inflammation,stricture,
abscesses, fistulae& mesenteritis.
Dignosis/assessing severity & extent:
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Video capsule endoscopy provides the most direct evidence
of small bowel ulcerations & approved in the diagnosis of
Crohn disease.
It is highly sensitive& can lead to a false-positive diagnosis
because 15% of normal volunteers may have ulcerations in
the small bowel.
In a patient with possible obstruction, a patency capsule,
which is a capsule system designed to determine smallbowel patency before video capsule endoscopy, should be
ingested by the patient.
Treatment :outline
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Treatment of inflammatory bowel disease
involves drug therapy and in certain cases
surgery
Treatment :
Medication
5-ASA (sulfasalazine, olsalazine,
balsalazide, mesalamine:
oral, rectal
Indication
Side Effects
UC: induction/maintenance
CD (weak): induction/maintenance
Inters nephritis (rare
Diarrhea (olsalazine)
Treatment :
Medication
Antibiotics: Metronidazole, Ciprofloxacin
Indication
Side Effects
CD: perianal/ colonic disease
Metronidazole:PN
, metallic taste, antabuse effect
Ciprofloxacin: arthropathy, seizure)
Treatment :
Medication
Indication
Side Effects
CS (oral, IV, rectal)
UC/CD: induction, not maintenance
Acne, moon facies, truncal obesity, osteoporosis, osteonecrosis, DM, hypertension, cataracts, inf
Budesonide
CD (ileal/R colon): induction
Minimal CS effects
Treatment :
Medication
Indication
Side Effects
Methotrexate
CD: induction/maintenance
Bone marrow suppression, hepatotoxicity, pulmonitis
6-MP, Azathioprine
UC/CD: steroid withdrawal, maintenance
Pancreatitis, fever, infection, leukopenia, hepatotoxicity, lymphoma
Anti–TNF-α: Infliximab
UC/CD: induction/maintenance
Infusion reaction, tuberculosis reactivation, demyelination, infection,HF,Lymphoma.
Adalimumab UC/CD: induction/maintenance
Cyclosporine
Hypertension, nephro &neurotoxicity
UC: steroid refractory
Treatment :Crohn Disease
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5-Aminosalicylates
MOA: anti-inflammatory effects secondary to inhibition of
arachidonic acid in the bowel mucosa by cyclooxygenase.
5 oral formulations developed from sulphaslazine.
2 mesalamines are released in the small bowel in a pH- timedependent manner used to treat both CD &ulcerative colitis.
Mesalamine is available in suppository & enema formulations,
which are effective alone in patients who have inflammation
limited to the rectosigmoid & may also be used in combination
with an oral 5-ASA.
Treatment :Crohn Disease
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Because Crohn disease is a transmural disease, the 5-ASA agents
have not proved to be as efficacious as they are in ulcerative colitis
but are often used in the treatment of mild disease.
Delayed-release mesalamine is commonly used for SB disease.
Other preparations of mesalamine are released in the distal
ileum& therefore may have a role in treating ileal disease.
The azo-bonded 5-ASAs, such as balsalazide, olsalazine, and
sulfasalazine have a potential effect only in Crohn colitis.
Treatment :Crohn Disease
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CSs:
Ileal-release preparations of budesonide are indicated for the
treatment of patients with mild ileal & right-sided colonic Crohn
disease.
Budesonide is a topically active corticosteroid with a very high
affinity for the glucocorticoid receptor (*15 that of prednisolone
*195 that of hydrocortisone).
Only 10-15% of the drug reaches the systemic circulation; the rest
is converted in the liver to inactive metabolites.
Conventional corticosteroids are effective in the short-term
induction of remission in patients with Crohn disease but are
generally used in patients with moderate disease at any location or
in patients with ileal disease who have failed to respond to the 5ASAs or budesonide.
Because of the toxic effects of long-term corticosteroid therapy
(for example, osteoporosis, avascular necrosis, psychosis), it is
important to devise a strategy for tapering the dosage&
discontinuing corticosteroid therapy before the therapy is started.
Treatment :Crohn Disease
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Immunomodulator:Azathioprine/ 6-mercaptopurine
Their onset of full activity is slow, may take up to 3 months.
These drugs are effective for the maintenance of remission in
patients with Crohn disease regardless of disease distribution.
Adverse side effects include leukopenia, hepatotoxicity.
Before being treated with these agents, patients should be tested
for thiopurine methyltransferase, the enzyme involved in the
conversion of 6-mercaptopurine to inactive metabolites; patients
who have low enzyme activity (or who are homozygous deficient
in thiopurine methyltransferase) should not be treated with these
agents.
Methotrexate is an immunomodulator induce / maintain
remission in Crohn disease but not in ulcerative colitis.
There is a risk for hepatotoxicity& patients with persistently
elevated liver tests may need to undergo liver biopsy.
Methotrexate is both a teratogen&abortifacient contraindicated
in pregnant patients & breastfeeding.
