Transcript Inflammatory Bowel Disease (IBD)

Inflammatory Bowel
Disease
E Rahimi, MD
Assiatant Professor
Department Of Internal Medicine
MUK
Inflammatory Bowel Disease (IBD)
Ulcerative colitis and Crohn's disease
Chronic inflammatory diseases of the gastrointestinal tract
No single finding is diagnostic for these diseases
Epidemiological, clinical, laboratory, imaging and
pathological characteristics
Some patients have a clinical picture that falls between the
two diseases
Introduction


IBD characterized by a tendency for chronic or
relapsing immune activation and inflammation
within the GIT.
Crohn’s disease (CD) and ulcerative colitis (UC)
are the 2 major forms of idiopathic IBD.
Less common entities are:
Others
Microscopic colitis
(collagenous and
lynphocytic)
Diversion
colitis
Radiation
colitis
Drug
induced
colitis
Infectious
colitis
Ischemic
colitis
Introduction
CD
UC
• is a condition of chronic inflammation
potentially involving any location of the
GIT from mouth to anus.
• UC is an inflammatory disorder that
affects the rectum and extends proximally
to affect variable extent of the colon.
IBD: Systemic Complications
Eye
inflammation*
Lower
bone density*
Liver and
bile duct
inflammation
Gallstones
Skin lesions
*Higher incidence in women.
Growth failure
in children
Kidney
stones
Subfertility*
Ovaries
Uterus
Arthritis and
joint pains
Epidemiology
CD:
• 1st peak 15-30 years
of age, 2nd peak
around 60 y
UC:
• High incidence areas:
US, UK, northern
Europe
• Young adults,
commoner in females
Epidemiology
Genetics
Studies suggested that 1st degree relatives of an affected
patient have a risk of IBD that is 4-20 times higher than
that of general population.
The best replicated linkage region, IBD1, on
chromosome 16q contains the CD susceptibility gene,
NOD2/CARD15.
Having one copy of the risk alleles confers a 2–4-fold
risk for developing CD, whereas double-dose carriage
increases the risk 20–40-fold.
Etiology
Mutations within
the NOD2/
CARD15 gene
contribute to CD
susceptibility.
inappropriate
responses to
bacterial
Initiating
pathogen?
Infectious?
the development
and persistence
of intestinal
inflammation.
? Possibly nonpathogenic
commensal
enteric flora
Pathogenesis



The mucosa of CD patients is dominated by Th1
(T helper), which produce interferon-γ and IL-2.
In contrast, UC dominated by Th2 phenotype,
which produce transforming growth factor (TGF-)
and IL-5.
Activation of Th1 cells produce the down-regulatory
cytokines IL-10 and TGF-.
Pathogenesis



A sequential casιade of inflammatory mediators
extends the response; each step is a potential target
for therapy.
Inflammatory cytokines such as IL- l ， IL-6， and
TNF have divers, effects on tissues.
They promote fibrogenesis, collagen production
activation of tissue metalloproteinases， and the
production of other inflammatory mediators; they
also activate the coagulation cascade.
Pathogenesis



These cytokines are normally produced in
response to infection but are usually turned off
or inhibited at the appropriate time to limit
tissue damage.
In IBD their activity is not regulated, resulting in
an imbalance between the proinflammatory and
antiinflammatory medíators.
Therapíes such as the 5 – aminosalicylic acid (5 ASA) compounds and glucocorticoids are
potent inhibitors
Environmental Precipitants

Factors:
NSAIDs use (?altered intestinal barrier), and
 Early appendectomy (increase UC incidence)
 Smoking (protects against UC but increases the risk
of CD).

CD: PATHOLOGY

Early Findings:
Aphthous ulcer.
 The presence of granulomas


Late findings:
Linear ulcers.
 The classic cobble stoned appearance may arise.
 Transmural inflammation
 Sinus tracts, and strictures.
 Fibrosis.

UC: PATHOLOGY


The inflammation is predominantly confined to
the mucosa.
Non-specific (can be seen with any acute
inflammation)
The lamina propria becomes edematous.
 Inflammatory infiltrate of neutrophils
 Neutrophils invade crypts, causing cryptitis &
ultimately crypt abscesses.


