What is the etiology of interstitial cystitis?

Etiology of Interstitial Cystitis/Bladder Pain Syndrome

The cause of interstitial cystitis (IC/BPS) remains unknown, but current evidence indicates it is a multifactorial systemic hypersensitivity disorder involving urothelial dysfunction, chronic inflammation, and neural upregulation rather than a single isolated bladder disease. 1

Primary Pathophysiologic Mechanisms

The most current understanding conceptualizes IC/BPS as part of a family of hypersensitivity disorders affecting multiple organs with overlapping pathophysiology, rather than a primary bladder disorder. 1 The key pathophysiologic components include:

Urothelial Barrier Dysfunction

• Deficiency of the glycosaminoglycan (GAG) layer allows urinary irritants to penetrate the bladder wall, triggering inflammation and pain. 1, 2
• This urothelial leakage permits toxic substances in urine to reach deeper bladder tissues. 3

Chronic Inflammation

• Mast cell activation and inflammatory mediators contribute to bladder wall changes and symptom generation. 2, 4
• Reactive oxygen species impair bladder function through multiple molecular mechanisms including kinase signaling pathways and nociceptive receptor activation. 2

Neural Dysregulation

• Both peripheral and central nervous system sensitization amplify pain signals. 1, 4
• Neural upregulation creates a state of heightened sensitivity that extends beyond the bladder. 1

Evidence for Systemic Rather Than Isolated Disease

IC/BPS commonly coexists with fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, Sjögren's syndrome, chronic headaches, and vulvodynia, strongly suggesting systemic dysregulation rather than isolated bladder pathology. 1 This clustering of conditions indicates shared underlying mechanisms of hypersensitivity and central sensitization. 1

Mental health disorders including depression and anxiety frequently co-occur, with evidence suggesting a common biological mechanism rather than purely reactive symptoms. 1

Proposed Contributing Factors

While the exact etiology remains elusive, multiple factors have been implicated:

• Autoimmune dysfunction may play a role in disease development. 4, 3
• Genetic predisposition combined with environmental triggers likely contributes to disease manifestation. 4
• Childhood trauma/abuse and subsequent stress response system dysregulation might be implicated in some patients. 3
• Bacterial infection has been proposed but not definitively proven. 2, 4
• Circadian rhythm disturbance has been linked to reactive oxygen species and IC/BPS pathogenesis. 2

Clinical Implications

Common Pitfall to Avoid

Do not conceptualize IC/BPS as purely a bladder disease requiring only urologic intervention. The systemic nature of the disorder means that patients often require multimodal treatment addressing inflammation, neural sensitization, and pain pathways simultaneously. 1

Diagnostic Consideration

IC/BPS is defined as bladder pain, pressure, or discomfort associated with lower urinary tract symptoms lasting more than six weeks in the absence of infection or other identifiable causes, making it fundamentally a diagnosis of exclusion. 5

The heterogeneity of IC/BPS phenotypes and the multifactorial nature of its pathophysiology explain why many clinical trials fail and why patients experience variable treatment responses to non-targeted interventions. 2