What is the pathophysiology of interstitial cystitis?

Pathophysiology of Interstitial Cystitis/Bladder Pain Syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is fundamentally a bladder pain disorder characterized by urothelial dysfunction, chronic inflammation, and neural upregulation that often exists as part of a broader systemic hypersensitivity syndrome rather than an isolated bladder pathology. 1

Primary Bladder Pathology vs. Systemic Disorder

The exact origin remains uncertain—IC/BPS may represent either a primary bladder disorder or bladder symptoms secondary to systemic dysregulation. 1 The most current understanding conceptualizes IC/BPS as a member of a family of hypersensitivity disorders affecting multiple somatic and visceral organs with overlapping pathophysiology. 1

Evidence for Systemic Involvement:

• IC/BPS commonly coexists with fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, Sjögren's syndrome, chronic headaches, and vulvodynia, suggesting systemic dysregulation rather than isolated bladder disease. 1
• Some patients exhibit IC/BPS as part of a continuum with overactive bladder syndrome, sharing pathophysiologic mechanisms. 1
• Mental health disorders including depression and anxiety frequently co-occur, with evidence suggesting a common biological mechanism rather than purely reactive symptoms. 1

Urothelial Dysfunction and Barrier Defects

The bladder urothelium demonstrates intrinsic pathology with defective barrier function as a central mechanism. 2, 3

Specific Urothelial Abnormalities:

• Antiproliferative factor (APF) is uniquely expressed by urothelial cells in IC/BPS bladders, representing a major pathophysiologic marker. 3
• Defects in the glycosaminoglycan (GAG) layer allow irritating urinary solutes to penetrate the urothelium, triggering inflammation and pain. 4, 5, 2
• Pentosan polysulfate sodium adheres to the bladder wall mucosal membrane and may act as a buffer controlling cell permeability, preventing irritating solutes from reaching cells. 5
• Urothelial cells express neuronal receptors and release neurotransmitters, functioning similarly to neurons in pain signaling. 3

Inflammatory Cascade

Chronic inflammation plays a confirmed central role in IC/BPS pathogenesis, creating a self-perpetuating cycle. 6

Inflammatory Mechanisms:

• Mast cell activation occurs in the bladder wall, releasing inflammatory mediators that perpetuate tissue damage. 7, 8
• Possible initiating factors include chronic or subclinical infection, autoimmunity, genetic susceptibility, toxin exposure, and pelvic floor dysfunction, though no single cause has been definitively established. 7, 6
• The inflammatory response becomes self-sustaining regardless of the initial trigger, requiring multimodal therapy to break the cycle. 6

Neural Upregulation: Peripheral and Central Sensitization

Neural upregulation occurs both peripherally in the bladder and centrally in the spinal cord, amplifying pain signals and creating hypersensitivity. 8

Peripheral Neural Changes:

• Upregulation of proteinase-activated receptors, tryptase, beta-nerve growth factor, inducible nitric oxide synthase, nuclear transcription factor-κB, c-Fos, phosphodiesterase 1C, cAMP-dependent protein kinase, and proenkephalin B occurs in bladder tissue. 8
• The purinergic pathway is upregulated in IC/BPS urothelial cells—bladder distention releases ATP from urothelial cells, activating purinergic P2X3 receptors on afferent nerves. 3, 8
• ATP activation of P2X3-expressing afferents represents fundamental signaling in bladder sensation and pain, playing a critical role in bladder reflexes. 8

Central Neural Changes:

• Fos proteins in spinal cord neurons are upregulated in chronic cystitis, indicating central sensitization. 8
• Neural upregulation contributes to chronicity of pain, urgency, and frequency, though whether this is causative or consequential remains unclear. 8

Hunner Lesion vs. Non-Hunner Subtypes

IC/BPS presents in two distinct phenotypes with different underlying pathology requiring different treatment approaches. 2

Hunner Lesion IC (HIC):

• Characterized by visible inflammatory lesions on cystoscopy with more severe inflammation and potential viral etiology. 2
• Associated with smaller bladder capacity and high-grade glomerulations. 2

Non-Hunner IC (NHIC):

• Demonstrates urothelial defects without visible lesions, primarily involving barrier dysfunction. 2
• Histopathology shows chronic inflammation and higher urothelial dysfunction without discrete lesions. 2

Clinical Implications of Pathophysiology

The multifactorial pathophysiology explains why no single treatment works universally and why multimodal therapy targeting different mechanisms is necessary. 6

Key Pathophysiologic Targets for Treatment:

• Urothelial barrier repair with GAG layer replacement agents like hyaluronic acid or pentosan polysulfate. 4, 5, 2
• Inflammation reduction through various anti-inflammatory approaches. 2, 6
• Neural modulation to address peripheral and central sensitization. 8
• Pain pathway interruption throughout the treatment course. 4

Common Pitfall:

Do not conceptualize IC/BPS as a single disease entity—it represents a final common pathway of bladder pain from multiple potential mechanisms, explaining the heterogeneous treatment responses and the need for individualized therapeutic combinations targeting the specific pathophysiologic mechanisms active in each patient. 1, 2