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Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis).

Traditional concepts of impermeability of the bladder have centered around unique cellular tight junctions and ion pumps. However, recent data from our laboratory have shown that the bladder epithelium in animals and humans relies primarily on its surface glycosaminoglycans to maintain its impermeability. This study demonstrates the first disease associated with an epithelial dysfunction of the bladder, that is a leaky epithelium. The study consisted of 31 normal subjects and 56 individuals with interstitial cystitis. Interstitial cystitis patients were shown to have a leaky epithelium by placing a solution of concentrated urea into the bladder and measuring the absorption. The normal subjects absorbed 4.3% in 45 minutes, while the interstitial cystitis patients absorbed 25% (difference is highly significant, p less than 0.005). Interstitial cystitis patients with Hunner's ulcers (10) had a 34.5% absorption rate, while those without ulcers absorbed 22.8% (46). This difference also was highly significant (p = 0.002) and supports the concept that patients with ulcers have clinically worse disease.

Absorption

Decreased expression of a glycoprotein component of bladder surface mucin (GP1) in interstitial cystitis.

Interstitial cystitis is a disease of unknown etiology characterized by unremitting urinary frequency, urgency and suprapubic pain. Recently, a change in urothelial permeability has been identified in interstitial cystitis patients that is presumably mediated by aberrations in bladder surface mucin. For this study we evaluated qualitative changes in a previously defined glycoprotein component of this layer (GP1) as it occurs in interstitial cystitis patients and normal controls. Paraffinized bladder biopsies were obtained from 23 interstitial cystitis patients (all meeting National Institutes of Health inclusion criteria) and 11 normal controls. All biopsy tissue was stained with hematoxylin and eosin, and periodic acid, Schiff reaction. The tissues were examined immunohistochemically for GP1 using an anti-GP1 serum. Periodic acid, Schiff staining clearly identified bladder surface proteoglycans in all specimens. Moderate GP1 reactivity was noted in all normal control specimens. Alternatively, GP1 expression was absent in 35% of the interstitial cystitis patient biopsies and decreased in 61%. These data demonstrate qualitative GP1 changes in a majority of interstitial cystitis patients. It is unknown whether these differences have an impact on the pathogenesis of interstitial cystitis. However, our findings suggest that the absence or decreased expression of GP1 in interstitial cystitis bladder biopsies may serve as a marker to characterize the disease further in conjunction with clinical findings.

Adult

Abnormal urothelial HLA-DR expression in interstitial cystitis.

Interstitial cystitis is a chronic inflammatory disorder of the urinary bladder that predominantly afflicts middle-age women. The end stage of the disease is ulceration of the urothelium, the so-called Hunner's ulcer. The aetiology of interstitial cystitis remains obscure. We have studied bladder biopsies from 22 cases of interstitial cystitis and control groups consisting of six cases of bacterial cystitis and eight healthy women. Indirect immunofluorescence was performed on the biopsies using murine MoAbs to human HLA class I molecules, and class II molecules, HLA-DP, HLA-DQ and HLA-DR. In interstitial cystitis, bacterial cystitis and normal controls most cells expressed HLA class I products. In six cases of interstitial cystitis and one case of bacterial cystitis there was evidence of HLA class I hyperexpression. In normal bladder and bacterial cystitis HLA class II expression was restricted to submucosal dendritic cells, Langerhans cells macrophages, vascular endothelial cells and activated lymphocytes. All but two cases of interstitial cystitis showed surface expression of HLA-DR (but not HLA-DP or DQ). In all cases of interstitial cystitis there was an increase in the numbers of macrophages, activated lymphocytes and vascular endothelial cells expressing HLA class II molecules within the submucosa. These findings provide further evidence for the importance of inappropriate HLA molecule expression in a disease suspected of having an autoimmune pathogenesis and where cellular autoimmune mechanisms play a decisive role in the destruction of the target cells--the bladder urothelium.

Adult

Increased urine histamine and methylhistamine in interstitial cystitis.

