Inflammatory Bowel Disease encompasses what other conditions?
- Ulcerative colitis: mucosal ulceration in colon
- Crohn's disease: transmural inflammation
What are the supposed components of pathogenesis of IBD?
- Genetic susceptibility
- Environmental triggers
- Luminal agents/Immune System
What are supposed environmental triggers for IBD?
- Especially early in life, may increase the risk for IBD
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
- Smoking can protect against UC
- Ex-smokers are more likely to develop UC
- 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
- Mycobacteria paratuberculosis (Johne’s d)
- Enteroadherent E. coli
- Cold chain hypothesis (Listeria)
- Sterile gut -> No IBD
- Bypassed segment -> No IBD
What supports genetic influence of IBD?
- Are genetics more significant in UC or CD?
- Chromosomes involved
- 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
- 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?
- Molecules involves
- Chrom 16q12
- Similar to plant disease resistant proteins
- Part of the innate immune system
- Related to immune response to bacteria
- Activates "down stream" inflammatory cell signals
- Innate immune system:
- Sampling of luminal antigens
- Recognition of commensals/pathogens
- Pattern recognition receptors (PRP)
- Pathogen-assoc Molecular Pattern (PAMP)
- Muramyl dipeptide in cell walls
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
- 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?
- P-glycoprotein efflux pump
- Mucosal integrity
- 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):
- IL-4, 6, 12, 18
- IL-1Ra, 10, 13
- 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
- Dysregulated immune response
Age and sex incidence of IBD?
- More in females
- Peak onset at age 20
- 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
What are common "imposters" in DDx of IBD?
- Infectious colitis (incl C. dificile)
- Ischemic colitis
- Drug-induced (NSAID) enterocolitis
- Solitary rectal ulcer syndrome
- Radiation enterocolitis
- Diversion colitis
- Functional: IBS
- Diverticular disease
How do the following clinical features differ between UC and CD?
- Abdominal pain
- Bloody diarrhea
- Abdominal mass
- Intestinal obstruction
- Perianal disease
- Effect of smoking
- Systemic symptoms: EIMs
T/F: The severity of UC is based upon its distribution?
- Based on stools/day and presence of blood
Distribution patterns of UC?
- Distal UC: inflammation limited to area below the splenic flexure
- Extensive UC: inflammation extends proximal to splenic flexure
What is a truism of UC?
Always involves the distal colon (?)
Describe the severity classes of UC
- Under 4 stools/day +/- blood
- Normal ESR
- No signs of toxicity
- 4+ stools/day
- Minimal signs of toxicity
- 6+ stools/day
- Fever, tachycardia, anemia, increased ESR
- 10+ stools/day with continuous bleeding
- Toxicity, abdominal tenderness/distension
- Transfusion requirement
- Colonic dilation on xray
What is the role of endoscopy in IBD?
- Confirm diagnosis
- Differentiate UC from CD
- Obtain histologic confirmation (severity and extent) and exclude other etiologies
- Surveillance for neoplasia
Describe the features of UC and CD in terms of:
- Mucosal involvement
- Rectal involvement
What is seen here?
Ulcerative colitis (spectrum of disease)
- Normal -> Mild -> Moderate -> Severe
What is seen here?
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 are components of the NonInvasive Assessment of IBD?
- Barium contrast
- Abdominal US
Nonspecific inflammation markers
- Platelet count
Serologic (disease specific)
What is seen here?
Sever ulcerative colitis
What are some intestinal complications of ulcerative colitis?
- Dilation (megacolon)
Systemic complications: related to inflammatory activity
Describe systemic complications in IBD?
- Extra-intestinal manifestations common but not predictable
- Sometimes more symptomatic than bowel disease
- Aphthous stomatitis
- Episcleritis and uveitis
- Vascular complications
- E. Nodosum
- P. gangrenosum
Describe epidemiology of EIMs (extra-intestinal manifestations)?
- How common
- Relation to IBD activity
- More in UC or CD?
- Occurs in up to 1/3 of IBD pts
- May parallel or be independent of IBD activity (may herald relapse)
More common associations:
- UC: PSC, pydoerma ganrenosum
- CD: Ankylosing spondylitis, erythema nodosum
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?
What are some skin-related EIMs of IBD?
- Erythemia nodosum
- Pyoderma gangrenosum
Joint related EIM of IBD?
- Large > small joint
- No synovial destruction
- No subcutaneous nodules
Central (axial) arthritis
- Ankylosing spondylitis
Bile duct EIMs of IBD?
- Sclerosing cholangitis
What are some thromboembolic complications in IBD?
(incidence of 0.5%)
- Usually occur with severe disease activity
(result of hypercoagubility associated with altered levels of clotting factors and platelet abnormalities)
- Other risk factors for thrombosis often present
Connection between inflammation and cancer- give examples of this in the GIT
- Gastric cancer, MALT : H. Pylori
- Liver Cancer : Chronic Hepatitis, both viral and non-viral etiologies
- Pancreatic Ca : Chronic pancreatitis
- Lymphoma : Celiac disease
Mechanism behind tie between inflammation and cancer?
Is cancer risk increased with IBD? How?
40x increased risk of colorectal cancer in ulcerative colitis (although, very low rates in normal population)
- Inflammatory change -> dysplasia
What is the anatomic distribution of Crohn's disease?
- Small bowel alone (33%)
- Ileocolic (45%)
- Colon alone (20%)
What are the clinical presentations of Crohn's disease?
- Chronic pain and diarrhea
- Intestinal obstruction
- Acute inflammation ("appendicitis-like")
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?
- "String sign"
What is an intestinal complication of Crohn's disease?
Small bowel related:
Does UC vs. CD diagnosis make a difference in regard to:
- Meds: no
- Complications: maybe
- Nutrition: yes
- Surgery: yes!!