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INFLAMMATORY BOWEL DISEASE

Moderator Dr. Poonam Nanwani


Speaker Dr. Sourabh Mandwariya

INTRODUCTION

Group of inflammatory disorders thought to be result of inappropriate activation of mucosal immune system driven by the presence of normal

luminal flora.
1. 2.

Two disorders

Ulcerative Colitis

Crohns Disease

Crohns disease
Ulcerative colitis
INDETERMINATE COLITIS

EPIDEMIOLOGY

Common in Female Age group Teens and early 20s Common in western world Prevalence increasing in developing nations

EPIDEMIOLOGY
Improved food storage

Decreased food contamination

Hygiene Hypothes is

Reduced frequency of enteric infection Inadequate development of mucosal immune response regulatory process Excessive response to self limited diseases

Chronic inflammatory disease

EPIDEMIOLOGY

Hygiene hypothesis supported by


Low

incidence of IBD in the helminthes

infection prevalent areas


IBD

may precedes by an episode of acute

infectious gastroenteritis

PATHOGENESIS

Idiopathic disorder

Intestinal Epithelial Dysfuncti on

Aberrant Mucosal Immune Respons e

Defect in Host Interaction with Intestinal Microbiota

PATHOGENESIS
1. 2. 3. 4.

Genetic factors Mucosal immune responses Epithelial defects Microbiota

PATHOGENESIS
1.

Genetic factors

More dominant in Crohns disease


Concordance rate in monozygotic twins
Crohn's

disease 50 % (Similar regions and with in 2 yr of each colitis 16 %

other)
Ulcerative

Concordance rate in Dizygotic twins 10 % (Both) HLA-DR associated familial predisposition HLA-DR2 Ulcerative colitis

PATHOGENESIS
1.

Genetic factors
Crohn's
NOD2

disease
(Nucleotide oligomerization binding domain

2) Gene; Chromosome 16q12


Regulate

immune response prevent

excessive activation by luminal microbes


Four

fold increase in Crohn's disease risk individual with mutation develop disease

<10%

PATHOGENESIS
NOD2

(Nucleotide oligomerization binding domain

2) Gene
Binds

to intracellular bacterial peptidoglycans NF-kB

Activates In

NOD2 Mutation Luminal microbes are less effectively recognized

Microbes enter to lamina propria

Trigger inflammatory responses

PATHOGENESIS
ATG16L1

(Autophagy-related 16-like) and IRGM

(Immunity-related GTPase M) Gene


Involved

in autophagy and clearance of

intracellular bacteria

None of these genes are associated with ulcerative colitis

PATHOGENESIS
2. Mucosal immune responses
Activation

of mucosal immunity and suppression

of immunoregulation

PATHOGENESIS

PATHOGENESIS
Transepitheli al flux of luminal bacterial components Increase flux of luminal material Activation of innate and adaptive immunity

Increase tight junction permeabilit y

Secretion of TNF and inflammatory mediator (In genetically susceptible Host)

PATHOGENESIS
3. Epithelial defects Critical component
Crohn's

disease
in intestinal epithelial tight junction barrier

Defects

function
Associated Mutation Defect

with NOD2 Mutation

of organic cation transporter SLC22A4

in secreted mucin

PATHOGENESIS
3. Epithelial defects
Ulcerative
ECM1

colitis

(Extracellular matrix protein 1)

polymorphism
Inhibition

of matrix metalloproteinase 9

PATHOGENESIS
4. Microbiota
Varies

between individuals and modified by diet may combat disease and other antibiotics are useful

Probiotic

Metronidazole

PATHOGENESIS
4. Microbiota
Implicated 1.

causative agent

Mycobacterium (Particularly M. Paratuberculosis)

2. 3. 4. 5.

E. Coli Yersinia Streptococcus Viruses (Including measles)

PATHOGENESIS
6. Other Factors

An episode of appendicitis Reduce risk of ulcerative colitis

Smoking Reduces risk of ulcerative colitis - Increases risk of Crohn's's disease

CROHN'S DISEASE

In 850 AD King Alfred, "England's Darling had a GI illness that began at age 20 yr

At the time the illness was thought to

be due to punishment for the King's


infidelities. It is now thought to be

Crohn's disease

Louis XIII of France (1601-1643)

CROHN'S DISEASE

1913 Dr. Dalziel - Described transmural intestinal

inflammation in 13 autopsied patients.

