Gi Pathophysiology Lecture 7: Mucosal Immunology And Inflammatory Bowel Disease

Front 1

Name 4 initiating events that lead to bowel inflammation

Back 1

1. Infection
2. Ischemia
3. Radiation
4. Chemical Toxins

Front 2

Describe the time course for wound healing as it applies to the bowel

Back 2

1. Clot formations/Resolution
(Fibrinolysis inc.)

2. Inflammation
(Macs and PMNS inc.)

3. Epithelial Healing
(Restitution+Proliferation/Maturation)

4. Granulation Tissue Formation

Front 3

The organization of the gut-associated lymphoid tissue.

A ________ contains a special follicle associated epithelium or "___ cells” overlies the lymphoid tissue.

Back 3

Peyer’s patch

M

Front 4

T/F

M cells take up molecules and particles from the gut lumen by endocytosis or phagocytosis.

This material is then transported through the interior of the cell in vesicles to the basal cell membrane, where it is released into the extracellular space.
------------------

This process is known as

Back 4

True

Transcytosis

Front 5

Mucosal Immunity:

The afferent immune response.

Antigen from pathogenic microorganisms is presented beneath mucosal surfaces to ______ lymphocytes within organized mucosal lymphoid tissue, for example _________. Activated lymphocytes leave this tissue via draining lymph nodes and reenter the circulation through the _________.

Back 5

naïve

Peyer’s patches

thoracic duct

Front 6

Mucosal Immunity

Efferent immune response

T/F

Primed lymphocytes reenter mucosal tissues throughout the body from the circulation, thereby disseminating a mucosal immune response

Back 6

True

Front 7

Mucosal Immunity

Polymeric ____ is transported into the gut lumen through epithelial cells at _________________

Back 7

IgA

at the base of the crypts

Front 8

Mucosal Immunity

Polymeric IgA binds to the _______ layer overlying the gut epithelium

Back 8

mucus layer

Front 9

Effector T cells home to the gut by combinations of relatively specific interactions involving adhesion molecules and chemokines.

a gut-homing lymphocyte adheres to the vascular endothelium of an intestinal blood vessel by the binding of lymphocyte ________
to MAdCAM-1 expressed on the endothelial surface.

Back 9

L-selectin and α4:β7 integrin

Front 10

T/F

Interaction between the T-cell integrin α4:β7 and epithelial E-cadherin weakens T-cell localization to the intestinal epithelium.

Back 10

False

Interaction between the T-cell integrin α4:β7 and epithelial E-cadherin STRENGTHENS T-cell localization to the intestinal epithelium.

Front 11

Inflammatory Bowel Disease

Ulcerative colitis

Back 11

produces colonic mucosal inflammation with small shallow ulcers, presents with bloody diarrhea, and involves ONLY the colon.

Ulcerative colitis confined to the rectum is termed ulcerative proctitis.

Front 12

Inflammatory Bowel Disease

Crohn's disease

Regional enteritis (Crohn's)

Enterocolitis (Crohn's)

Definitions:

Back 12

- produces transmural intestinal inflammation with granulomatous and inflammatory masses, and can occur anywhere in the gastrointestinal tract.

- If it involves only the small bowel, we use the term regional enteritis

- refers to both colonic and small bowel involvement.

Front 13

IBD

Presentation: UC vs. CD

Age of Onset:
Diarrhea:
Abdominal Pain:
Fever
Anorexia:

(These illustrate Similarities)

Back 13

Age of Onset:
Both, any age: Peak 10-35

Diarrhea:
UC: Common: 80-95%;
CD: Common: 70-90%

Abdominal Pain:
UC: 15-60% (mild);
CD: 70-80% (moderate-severe)

Fever
UC: Less Frequent;
CD: more frequent

Anorexia:
UC: Weight loss = 20-60% (mild);
CD: 45-70% (weight loss may be severe)

Front 14

Case 1.

Mr. C.F. is a 24-year-old white male with a six week history of bloody diarrhea (10-12 loose movements per day) and lower abdominal cramps relieved by the passage of small amounts of mucus. He is awakened at night with the pain and diarrhea, has had a marked loss of appetite, and has had an intermittent, low grade fever (100°F). Physical exam reveals a slightly tender abdomen, and fresh blood in the rectum. A 12-pound weight loss has occurred since a physical exam two years previously. There are no palpable masses.

Back 14

Ulcerative Colitis

Front 15

Case 2.

Mrs. J.R. is a 19-year-old white female with diarrhea and lower abdominal cramps for four months. During the past four months she has had 5-10 loose watery stools per day with no bleeding, has occasionally been awakened at night with cramps relieved by defecation, and, on two occasions, has had several days of malaise and fever (up to 101°F, orally). She has felt a frequent nagging sensation in the right lower quadrant, which does not radiate, and has noted protruding hemorrhoids plus occasional excruciating pain on defecation. Physical exam reveals a fullness in the right lower quadrant, painful external hemorrhoids, a rectal fissure, and a temperature of 100.8°F.

Back 15

Crohn's Disease

Front 16

Differences in Presentation:

Ulcerative Colitis vs. Crohn's Disease

Rectal Bleeding
Anal Lesions (fissures, fistulas)
Rectal Involvement
Abdominal Mass

(Differences)

Back 16

Rectal Bleeding:
UC: Common: 70-100%
CD:Occasional: 10-20% (especially with colitis)

Anal Lesions (fissures, fistulas)
UC: Unusual
CD:Common

Rectal Involvement
UC: More than 95%
CD: Less than 50%

Abdominal Mass
UC: Rare
CD: Common

Front 17

Inflammatory Bowel Disease

C. Differential Diagnosis.

Back 17

- Infectious diseases
amebiasis, shigellosis, salmonellosis, enteropathogenic E. coli, yersinia enterocolitis, giardiasis, tuberculosis, and viral enteritis.

