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Inflammatory Inflammatory Bowel DiseaseBowel Disease
A Aljebreen, MD, FRCPCA Aljebreen, MD, FRCPC
Jan 2010Jan 2010
ObjectivesObjectives
Introduction Introduction Classifications Classifications Clinical featuresClinical features DiagnosisDiagnosis Management Management Conclusion Conclusion
Introduction Introduction
IBD characterized by a tendency for IBD characterized by a tendency for chronic or relapsing immune chronic or relapsing immune activation and inflammation within activation and inflammation within the gastrointestinal tract (GIT)the gastrointestinal tract (GIT)
CrohnCrohn’’s disease (CD) and ulcerative s disease (CD) and ulcerative colitis (UC) are the 2 major forms of colitis (UC) are the 2 major forms of idiopathic IBD.idiopathic IBD.
Less common entitiesLess common entities
Microscopic colitis (collagenous and Microscopic colitis (collagenous and lynphocytic)lynphocytic)
OthersOthers Diversion colitisDiversion colitis Radiation colitisRadiation colitis Drug induced colitisDrug induced colitis Infectious colitisInfectious colitis Ischemic colitis Ischemic colitis
CD and UCCD and UC
CD is a condition of CD is a condition of Chronic inflammation potentially involving Chronic inflammation potentially involving
any location of the GIT from mouth to anus.any location of the GIT from mouth to anus. It is a lifelong disease arising from an It is a lifelong disease arising from an
interaction between genetic and interaction between genetic and environmental factorsenvironmental factors
UC is an inflammatory disorder that UC is an inflammatory disorder that affects the rectum and extends affects the rectum and extends proximally to affect variable extent of proximally to affect variable extent of the colon.the colon.
Epidemiology Epidemiology
CD:CD: 11stst peak 15-30 years of age, 2 peak 15-30 years of age, 2ndnd peak around peak around
60 y60 y There is a definite incidence surge in Saudi There is a definite incidence surge in Saudi
Arabia over the last 10 yearsArabia over the last 10 years UC:UC:
High incidence areas: US, UK, northern High incidence areas: US, UK, northern EuropeEurope
Young adults, commoner in femalesYoung adults, commoner in females
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.
EtiologyEtiology
Mutations within the NOD2/ CARD15 gene contribute to CD susceptibility.
Functional studies suggest that inappropriate responses to bacterial components may alter signaling pathways of the innate immune system, leading to the development and persistence of intestinal
inflammation. Initiating pathogen?Initiating pathogen?
Infectious?Infectious? ? Possibly non-pathogenic commensal enteric flora? Possibly non-pathogenic 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-.
Environmental Environmental PrecipitantsPrecipitants
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.
transmural inflammation with transmural inflammation with predominance of the inflammation in the predominance of the inflammation in the mucosa and submucosamucosa and submucosa..
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.
Diagnosis Diagnosis
Exclude other possibilities (need Exclude other possibilities (need good history, physical exam, labs, good history, physical exam, labs, imaging and endoscopy with biopsy)imaging and endoscopy with biopsy)
There are many distinguishing There are many distinguishing features of CD and UC.features of CD and UC.
In about 5% it is classified as In about 5% it is classified as indeterminate because of indeterminate because of overlapping features.overlapping features.