Interstitial cystitis is a painful bladder disorder occurring mostly in women, and is presently diagnosed by clinical presentation, as well as the presence of mucosal glomerulations and inflammation on bladder distention. An increased number of bladder mast cells have been implicated in the pathophysiology of interstitial cystitis but previous reports of spot urine histamine have not confirmed bladder mast cell activation. The availability of easily measurable objective criteria could make the diagnosis easier. Histamine and its major metabolite, methylhistamine, were measured in spot and 24-hour urine specimens from a number of normal female volunteers, control patients and interstitial cystitis patients. In interstitial cystitis patients the histamine levels were only slightly increased in the spot (p < 0.01) and 24-hour urine (p < 0.03) collections. Methylhistamine, on the other hand, was greatly elevated in spot (p < 10(-10)) and 24-hour (p < 0.0008) urine samples. These results indicate that methylhistamine levels could serve as useful diagnostic end points for interstitial cystitis.

Adolescent

Complement C3, eosinophil cationic protein and symptom evaluation in interstitial cystitis.

Interstitial cystitis is a painful, irritative voiding dysfunction of unknown etiology. In this study 19 women undergoing treatment for interstitial cystitis and 6 healthy women of similar age provided 2 urine and serum specimens with at least a 3-month interval between collections. Complement C3 and eosinophil cationic protein were determined by immunoassay methods, and symptom severity was quantitated with a visual analog scale questionnaire. Concentrations of complement C3 and eosinophil cationic protein from either serum or urine were not significantly different between interstitial cystitis patients and controls at either determination, although substantial differences were noted even between individual initial and followup determinations. Normalization of urine osmolality did not alter these results. Symptom severity scores were significantly greater in interstitial cystitis patients compared to controls but failed to correlate with the concentrations of complement C3 or eosinophil cationic protein. Therefore, the hypothesis that complement C3 and eosinophil cationic protein may be etiological factors of interstitial cystitis is not supported.

Adult

Interstitial cystitis.

Interstitial cystitis is a urologic disorder with protean pelvic manifestations (urologic, gynecologic, gastroenterologic) and variable prevalence. Although current research indicates a non-bacteriologic etiology, interstitial cystitis has features suggestive of autoimmunity, a deficient bladder wall lining, activated bladder sensory neuropeptides and bladder mastocytosis. Pentosan polysulfate sodium is a recently approved oral treatment for interstitial cystitis. Further research into the gynecologic and pain aspects of interstitial cystitis is clearly needed.

Anti-Inflammatory Agents, Non-Steroidal

Tamm-Horsfall autoantibodies in interstitial cystitis.

Interstitial cystitis presents a diagnostic and therapeutic challenge. Although many etiologies, including autoimmunity, have been proposed its pathogenesis remains obscure. Tamm-Horsfall protein has been identified in the superficial urothelium of patients with interstitial cystitis demonstrating abnormal urothelial permeability. Eight patients with a clinical diagnosis of interstitial cystitis underwent cystoscopy and bladder biopsy. Characteristic cystoscopic findings were present, and each patient had chronic inflammation and mast cells by histopathological analysis. Preoperative anti-Tamm-Horsfall protein serum antibody (IgG) titers were determined by enzyme-linked immunosorbent assay (range 500 to 8,000, mean 2,750). A control group of 8 patients with a negative urological history also had titers of 0 to 500 (p = 0.02). The humoral response to Tamm-Horsfall protein in these patients suggests a role for Tamm-Horsfall protein in interstitial cystitis. Measurement of serum Tamm-Horsfall protein antibody may prove to be useful as a noninvasive diagnostic test in patients with this disease.

Adult

Culture of bladder epithelium from cystoscopic biopsies of patients with interstitial cystitis.