Specific (suggest chronicity):

Distorted crypt architecture, crypt atrophy and a
chronic inflammatory infiltrate.
UC
Diagnosis



Exclude other possibilities (need good history,
physical exam, labs, imaging and endoscopy with
biopsy)
There are many distinguishing features of CD
and UC.
In about 5% it is classified as indeterminate
because of overlapping features.
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
50-75%
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
UC
CD
UC: Presentation



Must exclude infectious cause before making Dx.
Rectal Bleeding
Diarrhea:


Abdominal Pain:


frequent passage of loose or liquid stool, often associated
with passing large quantities of mucus.
it is not a prominent symptom.
Anorexia, nausea, fever…
DDX of UC



Infectious
Drug induced
Microscopic colitis
UC: Presentation
UC: Presentation



About 40-50% of patients have disease limited
to the rectum and rectosigmoid
30-40% have disease extending beyond the
sigmoid but not involving the whole colon
20% have a total colitis.
CD
Anatomic
distribution
 CD activity index
 DDx (lymphoma,
Yersinea
Enterocolitis, TB)

CD: clinical presentations

Disease of the ileum:



May present initially with a small bowel obstruction.
Patients with an active disease often present with anorexia,
loose stools, and weight loss.
Perianal disease



In 24% of patients with CD.
Skin lesions include superficial ulcers, and abscesses.
Anal canal lesions include fissures, ulcers, and stenosis.
CD ilitis: DDx

Lymphoma
 Yersinea
 TB
Enterocolitis and
CD: clinical presentations

colonic disease


The typical presenting symptom is diarrhea, occasionally with
passage of obvious blood.
proctitis

May be the initial presentation in some cases of CD
Extra-intestinal manifestations of IBD

Arthritis:
Peripheral arthritis, usu paralels the disease activity
 Ankylosing Spondylitis, 1-6%, sacroiliitis


Ocular lesions:


Iritis (uvietis) (0.5-3%), episcleritis, keratitis,
Skin and oral cavity:
Erythema nodosum 1-3%
 Pyoderma Gangrenosum 0.6%
 Aphthus stomatitis, metastatic CD.

Dermatologic




Erythema nodosum (EN) occurs in up to
15% of CD patients and 10% of UC patients.
Attacks usually correlate with bowel activity;
skin lesions develop after the onset of bowel
symptoms， and patients frequently have
concomitant active peripheral arthritis.
The lesions of EN are hot， red， tender
nodules measuring 1-5 cm in diameter and are
found on the anterior surface of the lower legs
， ankles， calves， thighs，and arms.
Therapy is directed toward theunderlying bowel
disease.
Dermatologic




Pyoderma gangrenosum (PG) is seen in 1 12% of UC patients and less ιommonly in
Crohn's ιolitis.
Although it usually presents after the diagnosis
of IBD.
PG may occur years before the onset of bowel
symptoms
A course independent of the bowel disease，
respond poorly to colectomy， and even
develop years after proctocolectomy.
Dermatologic



It is usually associated with severe disease.
Lesions are commonly found on the dorsal
surface of the feet and legs but may occur on the
arms，chest， stoma， and even the face. PG
usually begins as a pustule andthen spreads
concentrically to rapidly undermine healthy skin.
Lesions then ulcerate， with violaceous edges
surrounded by a margin of erythema.
Centrally， they contain necrotic tissue with
blood and exudates.
Dermatologic


Lesions may be single or multiple and grow as
large as 30 cm.
They are sometimes very difficult to treat and
often require IV antibiotics, IV glucocorticoid，
dapsone， azathioprine， thalidomide， IV
cyclosporine，or infliximab
Dermatologic




Other dermatologic manifestations include
pyoderma vegetans，which occurs in
intertriginous areas.
Pyostomatitis vegetans， which involves the
mucous membranes.
Sweet syndrome， a neutrophilic dermatosis.
metastatic CD， a rare disorder defined by
cutaneous granuloma formation.
Dermatologic



Psoriasis affects 5 - 1 0% of patients with IBD
and is unrelated to bowel activity consistent with
the potential shared immunogenetic basis of
these diseases.
Perianal skin tags are found in 75-80% of
patients with CD， especially those with colon
involvement.
Oral mucosal lesions， seen often in CD and
rarely in UC， include aphthous stomatitis and
cobblestone" lesions of the buccal mucosa.
Rheumatologic




