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Inflammatory Bowel Disease (IBD) - Long Question & Answer

Based on Robbins & Kumar Basic Pathology and Robbins, Cotran & Kumar Pathologic Basis of Disease

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Q1. Define IBD. What are its two major subtypes and how do they differ fundamentally?

1. Ulcerative Colitis (UC) - limited to the colon and rectum, involving only the mucosa and submucosa.
2. Crohn Disease (CD) - may involve any part of the GI tract (from mouth to anus) and typically produces transmural inflammation.

• Distribution of affected sites
• Morphologic expression of disease at those sites

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Q2. Describe the epidemiology of IBD.

• Both UC and Crohn disease most frequently present in adolescents and young adults (teenage years to early 20s), but can develop at any age.
• IBD is most common among people of European descent, and in the United States occurs 3-5 times more often in eastern European (Ashkenazi) Jewish people.
• Most common in North America, northern Europe, and Australia.
• Incidence is rising in Africa, South America, and Asia, where prevalence was historically low.

• Improved food storage and decreased food contamination
• Changes in gut microbiome composition
• Inadequate development of regulatory immune processes that limit mucosal immune responses
• This allows mucosa-associated microbes to trigger persistent chronic inflammation in susceptible hosts.

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Q3. Explain the pathogenesis of IBD in detail.

1. Genetic susceptibility
2. Abnormal mucosal immune responses
3. Host-microbiome interactions
4. Epithelial barrier dysfunction

A. Genetic Factors

• Over 200 IBD-associated risk alleles have been identified; they account for less than 20% of disease risk in Crohn disease.
• NOD2 gene (nucleotide oligomerization binding domain 2):
  • Most strongly associated with Crohn disease in European populations
  • Encodes an intracellular sensor of muramyl dipeptide (a bacterial cell wall component)
  • Disease-associated NOD2 variants are ineffective at defending against intestinal bacteria, allowing bacteria to penetrate the epithelium and trigger inflammatory reactions
  • Three major NOD2 risk alleles present in only ~30% of CD patients vs. 5% of healthy individuals
  • NOD2 variants are rare in Asian populations - so other factors are important
  • NOD2 and PTPN22 variants: increase Crohn risk but are protective in ulcerative colitis
• Concordance rates: Monozygotic twins - ~50% for CD, ~20% for UC (genetic factors less dominant in UC)
• Additional IBD-associated genes involve autophagy-related pathways - involved in host cell responses to intracellular bacteria.

B. Abnormal Mucosal Immune Responses

• Microbial antigens are presented to CD4+ helper T cells, inducing differentiation into Th1 and Th17 cells (driven by IL-12 and IL-23).
• These activate macrophages, recruit neutrophils, and release proinflammatory cytokines (especially TNF).
• Defects in regulatory T cells (especially IL-10-producing subset) may fail to dampen the immune response - individuals with mutations in IL-10 or IL-10 receptor genes develop severe early-onset colitis.
• IL-13 (Th2 cytokine): mucosal production is increased in UC and, to a lesser degree, in CD.
• Effective treatments with anti-TNF antibodies and anti-IL-12/IL-23 antibodies support the role of these cytokines.

C. Intestinal Microbiota

• The intestinal lumen contains the largest reservoir of potential antigens in the body.
• IBD is rare in germ-free animal models.
• Probiotic bacteria can be beneficial in IBD treatment.
• Dysbiosis - altered microbial composition is seen in IBD:
  • Decrease in protective species such as Faecalibacterium prausnitzii (produces butyrate)
  • Increase in mucosal-adherent/invasive bacteria
• It remains unclear if microbial changes are a cause or consequence of IBD.

D. Epithelial Defects

• Normally, intestinal epithelium forms a barrier that limits contact between luminal microbes and the mucosal immune system.
• ATG16L1 and IRGM (autophagy genes): IBD-associated polymorphisms affect autophagy in Paneth cells, impairing their antibacterial secretory function.
• IBD-associated barrier defects allow bacterial components to enter the lamina propria, triggering and sustaining the inflammatory cascade.

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Q4. Compare and contrast the gross and microscopic morphology of Crohn disease and Ulcerative Colitis.

Comparison Table (Table 17.8 / Table 13.5 from Robbins):

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Crohn Disease - Morphology

• Any part of GI tract affected; most commonly terminal ileum (ileocecal region in ~40-60% of cases)
• "Skip lesions" - alternating areas of disease and normal bowel separated by areas of normal mucosa ("skip areas")
• Cobblestone appearance - mucosal islands lift between deep ulcers and submucosal edema
• Deep, knife-like ulcers (fissures) that can penetrate the entire bowel wall
• Strictures - from transmural fibrosis; cause obstruction ("string sign" on barium)
• Creeping fat (fat wrapping) - mesothelial fat extends over the bowel surface
• Thick, rubbery bowel wall due to transmural edema and fibrosis
• Fistulas and sinuses - deep fissures may form internal fistulae (enterovesical, enterocutaneous, rectovaginal) or abscesses

• Transmural inflammation with lymphoid aggregates through all layers
• Non-caseating granulomas (~35% of cases) - a hallmark; can be present in all layers including lymph nodes and distant organs
• Crypt abscesses and crypt distortion
• Haphazard crypt organization from repeated injury and regeneration
• Active disease shows ulceration with purulent exudate
• Submucosal and serosal granulomas

