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Inflammatory Bowel Disease (IBD): Pathophysiology, Clinical Features, and Treatment

Introduction

Inflammatory Bowel Disease (IBD) is a chronic, relapsing, and remitting group of disorders primarily affecting the gastrointestinal tract. The two main types are Ulcerative Colitis (UC) and Crohn's Disease (CD). Both significantly impact quality of life and require a multidisciplinary approach for management. πŸ₯

Pathophysiology

The exact etiology of IBD remains unclear, but it is understood as a result of complex interactions between genetic susceptibility, immune dysregulation, environmental factors, and the gut microbiota.

  • Genetic Factors: Family history is a strong risk factor. Multiple susceptibility genes have been identified (e.g., NOD2 in Crohn's disease).
  • Immune Dysregulation: An inappropriate immune response to intestinal flora leads to chronic inflammation. In UC, inflammation is limited to the mucosa and submucosa, while in CD, it is transmural (involving all layers of the bowel wall).
  • Microbiome: Altered gut flora (dysbiosis) triggers or perpetuates inflammation.
  • Environmental Triggers: Smoking, diet, infections, and antibiotic use may influence disease onset and course.
  • Cytokines & Mediators: Pro-inflammatory cytokines like TNF-Ξ±, IL-1Ξ², and IL-6 play central roles in perpetuating inflammation.

πŸ“š Refer: Harrison's Principles of Internal Medicine, 20th Edition, Chapter 319; Robbins & Cotran Pathologic Basis of Disease, 10th Edition, Chapter 17.

Clinical Features

Ulcerative Colitis (UC)

  • Location: Confined to the colon and rectum; continuous lesions beginning at the rectum.
  • Symptoms:
  • Bloody diarrhea 🚽
  • Tenesmus (feeling of incomplete evacuation)
  • Abdominal pain (usually lower left quadrant)
  • Urgency and frequency
  • Systemic symptoms: fever, weight loss in severe cases
  • Extraintestinal Manifestations: Arthritis, uveitis, primary sclerosing cholangitis, erythema nodosum.

Crohn's Disease (CD)

  • Location: Can affect any part of the GI tract from mouth to anus; most commonly the terminal ileum and colon; skip lesions are characteristic.
  • Symptoms:
  • Chronic diarrhea (may or may not be bloody)
  • Crampy abdominal pain (often right lower quadrant)
  • Weight loss, malnutrition
  • Perianal disease: fissures, fistulas, abscesses
  • Extraintestinal Manifestations: Similar to UC but more frequent perianal involvement.

πŸ“š Refer: Harrison’s Principles of Internal Medicine, 20th Edition, Ch. 319; Kumar, Abbas & Aster’s Robbins & Cotran Pathologic Basis of Disease, Ch. 17; Mayo Clinic Proceedings on Crohn Disease[11], ACG Clinical Guidelines for UC[12].

Diagnosis

Diagnosis is based on a combination of clinical features, laboratory tests (CRP, ESR), endoscopic findings (colonoscopy with biopsy), and imaging studies. Histology helps differentiate UC from CD.

πŸ“š Refer: Lee JM et al., Clin Endoscop 2016; Spiceland & Lodhia, World J Gastroenterol 2018[19][15].

Treatment

General Principles

  • Goals: Induce and maintain remission, improve quality of life, minimize complications.
  • Approach: Depends on disease severity, location, complications, and patient preferences.

Ulcerative Colitis

  1. Aminosalicylates (5-ASA): First-line for mild-moderate disease.
  2. Corticosteroids: For moderate-severe flares; not for maintenance.
  3. Immunomodulators: Azathioprine or 6-MP for steroid-dependent/refractory cases.
  4. Biologic Therapy: Anti-TNF agents (infliximab), anti-integrins for moderate-severe or refractory cases.
  5. Surgery: Colectomy indicated for fulminant disease or cancer risk.

Crohn's Disease

  1. Corticosteroids: Mainstay for induction of remission.
  2. Immunomodulators: Azathioprine, methotrexate for maintenance.
  3. Biologics: Anti-TNF agents (e.g., infliximab), anti-integrins (vedolizumab), anti-interleukin agents.
  4. Antibiotics: For perianal or fistulizing disease.
  5. Surgery: Reserved for complications (strictures, fistulas); not curative.

πŸ“š Refer: Harrison’s Principles of Internal Medicine; Feuerstein JD et al., Mayo Clinic Proceedings 2017[11]; Rubin et al., Am J Gastroenterol 2019[12]; Cushing & Higgins JAMA 2021[20].

