patoloji-ders-notlari

Title

Serdar Balcı

Inflammatory Bowell Diseases

Serdar BALCI, MD

Inflammatory bowel disease (IBD)

Chronic condition

Inappropriate mucosal immune activation

Crohn disease

Ulcerative colitis

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

IBD

• More common in females
• Frequently present during adolescence or in young adults
• Most common among whites
• 3-5x more eastern European (Ashkenazi) Jews
• Most prevalent in North America, northern Europe, and Australia
• IBD incidence worldwide is on the rise
• Hygiene hypothesis
  • related to improved food storage conditions
  • decreased food contamination
  • reduced frequency of enteric infections due to improved hygiene
  • resulted in inadequate development of regulatory processes that limit mucosal immune responses early in life
  • inappropriate immune responses

The cause(s) of IBD remains uncertain

Combination of errant host interactions with intestinal microbiota

Intestinal epithelial dysfunction

Aberrant mucosal immune responses

Genetics

• Risk of disease is increased when there is an affected family member

• Concordance rate for monozygotic twins

  • Crohn disease 50%
  • Ulcerative colitis 16%

• NOD2 (nucleotide oligomerization binding domain 2)

  • susceptibility gene in Crohn disease
  • Protein that binds to intracellular bacterial peptidoglycans and subsequently activates NF-κB
  • Disease-associated NOD2 variants are less effective at recognizing and combating luminal microbes
    • Microbes enter the lamina propria and trigger inflammatory reactions
  • NOD2 prevent excessive activation by luminal microbes

• Disease develops in less than 10% of persons carrying NOD2 mutations

• NOD2 mutations are uncommon in African and Asian patients with Crohn disease

• ATG16L1 (autophagy-related 16–like-1)

  • autophagosome pathway
  • critical to host cell responses to intracellular bacteria

• IRGM (immunity-related GTPase M)

  • involved in autophagy and clearance of intracellular bacteria

• None of these genes are associated with ulcerative colitis

Mucosal immune responses

• Immunosuppressive and immunomodulatory agents remain mainstays of IBD therapy
• Polarization of helper T cells to the TH1 type in Crohn disease
• TH17 contribute to disease pathogenesis
• Polymorphisms of the IL-23 receptor confer protection from Crohn disease and ulcerative colitis
  • IL-23 is involved in the development and maintenance of TH17 cells
• anti-TNF therapy effective in some patients with ulcerative colitis

In ulcerative colitis significant TH2

Mucosal IL-13 production is increased in ulcerative colitis, Crohn disease

Polymorphisms of the IL-10 gene, IL10 receptor gene, have been linked to ulcerative colitis but not Crohn disease

Epithelial defects

• Defects in intestinal epithelial tight junction barrier function
  • in patients with Crohn disease and a subset of their healthy first-degree relatives
    • NOD2 polymorphisms
  • experimental models
    • activate innate and adaptive mucosal immunity
• Paneth cell granules
  • contain antimicrobial peptides that can affect composition of the luminal microbiota
  • abnormal in patients with Crohn disease carrying ATG16L1 mutations

Microbiota

• Intestinal microbiota contribute to IBD pathogenesis
  • Metronidazole, can be helpful in maintenance of remission in Crohn disease
  • Probiotic bacteria may be used for treatment
  • Fecal transplantation
  • A single episode of appendicitis is associated with reduced risk of developing ulcerative colitis
• Risk of Crohn disease is increased by smoking
  • whereas ulcerative colitis is reduced

Robbins Basic Pathology

Crohn Disease

• Regional enteritis
• May occur in any area of the gastrointestinal tract
• Most common sites
  • Terminal ileum, ileocecal valve, and cecum
• **Limited to the small intestine alone 40% **
• Small intestine and the colon both are involved in 30%
• Others are characterized by colonic involvement only
• Multiple, separate, sharply delineated areas of disease
• Skip lesions
• Strictures are common

Robbins Basic Pathology

Robbins Basic Pathology

• Earliest lesion
  • Aphthous ulcer
• Multiple lesions often coalesce into elongated, serpentine ulcers
• Oriented along the axis of the bowel
• Edema and loss of normal mucosal folds are common
• Sparing of interspersed mucosa
  • coarsely textured, cobblestone appearance
  • diseased tissue is depressed below the level of normal mucosa

Robbins Basic Pathology

Early lesion of the ileum showing hyperemia and focal ulceration

Autopsy Pathology: A Manual and Atlas

Chronic lesion involving the ileum

Sharp demarcation between the normal area on the right and the involved area on the left

Narrowing of the lumen, thickening of the intestinal wall, and coarsely textured (“cobblestone”) mucosa with fissures

Autopsy Pathology: A Manual and Atlas

• Fissures frequently develop between mucosal folds
• Extend deeply to become sites of perforation or fistula tracts
• Intestinal wall is thickened as a consequence of transmural edema, inflammation, submucosal fibrosis, and hypertrophy of the muscularis propria
  • contribute to stricture formation

Extensive transmural disease

Mesenteric fat frequently extends around the serosal surface

creeping fat

Robbins Basic Pathology

Active Crohn disease

Abundant neutrophils infiltrate and damage crypt epithelium

Clusters of neutrophils within a crypt crypt abscess

Crypt destruction

Ulceration is common

Abrupt transition between ulcerated and normal mucosa

Repeated cycles of crypt destruction and regeneration

-distortion of mucosal architecture

-Normally straight and parallel crypts take on bizarre branching shapes and unusual orientations to one another