Distinguishing characteristics of Distinguishing characteristics of CD and UCCD and UC
Feature CDUC
Location SB or colonOnly colon (rarely
“backwash ileitis”
Anatomic distribution
Skip lesionsContinuous, begins distally
Rectal involvement
Rectal spareInvolved in >90%
Gross bleeding
Only 25%Universal
Peri-anal disease
75%Rare
Fistulization Yes No
Granulomas 50-75%No
Endoscopic features of CD Endoscopic features of CD and UCand UC
Feature CDUC
Mucosal involvement
Discontinuous
Continuous
Aphthous ulcers
Common Rare
Surrounding mucosa
Relatively normal
Abnormal
Longitudinal ulcer
Common Rare
Cobble stoningIn severe cases
No
Mucosal friability
Uncommon Common
Vascular pattern
Normal distorted
Pathologic features of CD Pathologic features of CD and UCand UC
Feature CDUC
Transmural inflammation
Yes Uncommon
Granulomas 50-75%No
Fissures Common Rare
Fibrosis Common No
Submucosal inflammation
Common Uncommon
Radiologic features of CD Radiologic features of CD and UCand UC
Feature CDUC
Nodularitygranularity
cobble stoningstring sign of SB
Collar button ulcers
UC: PresentationUC: Presentation Must exclude infectious cause before Must exclude infectious cause before
making Dx.making Dx. Rectal Bleeding Rectal Bleeding Diarrhea:Diarrhea:
frequent passage of loose or liquid stool, often frequent passage of loose or liquid stool, often associated with passing large quantities of associated with passing large quantities of mucus.mucus.
Abdominal Pain:Abdominal Pain: it is not a prominent symptom. it is not a prominent symptom.
Anorexia, nausea, feverAnorexia, nausea, fever……
DDX of UCDDX of UC
InfectiousInfectious Drug inducedDrug induced Microscopic colitisMicroscopic colitis
UC: PresentationUC: Presentation
Mild attack:Mild attack: Most common form, mainly left sided Most common form, mainly left sided
colitis, <4 BM/day with no bloodcolitis, <4 BM/day with no blood Moderate attack:Moderate attack:
25% of all patients, 4-6 BM/day with blood.25% of all patients, 4-6 BM/day with blood. Severe or fulminant colitis:Severe or fulminant colitis:
~ 15% of cases, >6BM/day, bloody, fever, ~ 15% of cases, >6BM/day, bloody, fever, weight loss, diffuse abd tenderness, weight loss, diffuse abd tenderness, elevated WBC, most refractory to medical elevated WBC, most refractory to medical therapytherapy
CDCD
Anatomic Anatomic distributiondistribution
CD activity CD activity indexindex
DDx DDx (lymphoma, (lymphoma, Yersinea Yersinea Enterocolitis, Enterocolitis, TB)TB)
CD: clinical CD: clinical presentationspresentations
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: DDxCD ilitis: DDx
LymphomaLymphoma
Yersinea Enterocolitis andYersinea Enterocolitis and TBTB
CD: clinical CD: clinical presentationspresentations
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 Extra-intestinal manifestations of IBDof IBD
Arthritis:Arthritis: Peripheral arthritis, usu paralels the disease Peripheral arthritis, usu paralels the disease
activityactivity Ankylosing Spondylitis, 1-6%, sacroiliitisAnkylosing Spondylitis, 1-6%, sacroiliitis
Ocular lesions:Ocular lesions: Iritis (uvietis) (0.5-3%), episcleritis, keratitis,Iritis (uvietis) (0.5-3%), episcleritis, keratitis,
Skin and oral cavity:Skin and oral cavity: Erythema nodosum 1-3%Erythema nodosum 1-3% Pyoderma Gangrenosum 0.6%Pyoderma Gangrenosum 0.6% Aphthus stomatitis, metastatic CD.Aphthus stomatitis, metastatic CD.
Extra-intestinal manifestations Extra-intestinal manifestations of IBDof IBD
Liver and Biliary tract disease:Liver and Biliary tract disease: Pericholangitis, fatty infiltration, PSC Pericholangitis, fatty infiltration, PSC
(1-4%, more with UC), (1-4%, more with UC), cholangiocarcinoma, gallstonescholangiocarcinoma, gallstones
Thromboembolic disease, vasculitis, Thromboembolic disease, vasculitis, Renal disease (urolithiasis, GN), Renal disease (urolithiasis, GN), clubbing, amyloidosis.clubbing, amyloidosis.
Complications of IBDComplications of IBD
BleedingBleeding StrictureStricture FistulaFistula Toxic megacolonToxic megacolon CancerCancer
How to diagnose IBDHow to diagnose IBD
History History Physical examinationsPhysical examinations Labs Labs Radiology Radiology Endoscopy Endoscopy Histopathology Histopathology
Case scenario 1Case scenario 1
17 year old female presented with 1 year history of intermittent abdominal cramps and increasing abdominal gases and bloating.