Conclusion

IBD is a multifactorial disease involving genetic predisposition and immune dysregulation against environmental triggers. It presents with gastrointestinal and extraintestinal symptoms. Management is tailored to disease type and severity and involves medications ranging from aminosalicylates to biologics, with surgery as a last resort in refractory cases.

References

  1. Harrison's Principles of Internal Medicine, 20th Edition, Ch. 319
  2. Robbins & Cotran Pathologic Basis of Disease, 10th Edition, Ch. 17
  3. Feuerstein JD, Cheifetz AS. Crohn Disease: Epidemiology, Diagnosis, and Management. Mayo Clinic Proceedings. 2017; 92(7): p.1088-1103.[11]
  4. Rubin et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019; 114(3): p.384-413.[12]
  5. Spiceland CM, Lodhia N. Endoscopy in inflammatory bowel disease: Role in diagnosis, management, and treatment. World J Gastroenterol. 2018; 24(35): p.4014-4020.[15]
  6. Lee JM, Lee KM. Endoscopic Diagnosis and Differentiation of Inflammatory Bowel Disease. Clin Endoscop. 2016; 49(4): p.370-5.[19]

Inflammatory Bowel Disease (IBD) – the collective term for Ulcerative Colitis (UC) and Crohn Disease (CD) – is a chronic, relapsing–remitting inflammatory disorder of the gastrointestinal (GI) tract. Although both entities share epidemiologic and therapeutic features, they differ in anatomic distribution, depth of injury and pathologic sequelae. A concise, evidence-based understanding of their pathophysiology, clinical presentation and management is essential for clinicians.

──────────────────────────────────────── 1. Pathophysiology ──────────────────────────────────────── 1.1 Genetic susceptibility
β€’ Heritability is strongest in CD (β‰ˆ10 % concordance in dizygotic and 35–50 % in monozygotic twins).
β€’ Genome-wide association studies identify >250 risk loci. NOD2, ATG16L1 and IRGM (autophagy), IL-23R and JAK2 (cytokine signaling) are among the best validated for CD; HLA-DRB1*0103 and ECM1 polymorphisms are more specific to UC.ΒΉ

1.2 Mucosal immune dysregulation
β€’ Aberrant innate sensing of commensal microbes activates dendritic cells, skewing T-cell differentiation.
β€’ CD is dominated by Th1/Th17 cytokines (IL-12, IL-23, IFN-Ξ³, IL-17, TNF-Ξ±); UC shows a modified Th2 pattern (IL-5, IL-13) with relatively less IL-17.Β²
β€’ Defective regulatory T-cell (Treg) function fails to dampen this response.

1.3 Barrier dysfunction & microbiome
β€’ Paneth-cell dysfunction (ATG16L1 variants) and reduced Ξ±-defensins weaken innate antibacterial defense.
β€’ Tight-junction protein down-regulation increases epithelial permeability; bacterial components leak into the lamina propria and fuel inflammation.Β³
β€’ Dysbiosis: ↓ Firmicutes (e.g., Faecalibacterium prausnitzii) and ↑ Proteobacteria (e.g., adherent-invasive E. coli) correlate with disease activity.⁴

1.4 Environmental modulators
β€’ Cigarette smoking increases risk and worsens course of CD, but is paradoxically protective in UC.
β€’ NSAIDs, westernized diet (high emulsifiers), stress and antibiotic exposure early in life have been implicated as triggers.

──────────────────────────────────────── 2. Clinical Features ──────────────────────────────────────── 2.1 Ulcerative Colitis⁡
β€’ Distribution: Continuous inflammation confined to colonic mucosa, starting in rectum; backwash ileitis (<10 %).
β€’ Main symptoms: Bloody diarrhea with mucus, urgency, tenesmus, left-sided abdominal cramps.
β€’ Severity indices: Mayo score (0–12).
β€’ Complications: Severe fulminant colitis, toxic megacolon, colorectal carcinoma (risk begins β‰ˆ8 y after onset; cumulative 2 %/10 y, 8 %/20 y).

2.2 Crohn Disease⁡
β€’ Distribution: β€œSkip” lesions anywhere from mouth to anus; terminal ileum Β± right colon most common. Transmural inflammation β†’ strictures, fistulas, abscesses.
β€’ Main symptoms: Intermittent, crampy RLQ pain, chronic non-bloody diarrhea, weight loss.
β€’ Phenotypes: Inflammatory (B1), stricturing (B2), fistulizing (B3); Paris/Montreal classification guides therapy.
β€’ Complications: Malabsorption (B12, bile salts), nephrolithiasis, small-bowel adenocarcinoma, perianal disease (up to 40 %).