Interstitial cystitis is a chronic disease of unknown etiology characterized by bladder pain and urinary frequency and urgency. The epithelium may be critical in its pathogenesis; the hallmarks of the disease are visible epithelial defects (Hunner's ulcers and epithelial ruptures). Areas denuded of epithelium are commonly seen, and defects in epithelial permeability are characteristic. We report here the culture and characterization of epithelial cells from cystoscopic bladder biopsies obtained from 7 female patients with interstitial cystitis. Within 4 to 14 days cellular outgrowths appeared from explants incubated in cell medium. Monolayers reached confluence after 6 weeks. Cells of the monolayer were cytokeratin-positive and smooth muscle actin-negative, confirming their epithelial origin. They exhibited epithelial cell ultrastructure including intermediate filaments and junctional complexes. Vesicles bounded by a trilaminar plasma membrane and lateral interdigitations were also present. This is the first report of the culture of bladder epithelium from interstitial cystitis patients. Epithelial cells may be targets for initiating agents and inflammatory effects of interstitial cystitis and should be useful for studies of the pathogenesis of this disease.

Adult

Use and effectiveness of physical self-care strategies for interstitial cystitis.

Interstitial cystitis is a painful disease that primarily affects women. It involves a chronic bladder inflammation of unknown etiology and unpredictable course. There is no consensus about treatment. Women with interstitial cystitis report using multiple strategies and interventions to prevent and manage urinary urgency, frequency, and suprapubic pain. A survey questionnaire on self-care strategies was completed by 138 members of the Interstitial Cystitis Association. Subjects indicated how often they used more than 300 self-care strategies and the effectiveness of these strategies. This article reports findings from five physical subdomains (medications, treatments, hygiene, diet, and body comfort). Among those who report actually using the methods the effectiveness ratings for many body comfort strategies are comparable to the reported effectiveness of medications (including narcotics) for managing mild to moderate symptoms.

Chronic Disease

Do women with idiopathic sensory urgency have early interstitial cystitis?

Interstitial cystitis is rarely considered as a cause of urinary symptoms in referrals to gynaecology clinics. Recent concepts in the diagnosis of this condition mean that it is emerging as a much more common entity, with both early and late forms of the disease being described. Mast cell density in the detrusor muscle has been reported to be useful as a disease marker to substantiate the diagnosis of interstitial cystitis where no classical diagnostic features exist. We assessed mast cell counts in bladder biopsies from 27 women with idiopathic sensory urgency and 10 control patients about to undergo a colposuspension procedure for pure genuine stress incontinence; 30% of the study group had a clear increase in the detrusor muscle mast cell population (detrusor mastocytosis). No control patient showed such an increase. Early interstitial cystitis should be considered as a possible cause of lower urinary tract symptoms in patients with apparently idiopathic sensory urgency.

Adult

Pentosanpolysulphate for interstitial cystitis.

Interstitial Cystitis (IC) is a chronic disease of unknown etiology which primarily affects women aged 40-60 years. Many plausible theories for the development of IC have been postulated, and one current theory is that these patients have a quantitative and qualitative defect in the glycosaminoglycan (GAG) layer of the urothelium. Such a defect may allow toxic substances in the urine to gain access to the lamina propria and initiate a chronic inflammatory process. Pentosanpolysulphate (PPS) is a sulphated proteoglycan similar in structure to heparin sulphate, which is quantitatively the major GAG on cell surfaces. Exogenously administered PPS has been shown in several studies to decrease bladder pain and urinary frequency and to increase the voided volume. Further studies are required to evaluate the role of PPS in the management of IC patients, with particular emphasis on dosage, route of administration and combination with other compounds.

Anti-Inflammatory Agents, Non-Steroidal

The relationship between fibromyalgia and interstitial cystitis.

