McGuire had stated in his chapter that “sensory urgency is the common urodynamic finding in this discomfort bladder disease.” Indeed, IC is characterized by bladder pain, frequency and nocturia. NIDDK broadened the diagnostic criteria of IC and included persistent urge to void or frequency [4]. Although urgency has been a complaint of most patients, the content of urgency complained of by BPS patients is quite different from that which occurs in patients with OAB [5]. In order to solve the confused terminology of IC, the hypersensitive bladder syndrome (with or without pain) has been proposed by Homma Y. [6]. The fundamental diagnostic criteria for IC are bladder pain, reduced bladder capacity, and exclusion of other detectable diseases [4]. Although urodynamic study seems able to identify IC patients with increased bladder sensation and reduced bladder capacity, these urodynamic findings are not pathognomonic signs for IC. In order to increase the diagnostic accuracy, adding potassium sensitivity test (PST) might be helpful [7]. Even though, overlap of IC and OAB diagnosis remains in glomerulations and PST [8].

It is possible that mild degrees of urothelial dysfunction can also be found in other urinary tract diseases such as urolithiasis, bladder outlet obstruction, and overactive bladder syndrome [9]. These diseases cause urothelial dysfunction and, therefore, patients also have bladder irritative symptoms. If we classify IC according to symptoms and duration, these patients might also be categorized into having IC unless they were excluded by identifying characteristic pathologies. In addition, patients with IC have been found to have higher risks of irritable bowel syndrome, fibromyalgia, general fatigue and functional somatic syndrome, suggesting IC is involved in systemic inflammatory disorders [10–12]. Fluctuation of IC symptoms in non-ulcer IC might result from altered inert immunity from time to time. On the contrary, ulcer type IC might be organ confined disease that is resulted from localized bladder inflammation due to previous insult or trauma. The different IC phenotype and etiologies of disease make these two IC subtypes have different treatment strategy and outcome [13].

McGuire mentioned that some patients with IC might progress to a poorly compliant bladder in association with painful sensation. Urodynamic study provides evidence for an uncontrollable diseased bladder indicating that partial or total cystectomy with augmentation cystoplasty or urinary diversion are necessary. He also mentioned the urethral sphincter hyperactivity in IC. Because urethral striated sphincter activity is associated with inhibition of detrusor contractility, patients with IC usually complain of difficult urinating or interruption of urination. In AUA, EAU, Asian and ICI guidelines on IC, urodynamic study is considered as an optional procedure primarily to exclude other LUTD that might account for the similar IC symptoms [14–17]. However, patients with IC have been found to have increased bladder sensation, reduced bladder capacity, and increased outlet resistance. Some studies have reported a high percentage of IC patients have bladder outlet obstruction [18]. Increase of bladder afferent activities due to chronic inflammation might enhance urethral sphincter tonicity resulting in poor relaxation of pelvic floor muscle during voiding [19]. Whether the presence of bladder outlet obstruction is the cause or effect in the IC patient needs further evaluation. Based on the NIDDK criteria, those patients proven to have bladder outlet obstruction should be excluded from the diagnosis of IC [4]. Clinical research showed significant association between urodynamic variables and the degree of glomerulations after cystoscopic hydrodistention and the severity of clinical symptoms measured by IC symptom index and IC problem index [20].

In the original 1990 chapter, McGuire stated “we have not unreasonably assumed that inflammation may be the etiology of the uncomfortable symptoms in patients with interstitial cystitis. However, there is no real proof for that concept, and the actual cause of the uncomfortable bladder symptoms in IC remains unknown”. Up to now, IC remains a mysterious bladder disease. IC has been considered as an organ confined (bladder) inflammatory disease, but nowadays it is regarded as a heterogeneous syndrome. Patients might have different etiologies which result in similar clinical symptoms. Urothelial dysfunction, chronic bladder inflammation, and systemic functional disorders have been found closely related to the pathogenesis of IC and bladder pain syndrome (BPS). A distinct phenotype of IC patients with multiple sensitivities is identified [21]. Recent research on urine and serum biomarkers, and bladder tissue histopathology have also provided evidence for the clinical characteristics of IC, such as urothelial barrier defects, activation of sensory fibers and epitheliolymphocytic infiltration, all of which might contribute to the development of IC [22–25]. However, we still cannot classify IC into different subtypes for appropriate treatment.

Recent research on bladder mucosa have demonstrated that it has not only a barrier function, but also transmits sensory signals [26]. Abnormal urothelial function results in bladder hypersensitivity due to activation of sensory fibers. Abnormal proliferation of urothelial cells leads to immature intermediate cell location in the apical position, which lack barrier function. Inadequate e-cadherin and zonula occludens-1 cause tight junction defects and easy influx of urinary solutes such as potassium [27]. These pathogeneses are believed to result from chronic inflammation in the suburothelium. Increased plasma-lymphocytic cell infiltration has been demonstrated in IC patients with Hunner lesion, in which intense bladder pain and severe frequency urgency are the main symptoms [28].

PST has been recommended to detect the urothelial leakage in patients with IC [7]. However, urothelial leak is not only found in IC bladders but also in the bladders with urothelial cancer, irradiation cystitis, bladder outlet obstruction, overactive bladder or other LUTD [9]. Urothelial leakage is a pathology caused by acute or chronic inflammation in the bladder wall, therefore, any bladder insult that results in urothelial barrier defect may have a positive PST. More severe urothelial dysfunction is more susceptible to the stimulation of potassium, thus resulting in volume reduction in IC patients [20]. A previous study further found that in patients with storage symptoms refractory to medical treatment, small cystometric bladder capacity and a positive PST causing pain and elevated visual analog score, IC is highly likely [29]. The sensitivity of a positive PST in IC patients is higher than the glomerulations after hydrodistention [30].