- Author: Eric S Rovner, MD; Chief Editor: Edward David Kim, MD, FACS more...
Interstitial cystitis is a clinical syndrome characterized by daytime and nighttime urinary frequency, urgency, and pelvic pain of unknown etiology. Interstitial cystitis has no clear etiology or pathophysiology, and diagnostic criteria for the syndrome remain undefined. Despite considerable research, universally effective treatments do not exist; therapy usually consists of various supportive, behavioral, and pharmacologic measures. Surgical intervention is rarely indicated.
The International Continence Society has coined the term painful bladder syndrome (suprapubic pain with bladder filling associated with increased daytime and nighttime frequency, in the absence of proven urinary infection or other obvious pathology) and reserves the diagnosis of interstitial cystitis for patients with characteristic cystoscopic and histologic features of the condition.
An international consensus panel was able to generally agree on the following definition of interstitial cystitis/bladder pain syndrome (IC/BPS): unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder and associated with lower urinary tract symptoms of more than 6 weeks duration, in the absence of infection or other identifiable causes. American Urological Association (AUA) guidelines published in 2011 and amended in 2014 use an evidence-based approach to provide a clinical framework for the diagnosis and management of this condition.[2, 3, 4]
In 1887, Skene initially described a condition characterized by inflammation that destroyed the urinary bladder "mucous membrane partly or wholly and extended to the muscular parietes." Guy Hunner popularized the disease with the description of characteristic bladder wall ulcers in association with a symptom complex of chronic bladder inflammation. The first comprehensive epidemiologic description of interstitial cystitis is credited to Hand, who in 1949 described the widespread, small, submucosal bladder hemorrhages and the significant variation in bladder capacity characteristic of the condition.
Despite years of intensive research, there are no specific clinical or urinary markers currently clinically available; no absolutely specific radiographic, laboratory, or serologic findings; and no biopsy patterns that are pathognomonic for interstitial cystitis. Some research suggests that the following may all play a role in the disease pathophysiology: (1) pelvic floor dyfunction, (2) dysregulated immune or inflammatory signals, (3) neural hypersensitivity, and (4) disruption of the proteoglycan/glycosaminoglycan (GAG) layer. Interstitial cystitis, howerver, remains a diagnosis of exclusion (see Presentation, DDx, and Workup.)
Intensive study has been done to attempt to identify biomarkers for IC/BPS. Some interesting studies have shown that bladder nitric oxide is an accurate marker for Hunner lesions, but these are not present in all patients, and the test requires specific equipment, which has limited widespread clinical use. Differences in levels of cytokines and chemokines, specifically CXCL-10, have shown some ability to differentiate patients with and without Hunner lesions. Other studies of ulcerative IC/BPS have shown that numerous other cytokines and chemokines are up-regulated as well, heralding a possible urinary test to identify patients.
An additional substance shown to be up-regulated in IC/BPS patients is antiproliferative factor (APF). This small 8–amino-acid peptide has been associated with suppression of cell growth, increases in transcellular permeability, and lowering of levels of proteins that form intercellular junctional complexes. It is synthesized and secreted from bladder epithelial cells from patients with IC/BPS and may play a key role in pathophysiology. In vitro studies have shown that removal of APF from cell culture media restored cell proliferation and membrane integrity. Studies have also suggested APF in the therapeutic effect of hydrodistension in patients with IC/BPS, although further confirmatory studies are necessary.
The most important element in treating patients with interstitial cystitis is education and emotional support. Periodic exacerbations are managed as they occur because no long-term therapy has been shown to prevent or delay recurrent episodes. Therefore, the purpose of treatment is to palliate and alleviate symptoms.
Because no discrete pathognomonic pathologic criteria exist for assessing and monitoring disease severity, indications and goals for treatment are based on the degree of patient symptoms. Assessing patient response to treatment is also complicated because of the subjective nature of symptoms; the waxing and waning nature of symptoms without treatment; and the lack of objective serologic, physical, or histopathologic findings. Conservative measures and oral or intravesical treatments are considered first-line treatment. (See Treatment.)
The pathophysiology of interstitial cystitis is poorly understood. Various etiologies have been proposed, including infectious, inflammatory, autoimmune, hypoxia-related, and neurologically related. However, none of these adequately explains the variable presentations, clinical course, or response to therapies. This may indicate that interstitial cystitis represents a number of as yet undefined, disparate pathologic conditions that, over time, ultimately present as the clinical syndrome of urinary frequency, urgency, and pelvic pain.
The transitional cell apical membrane of the bladder is coated with GAGs and proteoglycans. Disruption of this layer can lead to transmigration of urinary solutes across the mucosal surface, affecting nerves and muscles and potentially leading to pain. Thus, restoration of this layer remains a mainstay in treatment if IC/BPS.