First fully described and published by Crohn's, Ginzburg, Oppenheimer (1932)

Regional enteritis or Granulomatous colitis

CROHN'S DISEASE

Equal frequency in both sexes Common in twenties to thirties Can manifest in any age from childhood to old age May occur in any area of GI tract Most common sites Terminal ileum - Iliocecal valve - Cecum

Crohn'ss Disease: CROHN'S DISEASE Anatomic Distribution

Small bowel alone (33%) Ileocolic (45%) Freq of involvement Most Least Colon alone (20%)

CROHN'S DISEASE

Gross features Earliest Crohn's disease lesion Aphthoid ulcers

Pinpoint reddish

purple erosions
of mucosa

Progress to elongated serpentine ulcers

CROHN'S DISEASE

Gross features

- Sharp demarcation between


normal and abnormal areas

CROHN'S DISEASE

Skip lesions multiple, separate sharply delineated areas of disease

CROHN'S DISEASE

Occasionally entire length of small bowel will be evolved ( Diffuse jejunoileitis)

Soggy feeling of small bowel

Edema, fibrosis and loss of normal mucosal


architecture

Intramural abscess formation

CROHN'S DISEASE

Transmural involvement

CROHN'S DISEASE

Cobblestone appearance Diseased tissue is depressed below the level of normal mucosa

CROHN'S DISEASE

Gross features

Cobblestone appearance

CROHN'S DISEASE

Gross features

Fissures Fistula tracts Perforation

CROHN'S DISEASE

Gross features

Perforation

CROHN'S DISEASE

Gross features Creeping fat In extensive transmural disease extension of mesenteric fat around the serosal surface

CROHN'S DISEASE

Gross features

Thickened and rubbery


intestinal wall

Due to transmural edema,


inflammation, submucosal

fibrosis, hypertrophy of
muscularis propria

CROHN'S DISEASE

Strictures are common Marked narrowing of lumen along with dilatation and hypertrophy of proximal segment

CROHN'S DISEASE

Microscopic features

Submucosal lymphedema Earliest change


Active disease Marked infiltration of neutrophils

and destruction of crypt epithelium

Mucosal ulceration, necrosis and atrophy with loss

of crypts

CROHN'S DISEASE

Microscopic features

Distortion of mucosal
architecture

By repeated cycles
of destruction and

regeneration

CROHN'S DISEASE

Microscopic features

Lymphoid hyperplasia Lamina propria and


submucosa

Chronic inflammatory cell infiltrate


Edema, lymphatic dilation, hyperemia along with

hyperplasia of muscularis mucosa

CROHN'S DISEASE

Microscopic features

Transmural involvement

CROHN'S DISEASE

Microscopic features

Transmural involvement

CROHN'S DISEASE

Microscopic features Noncaseating granulomas


Hallmark Sarcoid

of Crohn's disease (60% cases)

like with in center of lymphoid follicle of epithelioid cells and multinucleated

Composed

giant cells with absent or minimal necrosis

CROHN'S DISEASE

Microscopic features

CROHN'S DISEASE

Microscopic features

Noncaseating granulomas

May present anywhere in the wall of bowel, lymph


node, blood vessels (Granulomatous vasculitis)

CROHN'S DISEASE

Microscopic features

Fissures Slit like spaces with sharp edges and


narrow lumina, arranged perpendicularly to the

mucosa and extending


deeply into the submucosa or even upto the muscularis externa

CROHN'S DISEASE

Microscopic features

Obliterative muscularization

Increase in number of smooth muscle fibers in

submucosa

Stricture formation Tenascin Involved in morphogenesis of muscle tissue and wound healing

Enteritis cystica profunda Cystically dilated

CROHN'S DISEASE

Microscopic features

Disproportionate inflammation Well defined focus


of inflammatory cells surrounded by noninflamed

and histologically normal mucosa

Mesenteric lymph nodes May show granuloma formation

Metastatic Crohn's disease Formation of cutaneous granuloma

CROHN'S DISEASE

Clinical features Intermittent attacks of abdominal pain, fever and mild bloody diarrhea

Mimic acute appendicitis or bowel perforation


Active disease period is interrupted by

asymptomatic periods for weeks to many months

Undulating yet progressive course

CROHN'S DISEASE

Clinical features Reactivation is associated with Emotional stress - Specific dietary items - Smoking

CROHN'S DISEASE

Other associated clinical features Small bowel disease Malabsorption - Sever protein loss - Hypoalbuminemia - Vit. B12 deficiency,

Colonic disease - Iron deficiency anemia

CROHN'S DISEASE

Clinical features Extra intestinal manifestation (25%)

Ocular manifestation Uveitis

Musculoskeletal system - Migratory polyarthritis


- Osteoporosis - Ankylosing spondylitis

Skin involvement - Hidradenitis suppurativa - Clubbing of finger tips

CROHN'S DISEASE

Clinical features Extra intestinal manifestation (25%)

Skin involvement - Erythema nodosum

- Perianal abscess and fistula


formation - Erythema multiforme - Aphthous ulcer - Cutaneous vasculitis

CROHN'S DISEASE

Clinical features Extra intestinal manifestation (25%)

