10/13- Inflammatory Bowel Disease Flashcards
Inflammatory Bowel Disease encompasses what other conditions?
- Ulcerative colitis: mucosal ulceration in colon
- Crohn’s disease: transmural inflammation
- Ileitis
- Ileocolitis
- Colitis
What are the supposed components of pathogenesis of IBD?
- Genetic susceptibility
- Environmental triggers
- Luminal agents/Immune System
What are supposed environmental triggers for IBD?
- Stress
- Infections
- Antibiotics
- Especially early in life, may increase the risk for IBD
- Diet
- NSAIDs
- Smoking
What is the hygiene hypothesis in relation to IBD?
Limited antigenic exposure in infancy may lead to later hyper-responsiveness
- Linked to asthma, multiple sclerosis, other “auto-immune diseases”
- “Let the kids play in the dirt”
How does smoking relate to IBD?
- Ulcerative colitis
- Crohn’s disease
Ulcerative colitis
- Smoking can protect against UC
- Ex-smokers are more likely to develop UC
Crohn’s disease
- 2x risk in current smokers
- Smokers are less responsive to treatment
- Smokers are more likely to develop recurrence of disease after surgery
What is the role of bacteria in IBD
- Infectious etiologies
- Experimental models
- Other factors
Infectious etiology:
- Mycobacteria paratuberculosis (Johne’s d)
- Enteroadherent E. coli
- Cold chain hypothesis (Listeria)
Experimental models:
- Sterile gut -> No IBD
- Bypassed segment -> No IBD
Probiotics
Microbiome
What supports genetic influence of IBD?
- Are genetics more significant in UC or CD?
- Chromosomes involved
- Mutations
- More significant in Crohn’s disease (50% of identical twins will be singularly affected; 50% will both half it)
- Familial occurrence
- Clinical pattern of Crohn’s disease in families
- Polygenic susceptibility
Chrom/Mutations:
- Chromosomes 12 > 12, 6, 5
- NOD-2 mutations on chrom 16 in Crohn’s
- Cytokine cluster region on chrom 5 in Crohn’s
- Genotype/phenotype correlations
What is the first gene associated with Crohn’s disease?
- Chromosome
- Function
- Molecules involves
NOD2
- Chrom 16q12
- Similar to plant disease resistant proteins
- Part of the innate immune system
Function
- Related to immune response to bacteria
- Activates “down stream” inflammatory cell signals
- Innate immune system:
- Sampling of luminal antigens
- Recognition of commensals/pathogens
NOD(CARD)/TLR Molecules:
- Pattern recognition receptors (PRP)
- Pathogen-assoc Molecular Pattern (PAMP)
- Muramyl dipeptide in cell walls
Paneth cells
Not sure if gain or loss of function
What is the risk of developing Crohn’s disease with NOD2?
1 copy: 1.5-4x risk
2 copies: 15-40x risk
- 10% of CD pts have 2 copies
- 28% of CD pts have 1 copy
- Actual disease presence with 1-2 gene copies is still < 10%
What mutation may be protective for IBD?
- More in CD or UC
- Cells involved/function
IL-23 receptor
- Protective gene mutation
- (1.9% in ileal non-Jewish CD vx. 7% in controls)
- Protective in both CD and UC
- Other IL-23 mutations increase risk of CD
- Th17 immune response
What are other genetic components expected to play a role in IBD?
MDR-1 (UC)
- P-glycoprotein efflux pump
- Mucosal integrity
TNFSF 15
ATG16L1
- Autophagy pathway
- Cellular adaptation to starvation
- Inhibits TB survival in macrophages
Is the knowledge of a pt’s genetics helpful in diagnosing/treating IBD?
- Commercially available but NOT recommended in clinical practice
- NOD2 phenotype: ileal disease
- Predictor perhaps for need for surgery but not of response to therapy
New genes: - ___ may be found in 20% of _____
- > ___ genes linked to IBD
- NOD2(CARD15) may be found in 20% of Crohn’s disease
- > 150 genes linked to IBD
What are the changes in epidemiology (unexplained by genetics)?
- Increase in Crohn’s in US
- Rapid changes in Japan, Middle East, India
- Racial differences (e.g.no NOD2 in Blacks)
It is thought that the pathogenesis of IBD may involve an imbalance between pro and anti-inflammatory components.
What are some pro-inflammatory factors (loss of tolerance)?
What about anti-inflammatory (tolerance)?
Pro-inflammatory (loss of tolerance):
- TNF
- IL-1B
- IL-4, 6, 12, 18
- IFN-y
Anti-inflammatory (tolerance)
- IL-1Ra, 10, 13
- TGF-B
- PGE2 , PGJ2
Describe the macrophage/DC inflammatory pathway
- Memory CD4 cell path
Macrophages and DCs:
- IL-12 -> Th1 -> IFN-y/TNF/IL2
- IL-23 -> ThIL17 -> IL17, 17F, TNF, IL6
Memory CD4 cells, NKT, mast cells, and eos:
- IL-4 -> Th2 -> IL4, 5, 10, 13
Etiologic Hypothesis of IBD?
- Persistent Infection
- Defective mucosal integrity
- Dysbiosis
- Dysregulated immune response
Age and sex incidence of IBD?
Ulcerative colitis:
- More in females
- Peak onset at age 20
Crohn’s disease:
- More in males
- Peak onset at age 20
What races are most affected in IBD?
White > Black > Asian > Hispanic
- Crohn’s typically more common than UC (exception = Hispanics; more affected by UC)
Worldwide distribution of IBD?
- US, Scandinavia, UK
- N/S America, China, India, Australia, W Europe, S Africa
How do the following clinical features differ between UC and CD?
- Abdominal pain
- Bloody diarrhea
- Abdominal mass
- Intestinal obstruction
- Perianal disease
- Fistulae
- Effect of smoking
- Systemic symptoms: EIMs
Describe the features of UC and CD in terms of:
- Mucosal involvement
- Strictures
- Rectal involvement
What is seen here?
Ulcerative colitis (spectrum of disease)
- Normal -> Mild -> Moderate -> Severe
What is seen here?
Crohn’s disease
Top left: discrete “punched out” aphthae
Top right: Irregular stellate ulcer (looks as though punched out by cookie cutter)
Bottom left: longitudinal ulcer
Bottom right: macroulecerations and pseudopolyps (occur in both UC and CD)
What is seen here?
Sever ulcerative colitis
What is aphthous stomatitis?
EIM (CD > UC)
- Occurs in under 5% of UC and 20% of CD pts
- Usually presages or follows course of IBD
- Optimal maintenance therapy to prevent occurrence is crucial
What are eye-related EIMs of IBD?
Ulcerative colitis:
- Episcleritis
- Uveitis
What are some skin-related EIMs of IBD?
Ulcerative colitis:
- Erythemia nodosum
- Pyoderma gangrenosum
Joint related EIM of IBD?
- Characteristics
Ulcerative colitis:
Peripheral arthritis
- Monarticular
- Asymmetrical
- Large > small joint
- No synovial destruction
- No subcutaneous nodules
- Seronegative
Central (axial) arthritis
- Ankylosing spondylitis
- Sacro-iliitis
Bile duct EIMs of IBD?
Ulcerative colitis:
- Sclerosing cholangitis
- Cholangiocarcinoma
Mechanism behind tie between inflammation and cancer?
Crohn’s disease is a ___ process (histologically)?
Crohn’s disease is a transmural process
- May involve granulomas (although not necessarily)
Radiologic features of Crohn’s disease?
- Ileitis
- “String sign”