Up-regulation of histaminergic and muscarinic neurotransmitter receptors has been shown to be present in patients with IC/BPS, which may contribute to the storate and inflammatory symptoms present.[16, 17] Additionally, up-regulation of neural afferent pathways has been shown in IC/BPS, as well as a central hyperresponsiveness in association with other conditions, including fibromyalgia, irritable bowel syndrome, and depression/anxiety disorders.
Clinically, interstitial cystitis is often divided into 2 distinct subgroups based on findings at cystoscopy and bladder overdistention. These categories are the ulcerative (ie, classic) and nonulcerative (ie, Messing-Stamey) types. Such differences may have important implications for diagnosis and therapy. Evidence showing progression of ulcerative to nonulcerative disease, or vice versa, is lacking. Clinical presentation is also variable, with nonulcerative patients presenting with a more diffuse pain syndrome and multiple systemic complaints. Ulcerative patients tend to have higher daytime and nighttime frequency and lower bladder capacity, indicating that it may be more of a condition of the bladder itself than the nonulcerative type.
As such, the ulcerative subtype responds better to bladder-targeted therapies, including cauterization and cystectomy. Cystectomy has also led to significant improvements in quality of life in ulcerative patients. In terms of fulguration, long-term outcomes have shown that patients with ulcerative disease can be significantly helped by this therapy if the ulcers involve less than 25% of the bladder. However, a significant subpopulation require repeat treatment, and many progress to cystectomy.
The hallmark of classic interstitial cystitis is a diffusely reddened appearance to the bladder surface epithelium associated with 1 or more ulcerative patches surrounded by mucosal congestion (ie, Hunner ulcer) on the dome or lateral walls of the bladder upon cystoscopic examination. These ulcers may become apparent only after overdistention, because discrete areas of mucosal scarring rupture during the procedure. Overdistention in this type of interstitial cystitis results in fissures and cracks that bleed in the bladder epithelium.
In the United States, the ulcerative type is rare (< 10% of cases), and some authors consider this type to be more resistant to therapy. Biopsy findings show that the ulcerative lesion can be transmural, associated with marked inflammatory changes, granulation tissue, mast cell infiltration, and, in some cases, fibrosis. This classic form of interstitial cystitis can be associated with progressively smaller bladder capacity over time.
The nonulcerative type of interstitial cystitis is characterized by similar clinical symptoms (ie, frequency, urgency, pelvic pain), but the cystoscopic findings noted for the ulcerative lesion are absent. Instead, after overdistention, these patients demonstrate glomerulations that are discreet, tiny, raspberry-like lesions appearing on the dome and lateral walls of the bladder and tiny mucosal tears and submucosal hemorrhages. Bladder biopsy findings in these patients often are unremarkable, as compared with those found in patients with classic interstitial cystitis.
The etiology of interstitial cystitis remains unknown and is likely multifactorial.[25, 26] Proposed etiologies include the following:
Pathogenic role of mast cells in the detrusor and/or mucosal layers of the bladder
Deficiency in the glycosaminoglycan layer on the luminal surface of the bladder, resulting in increased permeability of the underlying submucosal tissues to toxic substances in the urine 
Infection with a poorly characterized agent (eg, a slow-growing virus or extremely fastidious bacterium)
Production of a toxic substance in the urine
Neurogenic hypersensitivity or inflammation mediated locally at the bladder or spinal cord level
Manifestation of pelvic floor muscle dysfunction or dysfunctional voiding
Although interstitial cystitis has not traditionally been considered a heritable condition, a 2005 study from the University of Maryland reported a higher occurrence of interstitial cystitis in monozygotic versus dizygotic twins, suggesting the disease has at least a partial genetic predisposition.
Patients with interstitial cystitis are more likely to have undergone prior gynecologic surgery and/or to have a history of urinary tract infections and are 10-12 times more likely to report childhood bladder problems. Interstitial cystitis is associated with several chronic illnesses, including inflammatory bowel disease, systemic lupus erythematosus, irritable bowel syndrome, fibromyalgia, and atopic allergy.
Other autoimmune conditions have also been shown to bear resemblance or be associated with IC/BPS. Sjögren syndrome and fibromyalgia syndrome show antibodies against urothelium, smooth muscle, and connective-tissue components of the urinary bladder. Indeed, the pathophysiology of these conditions is similar to that of IC/BPS.
Psychiatric conditions associated with interstitial cystitis include anxiety disorder, depression, and adjustment reactions.
Reports on the prevalence of interstitial cystitis conflict, depending on the country of origin and the criteria used for diagnosis. In addition, there is signficant overlap with conditions such as urinary tract infection, pelvic pain sydromes, and overactive bladder.