Hepatobiliary system Pericolangitis

- Primary sclerosing cholangitis

CROHN'S DISEASE

Differential diagnosis Tuberculosis Multiple circumferential ulcers - Caseous necrosis

Sarcidosis - Rarely involve small intestine - Associated with other systemic features

CROHN'S DISEASE

Differential diagnosis Yersiniosis Colonies of gram negative bacteria beneath the ulcers - Identification of organism in stool, lymph

node, blood and peritoneal fluid

Eosinophilic enteritis Peripheral eosinophilia with

ULCERATIVE COLITIS

Greek physician Soranus - 130 AD First officially described by Wilks and Moxon in 1875

Before this discovery, all diarrheal diseases were


believed to be caused by infectious agents and

bacteria

ULCERATIVE COLITIS

Severe ulcerating inflammatory disease limited to colon and rectum

Involves only mucosa and submucosa

Common age group 20 to 30 yr and 70 to 80 yr

ULCERATIVE COLITIS

Gross features Always involves rectum Extends proximally in continuous fashion to involve colon

Limited disease Ulcerative proctitis - Ulcerative proctosigmoiditis - Left sided colitis - Pancolitis

ULCERATIVE COLITIS

Gross features

- Backwash ileitis Involvement of distal ileum

Farmer RG, Easley KA, Ranking GB. Dig Dis Sci 1993;38(6):1137-1146.

ULCERATIVE COLITIS

37%

46%
17%

Farmer RG, Easley KA, Ranking GB. Dig Dis Sci 1993;38(6):1137-1146

ULCERATIVE COLITIS

Gross features

Mucosa Red and granular with petechial


hemorrhages

ULCERATIVE COLITIS

Gross features

Active disease (left)


atrophic changes(Right)

ULCERATIVE COLITIS

Gross features

Sharp demarcation between active ulcerative colitis


and normal area

ULCERATIVE COLITIS

Gross features

Broad based ulcer


with various size

ULCERATIVE COLITIS

Gross features

Pseudopolyps Elevated small


multiple sessile reddish nodule

due to isolated islands of


mucosal ulceration

ULCERATIVE COLITIS

Gross features

Pseudopolyps

ULCERATIVE COLITIS

Gross features

Pseudopolyps and cobblestone appearance

ULCERATIVE COLITIS

Gross features

Mucosal bridges
Fusion of tips of

Pseudopolyps

ULCERATIVE COLITIS

Gross features

Chronic disease Mucosal atrophy (Flat and smooth

ULCERATIVE COLITIS

Gross features

Submucosal fat deposition


Fibrotic, narrowed and shortened bowel

ULCERATIVE COLITIS

Gross features Toxic megacolon Due to destruction of muscularis propria and disturbed neuromuscular function due to inflammation and inflammatory mediators - Significant risk of perforation

ULCERATIVE COLITIS

Gross features

No stricture formation
No mural thickening

Normal serosal surface

ULCERATIVE COLITIS

Microscopic features Mucosal and submucosal involvement

ULCERATIVE COLITIS

Microscopic features Acute phase Inflammatory cell infiltrate in lamina propria

Progressive destruction of glands

ULCERATIVE COLITIS

Microscopic features Crypt abscess Collection of neutrophils in glandular lumen

ULCERATIVE COLITIS

Microscopic features - Crypt abscess

ULCERATIVE COLITIS

Microscopic features

Atrophic and regenerative changes present


together

Stromal inflammatory cell infiltrate

ULCERATIVE COLITIS

Microscopic features

Pseudopolyps formation - Composed of granulation


tissue mixed with inflamed and hyperemic mucosa

Duplication of muscularis mucosa


Obliterative endarteritis with dilation and

thrombosis of blood vessels

Accumulation of mast cells at the line of demarcation between normal and abnormal

ULCERATIVE COLITIS

Microscopic features

Pseudo pyloric metaplasia


- Presence of gastric antral

appearing glands

ULCERATIVE COLITIS

Clinical features Relapsing and remitting course Episode of Mucoid bloody diarrhea, lower abdominal pain and cramp may last for days to months

Relived by defecation
Triggering factors Infectious enteritis,

ULCERATIVE COLITIS

Clinical features

Extra intestinal manifestations


Ocular manifestation Uveitis

- Musculoskeletal system - Migratory polyarthritis


- Ankylosing spondylitis - Skin lesions - Pyoderma gangrenosus - Perianal abscess

ULCERATIVE COLITIS

Clinical features

Extra intestinal manifestations


Hepatobiliary system - Fatty infiltration

- Liver abscess
- Cirrhosis - Pericolangitis - Primary sclerosing cholangitis - Carcinoma of biliary tract