- Drug induced:
pseudomembranous colitis, drug allergy (e.g. penicillin allergy) and laxative abuse.

- Ischemic colitis vascular insufficiency, and radiation colitis:
present with manifestations similar to ulcerative colitis. Radiation enteritis can mimic Crohn's disease.

- Diverticulitis, carcinoma, polyps and familial polyposis are included in the differential diagnosis in patients with rectal bleeding and/or abdominal pain

- Irritable bowel syndrome (exclusion)

Front 18

Differential diagnosis of Crohn’s disease.

Back 18

Appendicitis
Tuberculosis
Lymphoma

Front 19

Differential Diagnosis of Ulcerative Colitis

Back 19

Enteric infections: Shigella, E. Coli, Salmonella, Campylobacter, Ameba, Yersinia

Pseudo membranous colitis

Ischemic colitis

Diverticulitis

Hemorrhoids

Front 20

CD vs. UC

Microscopic distribution differences

Back 20

UC is diffuse and stricly a mucosal disease - deeper muscularis layer = normal

CD is segmental and involves all layers of colon and wall (transmural)

Front 21

T/F

Granulomas are more commonly found in UC

Back 21

False

Granulomas are more commonly found in CD

Front 22

Some Microscopic Differential Points.

CD vs. UC

Inflammation
Crypt abscess
Granulomata
Fissures
Lymph node
Location

Back 22

Inflammation
UC: Mucosal
CD: Transmural

Crypt abscess
UC: Common
CD: Uncommon

Granulomata
UC: Rare
CD: Common: 60-70%

Fissures
UC: Rare
CD: Common

Lymph node
UC: Hyperplasia
CD: Granulomata

Location
UC: Colon
CD: Anywhere in GI tract mouth, duodenum, jejunum, ileum, colon

Front 23

Some Radiographic Differential Points

CD vs. UC

Distribution
Rectum
Terminal ileum
Mucosa
Strictures or fistula

Back 23

Distribution
UC: Continuous with rectum
CD: Discontinuous and segmental anywhere in GI tract: especially small bowel and colon

Rectum
UC: Almost always involved
CD: Often normal

Terminal ileum
UC: Usually normal
CD: Often involved: stenotic and irregular

Mucosa
UC: Often involved: stenotic and irregular
CD: Big longitudinal fissures "Cobblestone" appearance

Strictures or fistula
UC: Rare
CD: Frequent

Front 24

Some Differences in Long-Term Complications and Courses

CD vs. UC

Colonic Cancer
Toxic megacolon
Massive hemorrhage
Strictures
Internal fistulas

Back 24

Colonic Cancer
UC: Markedly increased in high risk patients
CD: Slightly increased in granulomatous colitis

Toxic megacolon
UC: 5-10%
CD: Uncommon but can occur

Massive hemorrhage
UC: 3%
CD: Uncommon but can occur

Strictures
UC: Uncommon
CD: Very common (obstruction)

Internal fistulas
UC: Uncommon
CD: Common

Front 25

Some Differences in Long-Term Complications and Course.

UC vs.CD.

Anorectal complications
Perianal abscess
Surgical cure

Back 25

Anorectal complications
UC: Occasional
CD: Common

Perianal abscess
UC: 3-4%
CD: Common

Surgical cure
UC: Yes
CD: No-disease recurs elsewhere

Front 26

Inflammatory Bowel Disease

Etiology and Pathogenesis.

Back 26

1. Genetic
The single most important risk factor is a first degree relative with the disease.

2. Environmental/Infectious

3. Immunologic
There is prolonged immune activation with infiltration with lymphocytes and macrophages and increased production of IgG.

Front 27

NOD2/CARD15 mutations

Back 27

NOD2/CARD15 is part of the innate immune system that recognizes bacterial products -

50% of patients with Crohn's disease have mutations in NOD2 but having NOD2 mutations doesn't necessarily mean you will have Crohn's

Front 28

Treatment.

Ulcerative colitis:

Back 28

1. Anti-inflammatory drugs.

a. NSAIDs are not useful.

b. 5-aminosalicylate and sulfasalazine are useful in mildly active disease and in inactive disease to prevent relapse. Mechanism of action is unknown; however, they are free radical scavengers and inhibit leukotriene synthesis.

c. Corticosteroids. Effective in reducing inflammation, but disease tends to relapse when drug is withdrawn.

2. Immunosuppressive drugs.

a. 6-mercaptopurine.

b. Cyclosporine.

3. Colectomy is curative.

Front 29

Treatment.

Crohn's Disease:

Back 29

1. Anti-inflammatory drugs.

a. NSAIDs are not effective.

b. 5-aminosalicylate and sulfasalazine are effective for mildly active disease especially in the colon.

c. Corticosteroids. Same as for ulcerative colitis.

2. Immunosuppressive drugs.

a. 6-mercaptopurine.

b. Cyclosporine.

3. Surgery. Useful for tight strictures, abscesses and fistulae. Resection of involved area is not curative: disease usually recurs in previously normal gut.