Current studies estimate that between 2.7% and 6.5% of American women have symptoms consistent with a diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS). The broad range in incidence depends on whether a high-sensitivity definition (6.53%) is used versus a highly specific definition (2.7%). Roughly translated, these numbers indicate 3.3-7.9 million women older than 18 years in the United States are affected by symptoms of IC/BPS. Of these women, however, only 9.7% report being assigned a diagnosis of IC/BPS.
In the United States, Curhan et al showed a prevalence of 60-70 cases per 100,000 women. The 2004 United States Nurses Health Study indicated a prevalence of 2.3%. However, the estimated overall incidence rate of interstitial cystitis is 2.6 cases per 100,000 women per year in the United States.
Reports from Europe indicate a prevalence of 18 cases per 100,000 women, whereas only 3-4 cases per 100,000 women are reported in Japan. The marked differences between these countries and the United States are likely due to differences in diagnostic criteria, varying from all-encompassing clinical criteria (eg, those from the National Institute of Diabetes & Digestive & Kidney Diseases [NIDDK] of the US National Institutes of Health) to very strict criteria based on a pathologic diagnosis. Epidemiological studies are difficult given the wide variability in which patients are identified as research subjects. Some studies ask individuals to self-identify, while others survey physicians who may be unfamiliar with IC/BPS.
Using a validated IC/BPS case definition, Berry et al discovered that only 50% of women who met criteria for IC/BPS had been evaluated by a urologist and only 10% carried the diagnosis, which strengthens the argument that this disease is largely underreported.
Race-, sex-, and age-related differences in incidence
Of patients with interstitial cystitis, 94% are white and approximately 90% are female. Household size, marital status, number of male sexual partners, educational status, and parity were previously not statistically different between patients with interstitial cystitis and healthy controls. However, new data from the RAND interstitial cystitis cohort have shown that according to a standardized definition, women in that study were considerably more likely to be uninsured, less likely to be married, and had more children than others with the reported diagnosis of IC/BPS.
Interstitial cystitis appears to be slightly more common in Jewish women.
The condition is also dramatically under-reported in men. There is significant overlap of symptoms of IC/BPS to symptoms of patients with chronic prostatitis/chronic pelvic pain syndrome. In fact, 17% of men were reported to have symptoms of both complexes. This supports the hypothesis that IC/BPS and chronic prostatitis/chronic pelvic pain syndrome share a common pathophysiology in men. However, many of these studies rely on the patient's self-reported symptoms, so estimates of incidence in men are likely higher than previously reported.
Median age at presentation is 40 years. However, Close et al have shown that interstitial cystitis may occur in children. In their series, the median age of onset was 4.5 years, with a mean age of diagnosis of 8.2 years. The children had diffuse glomerulations and terminal hematuria. Of the 16 children in the study, 15 improved after bladder hydrodistention.
Interstitial cystitis is a chronic condition most often with a variable course characterized by intermittent periods of exacerbations and remissions; however, rarely, there is chronic progression to a small-capacity bladder with resultant severe lower urinary tract symptoms and risk of upper tract deterioration. Unfortunately, the disorder responds poorly to treatment in many cases. No treatment to date has been shown to decrease disease progression; therefore, the purpose of treatment is to palliate and alleviate symptoms. Although rare, classic interstitial cystitis may lead to bladder wall scarring that results in a contracted, small-capacity bladder. These patients may require augmentation cystoplasty or some form of urinary diversion.
Because of the chronic nature of interstitial cystitis and the significant impact on the patient's quality of life, the psychological impact of the condition can be enormous. Ongoing emotional support is essential.[37, 38] Again, using the RAND interstitial cystitis cohort and a bladder symptom impact scale (BSI), women with a higher BSI score were more likely to have worse general mental and physical health–related quality of life, have more severe depressive symptoms, and a lower perceived control over life in general. They were also found to have worse coping skills overall than women with lesser or no symptoms.
An example of the impact of education and counseling on the treatment of the interstitial cystitis/bladder pain syndrome (IC/BPS) complex comes from 2 placebo-controlled trials with amitriptyline for IC/BPS. In these studies, patients receiving education plus placebo were compared with placebo alone and to amitriptyline alone, and patients receiving education achieved among the highest response rates.
More information about interstitial cystitis and support information for patients can be obtained from the following associations:
Interstitial Cystitis Association
51 Monroe St. Suite 1402
Rockville, MD 20580
Telephone toll-free: 1-800-help ICA
Urology Care Foundation
1000 Corporate Boulevard
Linthicum, MD 21090
Phone: 410-689-3700 or 1-800-828-7866
Interstitial Cystitis Network: The Interstitial Cystitis Network is a large archive of information on the Web for interstitial cystitis, including patient materials, a research library, and physician referrals
The National Institutes of Health maintains a patient information site for Interstitial Cystitis
For patient education information, see Urinary Tract Infections (UTIs).
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