Peripheral arthritis develops in 1 5-20% of IBD
patients， is more common in CD， and
worsens with exacerbations of bowel activity.
It is asymmetric， polyarticular， and migratory
and most often affects large joints of the upper
and lower extremities.
Treatment is directed at reducing bowel
inflammation.
In severe UC， colectomy frequently cures the
arthritis.
Rheumatologic



Ankylosing spondylitis (AS) occurs in about
10% of IBD patients and is more common in
CD than Uc.
About two-thirds of IBD patients with AS
express the HLA-B27 antigen. The AS activity is
not related to bowel activity and does not remit
with glucocorticoids or colectomy.
It most often affects the spine and pelvis，
producing symptoms of diffuse low-back pain，
buttock pain， and morning stiffness.
Rheumatologic



The course is continuous and progressive，
leading to permanent skeletal damage and
deformity.
Anti-TNF therapy reduces spinal inflammation
and improves functional status and quality of
life.
Sacroiliitis is symmetric， occurs equally in UC
and CD， is often asymptomatic， does not
correlate with bowel activity， and does not
always progress to AS.
Rheumatologic

Other rheumatic manifestations include hyper
trophic osteoarthropathy， pelvic!femoral
osteomyelitis， and relapsing polychondritis.
Ocular






The incidence of ocular complications in IBD
patients is 1 - 1 0%.
The most common are conjunctivitis， anterior
uveitis/iritis， and episcleritis.
Uveitis is associated with both UC and Crohn's
colitis
may be found during periods of remission
may develop in patients following bowel resection.
Symptoms include ocular pain， photophobia，
blurred vision， and headache.
Ocular

Prompt intervention， sometimes with
systemic glucocorticoids， is required to
prevent scarring and visual impairment.
Ocular




Episderitis is a benign disorder that presents
with synptoms of mild ocular burning.
It occurs in 3-4% of IBD patients
more commonly in Crohn's colitis
is treated with topical glucocorticoids
Hepatobiliary



Hepatic steatosis is detectable in about onehalf of the abnormal liver biopsies from patients
with CD and UC; patients usually present with
hepatomegaly.
Fatty liver usually results from a combination of
chronic debilitating illness, malnutrition, and
glucocorticoid therapy.
Cholelithiasis occurs in 10-35% of CD patients
with ileitis or ileal resection.
Hepatobiliary




Gallstone formation is caused by malabsorption
of bile acids, resulting in depletion of the bile
salt pool and the secretion of lithogenic bile.
Primary sclerosing cholangitis (PSC) is a
disorder characterized by both intrahepatic and
extrahepatic bile duct inflammation and fibrosis.
Frequently leading to biliary cirrhosis and
hepatic failure.
5% of patients with UC have PSC, but 50-75%
of patients with PSC have IBD.
Hepatobiliary





PSC occurs less often in patients with CD.
Although it can be recognized after the
diagnosis of IBD
PSC can be detected earlier or even years after
proctocolectomy.
Consistent with this, the immunogenetic basis
for PSC appears to be overlapping
IBD and PSC are commonly pANCA positive.
Hepatobiliary




Most patients have no symptoms at the time of
diagnosis; when symptoms are present， they
consist of fatigue, jaundice, abdominal pain，
fever, anorexia, and malaise.
The traditional gold standard diagnostic test is
endoscopic retrograde cholangiopancrea
tography (ERCP)
magnetic resonance cholangiopancreatography
(MRCP) is also sensitive and specific.
MRCP is reasonable as an initial diagnostic test
in children and.
Hepatobiliary



In patients with PSC. both ERCP and MRCP
demonstrate multiple bile duct strictures
alternating with relatively normal segments.
The bile acid ursodeoxycholic acid (ursodiol)
may reduce alkaline phosphatase and serum
aminotransferase levels， but histologic
improvement has been marginal.
High doses (25-30 mg/kg per day) may decrease
the risk of colorectal dysplasia and cancer in
patientswith UC and PSc.
Hepatobiliary