ULCERATIVE COLITIS

Differential diagnosis

Nonspecific bacterial colitis Acute inflammation


out

of proportion of chronic inflammation


- Absence of crypt distortion

Allergic colitis and proctitis Mucosal edema and


eosinophilic infiltration - Common in infants and children

ULCERATIVE COLITIS

Differential diagnosis

Pseudomembranous colitis Presence of yellow


white

mucosal plaques
- Focal explosive mucosal lesion

Cytomegalovirus colitis inclusion bodies


- Common in immunocompromised patient

LABORATORY INVESTIGATIONS

SEROLOGICAL STUDIES

Anti - neutrophil cytoplasmic antibodies Ulcerative colitis (75% cases) - Crohn's disease (11% cases)

Anti Saccharomyces cerevisiae antibodies - IgA and IgG against cell wall of Sac. cerevisiae Crohn's disease (60% cases)

SEROLOGICAL STUDIES

Anti-OmpC* Anti-Cbir1 Anti-I2 Anti-Glycan Abs Anti pancreatic Ab (PAB) Anti-laminaribocide Ab (ALCA) Anti-chitobioside (ACCA)

INDETERMINATE COLITIS

Definitive diagnosis is not possible in 10 % of cases

Pathological and clinical overlap between


Ulcerative colitis and Crohn's disease

Colonic disease in contentious pattern


Suggestive of ulcerative colitis

Patchy histological disease, fissure, family history of Crohn's disease, onset after initiating use of cigarette Against Ulcerative colitis

IBD ASSOCIATED NEOPLASM


Long term complication

Risk factors
Risk

increase after 8 to 10 years of disease

initiation
Patient Greater

with Pancolitis are at greater risk frequency and severity of active

inflammation increase risk (presence of neutrophils)

IBD ASSOCIATED NEOPLASM

Begins with dysplasia and develop into invasive carcinomas

Categories for dysplasia

1.
2.

Negative for dysplasia


Indefinite for dysplasia, probably negative

3.
4.

Indefinite for dysplasia, unknown


Indefinite for dysplasia, probably positive

IBD ASSOCIATED NEOPLASM

Indefinite for dysplasia

IBD ASSOCIATED NEOPLASM


5. Positive for dysplasia, low grade

IBD ASSOCIATED NEOPLASM


6. Positive for dysplasia, high grade

IBD ASSOCIATED NEOPLASM

IBD ASSOCIATED NEOPLASM


Adenocarcinoma Carcinoid tumor Anaplastic carcinomas Carcinosarcomas Malignant lymphomas Colonic adenomas may also occur Regular follow-up with mucosal biopsy

TREATMENT

Medical Immunosuppression - Elemental diet - Total parenteral nutrition

Surgical management Resection of involved bowel segment

CROHN'S DISEASE V/S ULCERATIVE COLITIS


Features Clinical Rectal bleeding Perforation Crohn's disease Inconspicuous 4% Ulcerative colitis Common 12%

Colon carcinoma Very rare Anal 75 %; Fissure, complications Fistulas, Ulceration Abdominal mass 10%-15% Abdominal pain Usually rightsided

5%-10% Rare; Minor

Practically never Usually left side

CROHN'S DISEASE V/S ULCERATIVE COLITIS


Features Radiographic Sparing of rectum Crohn's disease 90 % Ulcerative colitis Exceptional

Involvement of ileum Strictures Skip areas Internal fistulas Longitudinal and transverse ulcer

Common; Constricted Often present Common May be present Common

Rare; Dilated (Backwash ileitis) Absent Absent Absent Exceptional

CROHN'S DISEASE V/S ULCERATIVE COLITIS


Features Morphologic Distribution of involvement Crohn's disease Transmural Ulcerative colitis Mucosal and submucosal

Mucosal atrophy and regeneration Cytoplasmic mucin Lymphoid aggregates Edema

Minimal
Preserved Common Marked

Marked
Diminish Rare Minimal

CROHN'S DISEASE V/S ULCERATIVE COLITIS


Features Crohn's disease Minimal Rare Ulcerative colitis May be extreme Common

Morphologic Hyperemia Crypt abscesses Rectal involvement Granulomas Fissuring Lymph nodes

50 %
Present in 60% Present May contain granulomas

Practically always Absent Absent Reactive hyperplasia

REFERENCES

Rosai and Ackermans; surgical pathology Robbins and Cotran: pathological Basis of Disease An atlas of gross pathology; C D M Fletcher & P H McKee

New Concepts in the Pathophysiology of Inflammatory


Bowel Disease ; Annals of Internal Medicine

Harsh Mohan ; Textbook of Pathology Various internet link

CROHN'S DISEASE

Microscopic features

Fissures

THANK YOU

THANKS