10/13- Inflammatory Bowel Disease Flashcards
1
Q
Inflammatory Bowel Disease encompasses what other conditions?
A
- Ulcerative colitis: mucosal ulceration in colon
- Crohn’s disease: transmural inflammation
- Ileitis
- Ileocolitis
- Colitis
2
Q
What are the supposed components of pathogenesis of IBD?
A
- Genetic susceptibility
- Environmental triggers
- Luminal agents/Immune System
3
Q
What are supposed environmental triggers for IBD?
A
- Stress
- Infections
- Antibiotics
- Especially early in life, may increase the risk for IBD
- Diet
- NSAIDs
- Smoking
4
Q
What is the hygiene hypothesis in relation to IBD?
A
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”
5
Q
How does smoking relate to IBD?
- Ulcerative colitis
- Crohn’s disease
A
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
6
Q
What is the role of bacteria in IBD
- Infectious etiologies
- Experimental models
- Other factors
A
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
7
Q
What supports genetic influence of IBD?
- Are genetics more significant in UC or CD?
- Chromosomes involved
- Mutations
A
- 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
8
Q
What is the first gene associated with Crohn’s disease?
- Chromosome
- Function
- Molecules involves
A
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
9
Q
What is the risk of developing Crohn’s disease with NOD2?
A
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%
10
Q
What mutation may be protective for IBD?
- More in CD or UC
- Cells involved/function
A
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
11
Q
What are other genetic components expected to play a role in IBD?
A
MDR-1 (UC)
- P-glycoprotein efflux pump
- Mucosal integrity
TNFSF 15
ATG16L1
- Autophagy pathway
- Cellular adaptation to starvation
- Inhibits TB survival in macrophages
12
Q
Is the knowledge of a pt’s genetics helpful in diagnosing/treating IBD?
A
- Commercially available but NOT recommended in clinical practice
- NOD2 phenotype: ileal disease
- Predictor perhaps for need for surgery but not of response to therapy
13
Q
New genes: - ___ may be found in 20% of _____
- > ___ genes linked to IBD
A
- NOD2(CARD15) may be found in 20% of Crohn’s disease
- > 150 genes linked to IBD
14
Q
What are the changes in epidemiology (unexplained by genetics)?
A
- Increase in Crohn’s in US
- Rapid changes in Japan, Middle East, India
- Racial differences (e.g.no NOD2 in Blacks)
15
Q
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)?
A
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
16
Q
Describe the macrophage/DC inflammatory pathway
- Memory CD4 cell path
A
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
17
Q
Etiologic Hypothesis of IBD?
A
- Persistent Infection
- Defective mucosal integrity
- Dysbiosis
- Dysregulated immune response
18
Q
Age and sex incidence of IBD?
A
Ulcerative colitis:
- More in females
- Peak onset at age 20
Crohn’s disease:
- More in males
- Peak onset at age 20
19
Q
What races are most affected in IBD?
A
White > Black > Asian > Hispanic
- Crohn’s typically more common than UC (exception = Hispanics; more affected by UC)
20
Q
Worldwide distribution of IBD?
A
- US, Scandinavia, UK
- N/S America, China, India, Australia, W Europe, S Africa
21
Q
What are common “imposters” in DDx of IBD?
A
- Infectious colitis (incl C. dificile)
- Ischemic colitis
- Drug-induced (NSAID) enterocolitis
- Solitary rectal ulcer syndrome
- Radiation enterocolitis
- Diversion colitis
- Endometriosis
- Malignancy
- Functional: IBS
- Diverticular disease
22
Q
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
A
23
Q
T/F: The severity of UC is based upon its distribution?
A
False
- Based on stools/day and presence of blood
24
Q
Distribution patterns of UC?
A
- Distal UC: inflammation limited to area below the splenic flexure
- Extensive UC: inflammation extends proximal to splenic flexure
25
What is a truism of UC?
Always involves the distal colon (?)
26
Describe the severity classes of UC
- Mild
- Moderate
- Severe
- Fulminant
**Mild:**
- Under 4 stools/day +/- blood
- Normal ESR
- No signs of toxicity
**Moderate:**
- 4+ stools/day
- Minimal signs of toxicity
**Severe**
- 6+ stools/day
- Fever, tachycardia, anemia, increased ESR
**Fulminant**
- 10+ stools/day with continuous bleeding
- Toxicity, abdominal tenderness/distension
- Transfusion requirement
- Colonic dilation on xray
27
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
28
Describe the features of UC and CD in terms of:
- Mucosal involvement
- Strictures
- Rectal involvement
29
What is seen here?
Ulcerative colitis (spectrum of disease)
- Normal -\> Mild -\> Moderate -\> Severe
30
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)
31
What are components of the NonInvasive Assessment of IBD?
**Radiologic**
- Barium contrast
- Abdominal US
- CT
- MRI
**Nonspecific inflammation markers**
- ESR
- CRP
- Platelet count
**Serologic (disease specific)**
- ASCA
- pANCA
- ompC
**Fecal**
- Lactoferrin
- Calprotectin
32
What is seen here?
Sever ulcerative colitis
33
What are some intestinal complications of ulcerative colitis?
- Bleeding
- Toxicity
* Dilation (megacolon)
Systemic complications: related to inflammatory activity
34
Describe systemic complications in IBD?
- Extra-intestinal manifestations common but not predictable
- Sometimes more symptomatic than bowel disease
_Symptoms:_
- Aphthous stomatitis
- Episcleritis and uveitis
- Arthritis
- Vascular complications
- E. Nodosum
- P. gangrenosum
35
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
36
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
37
What are eye-related EIMs of IBD?
Ulcerative colitis:
- Episcleritis
- Uveitis
38
What are some skin-related EIMs of IBD?
Ulcerative colitis:
- Erythemia nodosum
- Pyoderma gangrenosum
39
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
40
Bile duct EIMs of IBD?
Ulcerative colitis:
- Sclerosing cholangitis
- Cholangiocarcinoma
41
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
42
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
43
Mechanism behind tie between inflammation and cancer?
44
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
45
What is the anatomic distribution of Crohn's disease?
- Small bowel alone (33%)
- **Ileocolic** (45%)
- Colon alone (20%)
46
What are the clinical presentations of Crohn's disease?
- Chronic pain and diarrhea
- Intestinal obstruction
- Acute inflammation ("appendicitis-like")
47
Crohn's disease is a ___ process (histologically)?
Crohn's disease is a **transmural** process
- May involve **granulomas** (although not necessarily)
48
Radiologic features of Crohn's disease?
- Ileitis
- "String sign"
49
What is an intestinal complication of Crohn's disease?
**Fistula**
- Mesenteric
- Enter-enteric
- Entero-vesicular
- Retroperitoneal
- Entero-cutaneous
**Small bowel related:**
**- Gallstones**
**- Malabsorption**
**Renal:**
- Stones
- Fistulae
- Hydronephrosis
- Amyloidosis
50
Does UC vs. CD diagnosis make a difference in regard to:
- Meds
- Complications
- Nutrition
- Surgery
- Meds: **no**
- Complications: **maybe**
- Nutrition: **yes**
- Surgery: **yes!!**