Endoscopic stenting may be palliative for
cholestasis secondary to bile duct obstruction.
Patients with symptomatic disease develop
cirrhosis and liver failure over 5 - 1 0 years and
eventually require liver transplantation.
PSC patients have a 10- 1 5% lifetime risk of
developing cholangiocarcinoma and then cannot
be transplanted Patients with IBD and PSC are
at increased risk of colon cancer and should be
surveyed yearly by colonoscopy and biopsy.
Hepatobiliary




Cholangiography is normal in a small percentage
of patients who have a variant of PSC known as
small duct primary sclerosing cholangitis.
This variant (sometimes referred to as
"pericholangitis") is probably a form of PSC
involving small-caliber bile ducts.
It has similar biochemical and histologic features
to classic PSc.
It appears to have a significantly better
prognosis than classic PSC， although it may
evolve into classic PSc.
Hepatobiliary

Granulomatous hepatitis and hepatic
amyloidosis are much rarer extraintestinal
manifestations of IBD.
Urologic



The most frequent genitourinary complications
are calculi， ureteral obstruction， and ileal
bladder fistulas.
The highest frequency of nephrolithiasis ( 1 020%) occurs in patients with CD following small
bowelresection.
Calcium oxalate stones develop secondary to
hyperoxaluria，which results from increased
absorption of dietary oxalate.
Urologic



Normally，dietary calcium combines with
luminal oxalate to form insoluble calcium
oxalate， which is eliminated in the stool.
In patients with ileal dysfunction， however，
nonabsorbed fatty acids bind calcium and
leaveoxalate unbound.
The unbound oxalate is then delivered to the
colon, where it is readily absorbed， especially
in the presence of inflammation hepatitis and
hepatic amyloidosis are much rarer
extraintestinal manifestations of IBD.
Metabolic Bone Disease




Low bone mass occurs in 3-30% of IBD
patients.
The risk is increased by glucocorticoids，
cyclosporine， methotrexate， and total
parenteral nutrition (TPN) .
Malabsorption and inflammation mediated by
IL- 1 ，IL 6， TNF， and other inflammatory
mediators also contribute t o low bone density.
An increased incidence of hip， spine， wrist，
and rib fractures has been noted: 36% in CD
and 45% in Uc.
Metabolic Bone Disease





The absolute risk of an osteoporotic fracture is
about 1 % per person per year.
Fracture rates， particularly in the spine and hip
， are highest among the elderly (age >60).
One study noted an OR of 1 .72 for vertebral
fracture and an OR of 1 .59 for hip fracture.
The disease severity predicted the risk of a
fracture.
Only 1 3 % of IBD patients who had a fracture
were on any kind of antifracture treatment.
Metabolic Bone Disease




Up to 20% of bone mass can be lost per year
with chronic glucocorticoid use.
The effect is dosage-dependent.
Budesonide may also suppress the pituitaryadrenal axis and thus carries a risk of causing
osteoporosis.
Osteonecrosis is characterized by death of
osteocytes and adipocytes and eventual bone
collapse.
Metabolic Bone Disease



The pain is aggravated by motion and swelling
of the joints.
It affects the hips more often than knees and
shoulders， and in one series， 4.3% of
patients developed osteonecrosis within 6
months of starting glucocorticoids.
Diagnosis is made by bone scan or MRI， and
treatment consists of pain control， cord
decompression，osteotomy， and joint
replacement.
Thromboembolic Disorder


Patients with IBD risk of both venous and arterial
thrombosis even if the disease is not active.
Factors responsible for the hypercoagulable state: d:
abnormalities of the plateletendothelial interaction
 Hyperhomocysteinemia
 alterations in the coagulation cascade
 impaired fibrinolysis
 involvement of tissue factor-bearing microvesicles
 disruption of coagulation system by autoantibodies
 genetic predisposition.