Robbins Basic Pathology

Crohn disease

• Epithelial metaplasia
  • chronic relapsing injury
• Gastric antral-appearing glands
  • pseudopyloric metaplasia
• Paneth cell metaplasia
  • occur in the left colon
• Architectural and metaplastic changes may persist even when active inflammation has resolved
• Mucosal atrophy, with loss of crypts, may result after years of disease

Noncaseating granulomas

-Hallmark of Crohn disease

-Found in approximately 35% of cases

-Arise in areas of active disease or uninvolved regions

Robbins Basic Pathology

Noncaseating granulomas

-In any layer of the intestinal wall

-May be found in mesenteric lymph nodes

-Cutaneous granulomas

–form nodules

–misnomer: metastatic Crohn disease

Robbins Basic Pathology

• Clinical features
• Fibrosing strictures
  • Common in terminal ileum
  • require surgical resection
  • Often recurs at the site of anastomosis
  • 40% of patients require additional resections
• Fistulas
  • Between loops of bowel
  • Involve the urinary bladder, vagina, and abdominal or perianal skin
  • Perforations and peritoneal abscesses are common
• Extraintestinal manifestations
  • Uveitis
  • Migratory polyarthritis
  • Sacroiliitis
  • Ankylosing spondylitis
  • Erythema nodosum
  • Clubbing of the fingertips
  • Pericholangitis and primary sclerosing cholangitis also occur in Crohn disease but are more common in ulcerative colitis
  • Risk of colonic adenocarcinoma is increased in patients with long-standing colonic Crohn disease

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Ulcerative Colitis

• Limited to the colon and rectum
• Extraintestinal manifestations of ulcerative colitis overlap with Crohn disease
  • migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, skin lesions, pericholangitis, and primary sclerosing cholangitis.
• Always involves the rectum
• Extends proximally in a continuous fashion
• Involve part or all of the colon
• Skip lesions are not seen

Robbins Basic Pathology

Robbins Basic Pathology

Disease of the entire colon is termed pancolitis

**Total colectomy with pancolitis showing active disease, with red, granular mucosa in the cecum (left) and smooth, atrophic mucosa distally (right). **

Robbins Basic Pathology

broad-based ulceration of the colonic mucosa of the distal colon

Pseudopolyps

Autopsy Pathology: A Manual and Atlas

• Ulcerative proctitis
  • Disease limited to the rectum
• Ulcerative proctosigmoiditis
  • Disease limited to rectosigmoid
• Small intestine is normal
  • Mild mucosal inflammation of the distal ileum, backwash ileitis, may be present in severe cases of pancolitis

Involved colonic mucosa may be slightly red and granular-appearing or exhibit extensive broad-based ulcers

The transition between diseased and uninvolved colon can be abrupt

Sharp demarcation between active ulcerative colitis (bottom) and normal (top)

Robbins Basic Pathology

• Ulcers are aligned along the long axis of the colon
• Pseudopolyps
  • Isolated islands of regenerating mucosa often bulge into the lumen to create small elevations
• Chronic disease may lead to mucosal atrophy
• Flat, smooth mucosal surface lacking normal folds
• Unlike in Crohn disease
  • mural thickening is absent
  • serosal surface is normal
  • strictures do not occur
• Toxic megacolon
  • Inflammation and inflammatory mediators can damage the muscularis propria
  • Disturb neuromuscular function
  • Colonic dilation
  • Significant risk of perforation

Histologic features of Ulcerative Colitis

• Similar to those in colonic Crohn disease
  • inflammatory infiltrates
  • crypt abscesses
  • crypt distortion
  • epithelial metaplasia
• Different from Crohn
  • skip lesions are absent
  • inflammation generally is limited to the mucosa and superficial submucosa
  • Granulomas are not present

Robbins Basic Pathology

Ulcerative Colitis

• In severe cases
  • Mucosal damage may be accompanied by ulcers that extend more deeply into the submucosa
  • Muscularis propria is rarely involved
• Submucosal fibrosis, mucosal atrophy, and distorted mucosal architecture remain as residua of healed disease
• Histologic pattern also may revert to near normal after prolonged remission

Relapsing disorder

Attacks of bloody diarrhea

Expulsion of stringy, mucoid material

Colectomy cures intestinal disease, but extraintestinal manifestations may persist

Indeterminate Colitis

Histopathologic and clinical overlap between ulcerative colitis and Crohn disease is common

Not possible to make a distinction in up to 10% of patients with IBD

Colitis-Associated Neoplasia

• Long-term complications of ulcerative colitis and colonic Crohn disease
• Begins as dysplasia
  • Low grade
    • treated with colectomy or monitored closely
  • High grade
    • associated with invasive carcinoma at the same site or elsewhere in the colon
    • colectomy

Risk of dysplasia:

Risk increases sharply 8 to 10 years after disease initiation

Pancolitis are at greater risk than those with only left-sided disease.

Greater frequency and severity of active inflammation (characterized by the presence of neutrophils) may increase risk

Patients enrolled in surveillance programs approximately 8 years after diagnosis of IBD

If there is primary sclerosing cholangitis screen at time of diagnosis