What is the pathophysiology of Crohn's disease?

Pathophysiology of Crohn's Disease

Crohn's disease results from an inappropriate inflammatory reaction to intestinal flora in genetically predisposed individuals, characterized by transmural granulomatous inflammation that can affect any part of the gastrointestinal tract. 1

Genetic and Environmental Factors

• Crohn's disease arises from a complex interplay between genetic susceptibility, environmental factors, and altered gut microbiota, leading to dysregulated immune responses 2
• The disease is more prevalent in developed countries, suggesting environmental influences play a significant role in disease development 1
• Genetic predispositions have been identified, with NOD2 gene mutations being particularly important as they affect innate immune handling of bacterial components 3

Immune System Dysfunction

• The primary defect appears to be failure of the innate immune system's protective function in containing intraluminal bacteria locally 3
• Traditional understanding described Crohn's disease as primarily T-helper-1 mediated, but recent evidence points to additional pathways, particularly the interleukin-23/Th17 axis 3
• The dysregulated immune response leads to chronic inflammation and tissue damage 2

Barrier Dysfunction

• Epithelial barrier dysfunction is a key component in Crohn's disease pathophysiology 4
• There is significant reduction in intestinal secretion of products involved in barrier function 4
• Increased intestinal permeability allows overwhelming amounts of antigens to penetrate the mucosa, resulting in abnormal dendritic cell activation 4
• This barrier defect affects both para- and transepithelial routes of antigen transport 4

Inflammatory Process

• The inflammation in Crohn's disease is transmural (affecting all layers of the bowel wall) and granulomatous in nature 1
• Unlike ulcerative colitis, Crohn's disease is characterized by discontinuous or "skip" lesions that can occur anywhere in the gastrointestinal tract 1
• The inflammatory process leads to progressive structural damage over time with recurrent bouts of inflammation, resulting in stricture formation, penetrating sinuses, or fistulas 1

Alternative Hypothesis: Immunodeficiency

• Some researchers propose that Crohn's disease may actually represent an immunodeficiency rather than an excessive immune response 5
• This theory is supported by observations that genetic disorders with neutrophil function deficiencies can produce a syndrome indistinguishable from Crohn's disease 5
• Abnormal neutrophil function is well-documented in Crohn's disease patients 5
• This hypothesis suggests impaired mucosal neutrophil function leads to failure to effectively clear intramucosal microbes 5

Anatomical Distribution and Presentation

• Any portion of the gastrointestinal tract may be involved, with the small bowel alone affected in about one-third of patients, the colon alone in a somewhat higher percentage, and combined involvement in less than one-third 1
• Perianal disease is another common manifestation, occurring in 15-25% of pediatric patients 1
• In children, there is an inverse relationship between age and colonic involvement - younger patients are more likely to have colonic disease 1
• Pediatric patients are more likely to have upper gastrointestinal involvement than adults 1

Clinical Implications

• The chronic inflammatory process leads to common symptoms including abdominal pain, diarrhea, weight loss, and fatigue 6
• The transmural nature of inflammation explains complications like fistulas, abscesses, and strictures that are characteristic of Crohn's disease 1
• Understanding the pathophysiology has led to targeted therapies aimed at modulating the immune response 6
• The goal of treatment is to achieve deep and long-lasting remission to prevent complications and block disease progression 2