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