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Ulcerative Colitis - Morphology

• Always involves the rectum and extends proximally in a continuous (non-skip) fashion
• Pancolitis = disease of entire colon; left-sided UC, ulcerative proctitis, proctosigmoiditis based on extent
• Small intestine not affected - may have backwash ileitis (mild distal ileal inflammation in severe pancolitis)
• Focal appendiceal or cecal inflammation ("cecal red spot") may be present in left-sided UC
• Mucosa: ranges from slightly red and granular to extensive, broad-based ulcers
• Pseudopolyps (inflammatory polyps) - isolated islands of regenerating mucosa bulging into lumen; tips may fuse to form mucosal bridges
• No skip lesions, no thickening of wall, no strictures, serosal surface normal
• Chronic disease: mucosal atrophy with smooth surface, loss of normal folds

• Mucosal and submucosal inflammation only (not transmural)
• Crypt abscesses (neutrophils within crypt lumens)
• Crypt distortion
• Pseudopyloric metaplasia and Paneth cell metaplasia in chronic disease
• No granulomas (a key distinguishing feature from Crohn disease)
• Basal plasmacytosis and increased lamina propria cellularity

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Q5. What are the clinical features of Crohn Disease and Ulcerative Colitis?

Crohn Disease - Clinical Features

• Intermittent bouts of diarrhea, fever, and abdominal pain separated by asymptomatic intervals
• Abdominal right lower quadrant pain and tenderness (due to terminal ileal involvement)
• Malabsorption - fat and fat-soluble vitamins (A, D, E, K), vitamin B12 (terminal ileum)
• Weight loss, anemia, hypoproteinemia
• Fistulas and abscesses
• Perianal disease - fistulas, skin tags, abscesses
• Strictures leading to bowel obstruction
• Up to 75% have disease recurrence after surgical resection

Ulcerative Colitis - Clinical Features

• Bloody diarrhea - most common presenting symptom
• Colicky abdominal pain relieved by defecation
• Tenesmus (rectal urgency)
• Disease follows a relapsing and remitting course
• Factors triggering onset: smoking cessation can precede or worsen UC; some cases follow infectious enteritis
• Smoking is actually partially protective in UC (opposite of Crohn disease)
• p-ANCA (perinuclear antineutrophil cytoplasmic antibodies): present in up to 75% of UC patients, only ~10% of Crohn patients - a useful serology
• ASCA (anti-Saccharomyces cerevisiae antibodies): more common in Crohn disease

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Q6. What are the extraintestinal (systemic) manifestations of IBD?

• No granulomas are found in extraintestinal sites in UC (unlike Crohn disease, where granulomas can be found in lymph nodes and other distant organs).

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Q7. Discuss the risk of colorectal cancer in IBD.

1. Duration of disease - risk increases beginning 8-10 years after disease initiation
2. Extent of involvement - pancolitis carries greater risk than partial involvement
3. Severity and frequency of active inflammation - more neutrophilic activity = greater carcinogenic risk

• Risk in UC is confined to the colon
• In Crohn disease, patients are also at increased risk of small intestinal adenocarcinoma

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Q8. What are the serologic markers and lab findings in IBD?

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Q9. What is toxic megacolon and when does it occur?

• Characterized by massive colonic dilation (>6 cm on X-ray) with systemic toxicity (fever, leukocytosis, tachycardia, hemodynamic instability)
• Results from severe transmural inflammation (when inflammation extends beyond the mucosa) impairing neuromuscular function of the colon
• Risk of perforation is high
• Requires emergent management - if unresponsive to medical therapy, emergency colectomy is needed

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Q10. What is the treatment approach for IBD?

Medical Therapy:

• Therapies effective in Crohn disease (especially anti-TNF) are also effective in UC.
• Smoking cessation may worsen UC - nicotine trials have been disappointing.

Surgery:

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Q11. Write a short note on Granulomas in Crohn Disease.

• Non-caseating (sarcoid-like) granulomas are found in approximately 35% of Crohn disease cases - they are a hallmark but not universal.
• Unlike tuberculosis, they do NOT undergo central caseous necrosis.
• They can be found in:
  • Any layer of the bowel wall (mucosa, submucosa, muscularis, serosa)
  • Mesenteric lymph nodes
  • Extraintestinal sites (liver, lungs, skin, eyes) in Crohn disease
• Ulcerative colitis does NOT produce granulomas - this is a key distinguishing histologic feature.
• The presence of granulomas in surgical biopsy specimens helps confirm the diagnosis of Crohn disease when the clinical picture is ambiguous.

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Q12. What is meant by "skip lesions" and "cobblestone appearance" in Crohn disease?

• Alternating segments of diseased and grossly normal bowel, typically separated by several centimeters to several centimeters of uninvolved mucosa.
• This discontinuous pattern distinguishes Crohn disease from UC, which shows continuous mucosal involvement.
• Skip lesions can involve multiple bowel segments simultaneously (e.g., terminal ileum and sigmoid colon, with normal intervening bowel).

• Deep, knife-like ulcers (fissures) run along and between the mucosal folds of the bowel.
• The remaining edematous but intact mucosa is elevated by submucosal edema and fibrosis.
• The result is a surface that resembles cobblestones - irregular nodular mucosal islands interspersed with linear ulcer furrows.
• Seen endoscopically and on barium studies.

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Summary: Key "Buzzwords" to Remember

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