Treatment :Crohn Disease
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Biologicals:
(TNF-α) is a potent proinflammatory cytokine involved in the
pathogenesis of both IBDs.
Infliximab / adalimumab are monoclonal antibodies against TNFα: infliximab a chimeric antibody givenIV; adalimumab /
certolizumab are humanized antibodies given subcutaneously.
These medications can reduce & close fistulae&induce remission
in inflammatory Crohn disease within 4 to 8 weeks.
? earlier use of potent biologic therapies to induce remission
quickly while sparing the effects of systemic corticosteroid
therapy.
All three anti-TNF-α agents are contraindicated in patients with
active tuberculosis, tuberculin skin test / chest radiograph are
required before the initiation of therapy.
Patients with latent tuberculosis require isoniazid prophylaxis
because the disease can reactivate.
Treatment can lead to the reactivation of viral hepatitis , results in
other infections& possibly lymphomam,specially concomitant use
of infliximab /6-mercaptopurine.
Treatment :Crohn Disease
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Biologicals:
In fibrostenotic stricturing disease leading to bowel obstruction,
there is generally no viable medical therapy.
Limited small-bowel or ileocolic resection or bowel-sparing smallbowel stricturoplasties are the only therapy in this setting.
Recurrence of disease at the sites of previous surgery is common,
and therefore surgery is not a preferred strategy for
inflammatory disease.
3 months of metronidazole reduce severe recurrences 12 months
after surgery.
6-mercaptopurine& likely azathioprine is modestly effective for
decreasing both endoscopic&clinical postoperative recurrences in
patients with Crohn disease.
Treatment :UC
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The choice depends on both severity& extent of disease.
The 5-ASAs, which are not widely effective in Crohn disease, have
well-documented efficacy& remain the mainstay of both induction
& maintenance therapy in mild to moderate ulcerative colitis.
The 5-ASAs are the only medications shown to be effective as
chemoprophylaxis for colorectal cancer in patients with ulcerative
colitis.
Treatment :UC
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CSs:
In patients not responsive to the 5-ASAs or in those with more
severe disease, corticosteroids may induce remission.
In hospitalized patients IV therapy is usually administered,
whereas in the outpatient setting oral & rectal corticosteroids are
used.
No dose effect above the equivalent of prednisone 60 mg/d has
been found.
Corticosteroid therapy does not maintain remission & is
appropriate only as short-term therapy.
Although some patients may be put back successfully to 5-ASA as
maintenance therapy after corticosteroid induction therapy, often
an immunomodulator such as 6-mercaptopurine or its prodrug
azathioprine is warranted; these agents are corticosteroid-sparing
& maintain remission.
Treatment :UC
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Inflixi/cyclospoine:
If corticosteroid therapy does not induce remission, patients may
be treated with either infliximab or cyclosporine; in hospitalized
patients, these medications are considered after a 7- to 10-day
trial of corticosteroids.
Cyclosporine requires close monitoring for hypertension,
neurologic& renal toxicity, infliximab may be favored despite its
increased risk for opportunistic infection & possibly malignancy.
Treatment :UC
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Surgery:
Medically refractory UC is treated surgically with curative total
proctocolectomy with either end-ileostomy or ileal pouch-anal
anastomosis, in which a neorectum is constructed from a segment
of ileum and connected to the anus to retain continence.
Total proctocolectomy may also be warranted in patients with
neoplasia, toxic megacolon, perforation, and refractory bleeding.
Infliximab - mucosal healing
Baseline
Week 10
Week 54
Rutgeerts et al.
DDW 2002: [abstract] W1367.
Microscopic colitis
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Microscopic colitis is another type of IBD and may be classified as
lymphocytic colitis or collagenous colitis.
The incidence of microscopic colitis parallels that of ulcerative
colitis, more common in northern industrialized countries.
The disorder occurs disproportionately in middle-aged women,
with a peak incidence at age 65 years.
Symptoms include a chronic relapsing-remitting pattern of
watery diarrhea that varies in severity and may be accompanied
by weight loss, abdominal pain, fatigue, and nausea.
Comorbid autoimmune diseases are common, including thyroid
disorders, celiac disease, diabetes mellitus, RA.
The cause is probably multifactorial& likely represents an
abnormal mucosal response to various luminal exposures
including infection and drugs such as NSAIDs.
The mucosa usually appears normal macroscopically
Diagnosis is made solely on characteristic histologic findings.
Microscopic colitis
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Collagenous colitis is characterized by a thickened subepithelial
collagen layer
Lymphocytic colitis by increased number of intraepithelial
lymphocytes is found in.
Supportive treatment with antidiarrheal agents, as loperamide,
bismuth subsalicylate, diphenoxylate, may be effective for mild
cases.
Otherwise, budesonide has the best-documented efficacy;
prednisolone, 5-ASA, antibiotics& probiotics have been studied
but the data is less robust.