2.3 Extra-intestinal manifestations (both)
Arthropathies (peripheral & axial), erythema nodosum, pyoderma gangrenosum, uveitis/episcleritis, primary sclerosing cholangitis (more UC), venous thrombo-embolism.

──────────────────────────────────────── 3. Principles of Treatment ──────────────────────────────────────── Goals: Induce remission, maintain steroid-free remission, prevent structural damage, improve quality of life. Management is individualized by disease, location, severity, prior therapy and comorbidities.⁢

3.1 Ulcerative Colitis
Mild–Moderate (proctitis / left-sided)
β€’ 5-Aminosalicylates (topical Β± oral mesalamine 2–4 g/d) – induction & maintenance.
β€’ Budesonide MMX 9 mg/d if 5-ASA failure. 

           Moderate–Severe  
           β€’  Systemic corticosteroid (prednisone 40–60 mg/d PO or IV methylpred 60 mg/d).  
           β€’  If steroid-dependent/refractory β†’ immunomodulator (azathioprine 2–2.5 mg/kg) or biologic.

           Biologics/Small molecules  
           β€’  TNF-Ξ± antagonists: infliximab, adalimumab, golimumab.  
           β€’  Anti-integrin: vedolizumab (Ξ±4Ξ²7 gut-selective).  
           β€’  Anti-IL-12/23: ustekinumab.  
           β€’  JAK inhibitor: tofacitinib (oral).

           Acute severe UC (Truelove & Witts criteria)  
           β€’  IV steroids; if no response in 3–5 d β†’ rescue with infliximab or cyclosporine.  
           β€’  Colectomy indicated for perforation, uncontrolled hemorrhage or refractory disease.

3.2 Crohn Disease
Mild ileocecal
β€’ Budesonide-CR 9 mg/d up to 12 wk Β± antibiotics for bacterial overgrowth. 

           Moderate–Severe or Any Perianal/Fistulizing  
           β€’  Prednisone 40–60 mg/d PO for induction; no role in maintenance.  
           β€’  Early introduction of biologic (β€œtop-down”) improves mucosal healing in high-risk patients (young onset, deep ulcers, perianal disease).  
           β€’  Maintenance: azathioprine, methotrexate SC 25 mg/wk, TNF-Ξ± antagonists, vedolizumab or ustekinumab.  
           β€’  Fistulas: combined infliximab + surgical setons; add antibiotics (cipro/metronidazole).

           Stricture/Obstruction  
           β€’  Endoscopic balloon dilation for short fibrotic lesions; otherwise resection or stricturoplasty.

3.3 General measures
β€’ Vaccinations (influenza, pneumococcus, HBV, HPV) before immunosuppression.
β€’ Screen for latent TB and viral hepatitis prior to biologics.
β€’ Calcium/vitamin D + bisphosphonate prophylaxis if long-term steroids.
β€’ Colonoscopic dysplasia surveillance: begin 8 y after diagnosis in pancolitis (interval 1–3 y).

──────────────────────────────────────── 4. Prognosis ──────────────────────────────────────── β€’ Up to 50 % of CD patients will require at least one surgery within 10 y; postoperative biologic therapy halves recurrence-free intervals.
β€’ Colectomy is curative for colonic UC but does not remove extra-intestinal risks.
β€’ With early use of steroid-sparing and biologic agents, sustained deep remission (clinical + endoscopic) is achievable in 40–60 % of patients within 1–2 y.⁷

──────────────────────────────────────── References (primary texts & key guidelines) ──────────────────────────────────────── 1. Colombel J-F, Mahadevan U. Inflammatory Bowel Disease. In: Jameson J et al., eds. Harrison’s Principles of Internal Medicine. 21st ed. New York: McGraw-Hill; 2022. Ch 357.
2. Podolsky DK. Inflammatory Bowel Disease. N Engl J Med. 2002;347:417-429.
3. Baumgart DC, Sandborn WJ. Crohn’s Disease. Lancet. 2012;380:1590-1605.
4. Kostic AD, Xavier RJ, Gevers D. The Microbiome in IBD. Nat Rev Gastroenterol Hepatol. 2014;11:497-505.
5. Feuerstein JD, Issokson LS, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2020;115:1628-1652.
6. Lichtenstein GR, Loftus EV Jr, et al. ACG Clinical Guideline: Management of Crohn’s Disease. Am J Gastroenterol. 2018;113:481-517.
7. Louis E, et al. Early Combined Immunosuppression for CD (SONIC trial). N Engl J Med. 2010;362:1383-1395.

(Chapter numbers correspond to the 21st edition of Harrison’s Principles of Internal Medicine, 2022.)