INFLAMMATORY BOWEL DISEASE

Moderator – Dr. Poonam NanwaniSpeaker – 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.

Two disorders

1. Crohn‘s disease

2. Ulcerative colitis

Crohn‘s Disease

INDETERMINATE COLITIS

Ulcerative Colitis

EPIDEMIOLOGY

Common in Female

Age group – Teens and early 20s

Common in western world

Prevalence increasing in developing nations

EPIDEMIOLOGYImproved food storage

Decreased food contamination

Reduced frequency of enteric infection

Inadequate development of mucosal immune response regulatory process

Excessive response to self limited diseases

Chronic inflammatory disease

Hygiene Hypothe

sis

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

Defect in Host

Interaction with

Intestinal Microbiota

Aberrant

Mucosal

Immune

Response

Intestinal

Epithelial

Dysfunction

PATHOGENESIS

1. Genetic factors

2. Mucosal immune responses

3. Epithelial defects

4. Microbiota

PATHOGENESIS

1. Genetic factors

More dominant in Crohn‘s disease

Concordance rate in monozygotic twins

Crohn's disease – 50 % (Similar regions and with in 2 yr of

each other)

Ulcerative colitis – 16 %

Concordance rate in Dizygotic twins – 10 % (Both)

HLA-DR associated familial predisposition

HLA-DR2 – Ulcerative colitis

HLA-DR5 – Crohn‘s Disease

PATHOGENESIS

1. Genetic factors

Crohn's disease

NOD2 (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

<10% individual with mutation develop disease

PATHOGENESIS

NOD2 (Nucleotide oligomerization binding domain 2)

Gene

Binds to intracellular bacterial peptidoglycans

Activates NF-kB

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

Transepithelial flux of luminal

bacterial components

Activation of innate and adaptive immunity

Secretion of TNF and inflammatory

mediator (In genetically

susceptible Host)

Increase tight junction

permeability

Increase flux of luminal material

PATHOGENESIS

PATHOGENESIS

3. Epithelial defects – Critical component

Crohn's disease

Defects in intestinal epithelial tight

junction barrier function

Associated with NOD2 Mutation

Mutation of organic cation transporter

SLC22A4

Defect in secreted mucin

PATHOGENESIS

3. Epithelial defects

Ulcerative colitis

ECM1 (Extracellular matrix protein 1)

polymorphism

Inhibition of matrix metalloproteinase 9

PATHOGENESIS

4. Microbiota

Varies between individuals and modified by

diet

Probiotic may combat disease

Metronidazole and other antibiotics are

useful

PATHOGENESIS

4. Microbiota

Implicated causative agent

1. Mycobacterium (Particularly M.

Paratuberculosis)

2. E. Coli

3. Yersinia

4. Streptococcus

5. 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'S DISEASECrohn's’s Disease:

Anatomic Distribution

Small bowelalone(33%)

Colon alone(20%)

Ileocolic(45%)

LeastMost

Freq of involvement

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

Transmural involvement

CROHN'S DISEASE

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

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 of Crohn's disease (60% cases)

Sarcoid – like – with in center of lymphoid

follicle

Composed of epithelioid cells and

multinucleated giant cells with absent or

minimal necrosis

CROHN'S DISEASE

Microscopic featuresCROHN'S DISEASE

CROHN'S DISEASE

Microscopic features

Noncaseating granulomas

– May present anywhere in the wall of bowel,

lymph

node, blood vessels (Granulomatous

vasculitis)

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

glands in the wall of bowel

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

- Pyoderma gangrenosum

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 allergic symptoms

Extra intestinal manifestation (25%) –

Hepatobiliary system – Pericolangitis

- Primary sclerosing

cholangitis

CROHN'S DISEASE

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

ULCERATIVE COLITIS

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

37%37%

17%17%

46%46%

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

mucosal surface)

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

mucosa

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,

psychological stress, Cessation of smoking

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

ULCERATIVE COLITIS

LABORATORY INVESTIGATIONS

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)

SEROLOGICAL STUDIES

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

INDETERMINATE COLITIS

Long term complication

Risk factors

Risk increase after 8 to 10 years of disease

initiation

Patient with Pancolitis are at greater risk

Greater 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. Negative for dysplasia

2. Indefinite for dysplasia, probably negative

3. Indefinite for dysplasia, unknown

4. 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

IBD ASSOCIATED NEOPLASM

TREATMENT

Medical – Immunosuppression

- Elemental diet

- Total parenteral nutrition

Surgical management – Resection of involved

bowel segment

Features Crohn's disease

Ulcerative colitis

Clinical

Rectal bleeding

Inconspicuous Common

Perforation 4 % 12%

Colon carcinoma

Very rare 5%-10%

Anal complications

75 %; Fissure, Fistulas, Ulceration

Rare; Minor

Abdominal mass

10%-15% Practically never

Abdominal pain

Usually right-sided

Usually left side

CROHN'S DISEASE V/S ULCERATIVE COLITIS

Features Crohn's disease

Ulcerative colitis

Radiographic

Sparing of rectum

90 % Exceptional

Involvement of ileum

Common; Constricted

Rare; Dilated (Backwash ileitis)

Strictures Often present Absent

Skip areas Common Absent

Internal fistulas

May be present

Absent

Longitudinal and transverse ulcer

Common Exceptional

CROHN'S DISEASE V/S ULCERATIVE COLITIS

Features Crohn's disease

Ulcerative colitis

Morphologic

Distribution of involvement

Transmural Mucosal and submucosal

Mucosal atrophy and regeneration

Minimal Marked

Cytoplasmic mucin

Preserved Diminish

Lymphoid aggregates

Common Rare

Edema Marked Minimal

CROHN'S DISEASE V/S ULCERATIVE COLITIS

Features Crohn's disease

Ulcerative colitis

Morphologic

Hyperemia Minimal May be extreme

Crypt abscesses

Rare Common

Rectal involvement

50 % Practically always

Granulomas Present in 60%

Absent

Fissuring Present Absent

Lymph nodes May contain granulomas

Reactive hyperplasia

CROHN'S DISEASE V/S ULCERATIVE COLITIS

REFERENCES Rosai and Ackerman’s; 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

THANK YOU

Microscopic features

Fissures

CROHN'S DISEASE

THANK YOU

THANKS