A spectrum of vasculitides involving small，
medium， and large vessels has also been observed.
Extra-intestinal manifestations of IBD

Liver and Biliary tract disease:


Pericholangitis, fatty infiltration, PSC (1-4%, more
with UC), cholangiocarcinoma, gallstones
Thromboembolic disease, vasculitis, Renal
disease (urolithiasis, GN), clubbing, amyloidosis.
IBD: Systemic Complications
Eye
inflammation*
Lower
bone density*
Liver and
bile duct
inflammation
Gallstones
Skin lesions
*Higher incidence in women.
Growth failure
in children
Kidney
stones
Subfertility*
Ovaries
Uterus
Arthritis and
joint pains
Complications of IBD





Bleeding
Stricture
Fistula
Toxic megacolon
Cancer
Complications of IBD
Treatment

Goals of therapy
Induce and maintain remission.
 Ameliorate symptoms
 Improve pts quality of life
 Adequate nutrition
 Prevent complication of both the disease and
medications

5-Aminosalicylic Acids


The mainstay treatment of mild to moderately
active UC and CD (induction).
5-ASA may act by
blocking the production of prostaglandins and
leukotrienes,
 inhibiting bacterial peptide–induced neutrophil
chemotaxis and adenosine-induced secretion,
 scavenging reactive oxygen metabolites

5-Aminosalicylic Acids


For patients with distal colonic disease, a
suppository or enema form will be most
appropriate.
Maintenance treatment with a 5-aminosalicylic
acid can be effective for sustaining remission in
ulcerative colitis but is of questionable value in
Crohn's disease.
Corticosteroids



Topical corticosteroids can be used as an
alternative to 5-ASA in ulcerative proctitis or
distal UC.
Oral prednisone or prednisolone is used for
moderately severe UC or CD, in doses ranging
up to 60 mg per day.
IV is warranted for patients who are sufficiently
ill to require hospitalization; the majority will
have a response within 7 to 10 days.
Corticosteroids



No proven maintenance benefit in the treatment
of either UC or CD.
Many and serious side effects.
Budesonide:
less side effects,
 its use is limited to patients with distal ileal and rightsided colonic disease

Immunosuppressive Agents


These agents are generally appropriate for patients in
whom the dose of corticosteroids cannot be tapered or
discontinued.
Azathioprine & 6-MP


The most extensively used immunosuppressive agents.
The mechanisms of action unknown but may include



suppressing the generation of a specific subgroup of T cells.
The onset of benefit takes several weeks up to six months.
Dose-related BM suppression is uniformly observed
Immunosuppressive Agents

Methotrexate


Effective in steroid-dependent active CD and in
maintaining remission.
Cyclosporine
Severe UC not responding to IV steroid &need
urgent proctocolectomy.
 50% of the responders will need surgery within a
year.

Anti-TNF Therapy: Infliximab




It is a chimeric monoclonal antibody, binds soluble
TNF.
Prompt onset, effects takes 6weeks to max of 6m.
Indicated in fisulizing crohns, refractory CD and
refractory UC
Complications (it is safe and usu tolerable)


Acute infusion reactions, which may include chest tightness,
dyspnea, rash, and hypotension.
Delayed hypersensitivity reactions, consisting of severe
polyarthralgia, myalgia, facial edema, urticaria, or rash, are an
unusual complication occurring from 3 to 12 days after an
infusion.
Infliximab: side effects



Increase risk of upper respiratory infections.
Any patient suspected of having a pyogenic
complication of CD or any serious infection
should undergo adequate drainage and treatment
with antibiotics before starting infliximab.
Reactivation of tuberculosis has been observed
and has resulted in disseminated disease and
death.
INDICATIONS FOR SURGERY

In patients with UC:





Severe attacks that fail to respond to medical therapy.
Complications of a severe attack (e.g., perforation, acute
dilatation).
Chronic continuous disease with an impaired quality of life.
Dysplasia or carcinoma.
In patients with CD


Obstruction, severe perianal disease unresponsive to medical
therapy, difficult fistulas, major bleeding, severe disability
30 % relapse rate
IBD Sequelae

UC:
Risk of cancer begins after 8 years, risk of pancolitis
7% at 20 years and 17% at 30 years.
 Increased risk: early age of onset, pancolitis.
 Need for colonoscopic screening after 8 years


CD:
True incidence of cancer is uncertain, but could be
as high as UC
 Need the same screening policy.

IBD conclusion




It is a chronic disorders
Need to exclude other possibilities
Need to differentiate between the two
Need long term management with primary goal
to induce then maintain remission and prevent
complications of both the disease and drugs.