What other history you want?
Case scenario 2Case scenario 2
65 year old male presented with 6 months history of bleeding per rectum.
What other history you want? What else you need?
Treatment Treatment
Goals of therapyGoals of therapy Induce and maintain remission.Induce and maintain remission. Ameliorate symptomsAmeliorate symptoms Improve pts quality of lifeImprove pts quality of life Adequate nutritionAdequate nutrition Prevent complication of both the Prevent complication of both the
disease and medicationsdisease and medications
5-Aminosalicylic Acids5-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 Acids5-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.
CorticosteroidsCorticosteroids
No proven maintenance benefit in No proven maintenance benefit in the treatment of either UC or CD. the treatment of either UC or CD.
Many and serious side effects. Many and serious side effects. Budesonide: Budesonide:
less side effects, less side effects, its use is limited to patients with distal its use is limited to patients with distal
ileal and right-sided colonic diseaseileal and right-sided 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 The onset of benefit takes several weeks up to six
months.months. Dose-related BM suppression is uniformly observedDose-related BM suppression is uniformly observed
Immunosuppressive Agents
MethotrexateMethotrexate Effective in steroid-dependent active Effective in steroid-dependent active
CD and in maintaining remission.CD and in maintaining remission. CyclosporineCyclosporine
Severe UC not responding to IV steroid Severe UC not responding to IV steroid &need urgent proctocolectomy.&need urgent proctocolectomy.
50% of the responders will need 50% of the responders will need surgery within a year.surgery within a year.
Anti-TNF Therapy Anti-TNF Therapy
It is a chimeric monoclonal antibody, binds soluble TNF.
Infleximab, Adalimumab (Humira) and Certolizumab
Prompt onset, effects takes 6weeks to max of 6m.
Indicated in fistulising crohns, moderate to severe CD
Infleximab also indicated in severe ulcerative colitis
Side effects They are safe and usually 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.
Side effectsSide effects
Increase risk of infections including exacerbations of abdominal abscess or increasing upper respiratory infections.
Reactivation of tuberculosis has been observed and has resulted in disseminated disease and death.
INDICATIONS FOR SURGERYINDICATIONS FOR SURGERY
In patients with UC:In patients with UC: Severe attacks that fail to respond to medical therapy. Severe attacks that fail to respond to medical therapy. Complications of a severe attack (e.g., perforation, Complications of a severe attack (e.g., perforation,
acute dilatation). acute dilatation). Chronic continuous disease with an impaired quality Chronic continuous disease with an impaired quality
of life. of life. Dysplasia or carcinoma.Dysplasia or carcinoma.
In patients with CDIn patients with CD Obstruction, severe perianal disease unresponsive to Obstruction, severe perianal disease unresponsive to
medical therapy, difficult fistulas, major bleeding, medical therapy, difficult fistulas, major bleeding, severe disabilitysevere disability
30 % relapse rate30 % relapse rate
IBD Sequelae IBD Sequelae UC:UC:
Risk of cancer begins after 8 years, risk of Risk of cancer begins after 8 years, risk of pancolitis 7% at 20 years and 17% at 30 pancolitis 7% at 20 years and 17% at 30 years.years.
Increased risk: early age of onset, pancolitis.Increased risk: early age of onset, pancolitis. Need for colonoscopic screening after 8 yearsNeed for colonoscopic screening after 8 years
CD:CD: True incidence of cancer is uncertain, but True incidence of cancer is uncertain, but
could be as high as UCcould be as high as UC Need the same screening policy.Need the same screening policy.
IBD conclusionIBD conclusion
It is a chronic disordersIt is a chronic disorders Need to exclude other possibilitiesNeed to exclude other possibilities Need to differentiate between the Need to differentiate between the
twotwo Need long term management with Need long term management with
primary goal to induce then maintain primary goal to induce then maintain remission and prevent complications remission and prevent complications of both the disease and drugs.of both the disease and drugs.