Current Understanding and Future Perspectives of Interstitial Cystitis/Bladder Pain Syndrome

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by suprapubic pain and lower urinary tract symptoms. Perhaps because of the heterogeneous nature of this disease and its multifactorial etiology, clinical trials in allinclusive populations of IC/BPS patients without phenotyping in the last decade have mainly failed to discover new therapeutic modalities of IC/BPS. Thus, phenotyping IC/BPS, aimed at identifying bladder-centric and/or bladder-beyond pathologies, including cystoscopic observation of Hunner or non-Hunner lesions of the bladder mucosa, is particularly important for the future of IC/BPS management. Based on recent discussions at international conferences, including the International Consultation on IC, Japan, it has been proposed that Hunner-lesion IC should be separated from other non-Hunner IC/BPS because of its distinct inflammatory profiles and epithelial denudation compared with non-Hunner IC/BPS. However, there are still no standard criteria for the diagnosis of Hunner lesions other than typical lesions, while conventional cystoscopic observations may miss atypical or small Hunner lesions. Furthermore, diagnosis of the bladder-centric phenotype of IC/BPS requires confirmation that identified mucosal lesions are truly a cause of bladder pain in IC/BPS patients. This review article discusses the current status of IC/BPS pathophysiology and diagnosis, as well as future directions of the proper diagnosis of bladder-centric IC/BPS, in which pathophysiological mechanisms other than those in inflammatory pathways, such as angiogenic and immunogenic abnormalities, could also be involved in both Hunner-lesion IC and non-Hunner IC/BPS. It is hoped that this new paradigm in the pathophysiological evaluation and diagnosis of IC/BPS could lead to pathology-based phenotyping and new treatments for this heterogeneous disease.

Keywords: Angiogenesis; Bladder pain syndrome; Cystoscopy; Hunner lesion; Interstitial cystitis; Narrow-band imaging.

Fig. 1.

Cystoscopic images of Hunner lesions. Typical Hunner lesions, based on the definition in the ESSIC classification (BPS type 3), in 4 different IC/BPS patients are shown. ESSIC, International Society for the Study of Bladder Pain Syndrome; BPS, bladder pain syndrome; IC, interstitial cystitis.

Fig. 2.

Overexpression of angiogenic factors in the bladder of IC/BPS patients. The images show the results of immunohistochemical staining for epithelial and submucosal CD44, transforming growth factor (TGF)-β, and PD-ECGF/TP in bladder tissue sections from patients with IC/BPS. (A) Positive staining in the severe IC type (Hunner-type IC [HIC] patients with severe pain) is seen in the deeper part of the submucosal layer. (B) Positive staining in the mild IC type (non-Hunner-type patients with relatively mild pain) is present along the basement membrane of the bladder epithelium; ×200 magnification. (Reproduced from Ueda T, et al. J Urol 2002;167:347-51 [32]). PD-ECGF, platelet-derived endothelial cell growth factor; TP, thymidine phosphorylase; IC, interstitial cystitis; BPS, bladder pain syndrome.

Fig. 3.

The angiogenic mechanisms inducing glomerulations. In IC/BPS bladders, overexpression of angiogenic factors such as VEGF and PD-ECGF includes neovascularization with increases in weak microvessels, leading to rupture of microvessels during bladder distention, seen as glomerulations during cystoscopy (Reproduced from Ueda T, et al. J Urol 2002;167:347-51 [32]). IC, interstitial cystitis; BPS, bladder pain syndrome; VEGF, vascular endothelial growth factor; PD-ECGF, platelet-derived endothelial cell growth factor.

Fig. 4.

Immunogenic and angiogenic pathophysiology of IC/BPS. In bladder-centric IC/BPS, increased bladder epithelial permeability due to disturbances in the glycosaminoglycan (GAG) layer and activation of inflammatory cells including mast cells, T cells, and B cells has been proposed as part of multiple etiologies. Disturbance of the bladder epithelium, overexpression of angiogenic factors, such as platelet-derived endothelial cell growth factor (PD-ECGF), occurs in the submucosa. These angiogenic factors are present in very small amounts in the body or bladder under normal conditions. However, angiogenic factor overexpression in IC/BPS may result from abnormalities in GAG because disruption of the GAG layer, which is a protective factor of the bladder epithelium, causes the release of adhesion factors in the GAG layer, such as CD44 and TGF-β (an adhesion molecule), which are known to bind with angiogenic factors that are present in very small amounts via heparin-binding and become solidified. This has been elucidated as part of the wound healing process; thus, it is considered that overexpression of angiogenic factors is involved in tissue fibrosis leading to bladder atrophy. The onset of IC/BPS starts with various insults to the bladder epithelium, for example by previous bacterial infection and/or harmful substances such as K⁺ and H⁺ ions in the urine. These noxious stimuli are detected by inflammatory cells such as type 2 helper T lymphocytes, which then send signals to activate mast cells. Mast cells play an important role in the inflammatory process to induce angiogenic factors and immunostimulatory factors to activate other immunocompetent cells. These stimulating factors are presumed to sensitize bladder afferent pathways, especially the C-fiber type, thereby causing IC/BPS symptoms (pain and urgency). MΦ, macrophage; Eos, eosinophils; IC, interstitial cystitis; BPS, bladder pain syndrome; TGF, transforming growth factor.

Fig. 5.

Symptomatic and pathophysiological overlaps between IC and OAB as the frequency-urgency syndrome. Bladder-centric IC and OAB exhibit pathophysiological changes at a higher degree in the epithelial/submucosal and submucosal/muscle regions, respectively; however, hallmark symptoms such as urgency are often found in both disease conditions. IC, interstitial cystitis; OAB, overactive bladder.

Fig. 6.

Hunner lesions: white-light imaging (A) and narrow-band imaging (B) in 2 patients with IC/BPS. IC, interstitial cystitis; BPS, bladder pain syndrome.

Fig. 7.

Representative cystoscopic images of the normal bladder (A) and the non-Hunner IC bladder under white-light imaging (B) or narrow-band imaging (NBI) (C). (A) The bladder epithelial mucosa is largely whitish in color with multiple folds on the mucosal surface in the normal bladder. Furthermore, the normal mucosal epithelium is stretchable in all directions during bladder distention because it is loosely connected to the underlying muscle layer. (B, C) Abnormal bladder epithelium characterized by stretched, hypervascular mucosa without mucosal folds in the non-Hunner IC bladder, the appearance of which is similar to the so-called “lead pipe sign” of ulcerative colitis during colonoscopy. IC, interstitial cystitis.