Interstitial cystitis (IC) is a relatively uncommon and enigmatic disorder characterized by pain in the bladder and pelvic region, typically accompanied by urinary urgency and frequency. Fibromyalgia is a more common disorder, with the prominent symptoms being diffuse musculoskeletal pain and fatigue, and it has been well established that there is substantial clinical overlap between fibromyalgia and chronic fatigue syndrome (CFS). Although genitourinary and musculoskeletal symptoms predominate in IC and fibromyalgia respectively, both disorders share a number of features, including similar demographics, "allied conditions" (e.g. irritable bowel syndrome, headaches, etc.), natural history, aggravating factors, and efficacious therapy. We hypothesized that there was substantial clinical overlap between fibromyalgia and IC, and examined cohorts of individuals with these two disorders in parallel, to compare the spectrum of symptomatology. Sixty fibromyalgia patients, 30 IC patients, and 30 age-matched healthy controls were questioned regarding current symptomatology. A dolorimeter examination was also performed in the three groups to assess peripheral nociception. We found that the frequency of current symptoms was very similar for the fibromyalgia and IC groups. Both the fibromyalgia and IC patients displayed increased pain sensitivity when compared to healthy individuals, at both tender and control points. These data suggest that IC and fibromyalgia have significant overlap in symptomatology, and that IC patients display diffusely increased peripheral nociception, as is seen in fibromyalgia. Although central mechanisms have been suspected to contribute to the pathogenesis of fibromyalgia for some time, we speculate that these same types of mechanisms may be operative in IC, which has traditionally been felt to be a bladder disorder.

Adult

Recontextualizing sexuality in chronic illness: women and interstitial cystitis.

Interstitial cystitis (IC) is a chronic bladder condition that affects ten times more women than men. The major symptoms of IC include urinary frequency, urgency, and suprapubic pain. Dyspareunia is another common complaint. The construct of sexuality can best be understood in context, from the perspective of the study participants. To better understand the changes in sexuality experienced by women with IC, the findings from a survey of 138 women with IC are compared with responses from an earlier pilot interview with ten women with IC. Managing any chronic illness requires changes in many aspects of one's life, including activities, self-perceptions, relationships, and roles. Women with IC described what was important to them "as women" in the context of their current primary life values of health, love, and family. Changes in the sexual relationship were described in the context of the effects of having IC and the centrality of maintaining relationships. The healing potential of participation in support groups is discussed in relation to the women's desire to maintain independence and to help others with the disease.

Adaptation, Psychological

Urine autoantibodies in interstitial cystitis.

Interstitial cystitis is a chronic bladder disease with certain features that suggest autoimmunity may play a role in initiating or maintaining the disease process. We therefore determined whether immunoglobulin fractions from 14 IC patient and 19 control urine specimens bound in vitro to primary cultures of human bladder epithelial cells, as well as epithelial cells from a variety of other tissues. Urine autoantibodies that bound to normal human bladder epithelial cells were present in 8 of 14 IC specimens (from 6 of 9 IC patients) as compared to 3 of 23 control specimens (from 2 of 17 control patients). These antibodies, which were usually also present at low titers in sera from these persons, bound to at least four nuclear or cytoplasmic antigens, with the specificity of autoantibodies from a given individual varying over time. The autoantibodies were not specific for normal or malignant bladder epithelial cells, but bound to epithelial cells from a variety of tissues. These data show that anti-epithelial cell autoantibodies are present in the urine of IC patients, but suggest that these antibodies are not likely to be a primary cause of this disease.

Adult

[Interstitial cystitis].

Interstitial cystitis (IC) is a complex of painful mictional symptomatology of unknown etiology. Is occurs more frequently in women. By cystoscopy the ulcerative and non-ulcerative form is differentiated. A typical diagnosis symptom are glomerulations during cystoscopy under general anaesthesia. There are diagnostic criteria which rule out IC. Histopathologically the following are differentiated: classical IC with proliferation of mastocytes in the detrusor, detrusor myopathy and eosinophil cystitis. Treatment includes intervesical instillation of various substances, transurethral procedures or supratrifonal cystectomy, incl. enterocystoplasty.

Adult

Modified urodynamics for interstitial cystitis.

Interstitial cystitis (IC) is a poorly understood syndrome. Patients with pelvic pain, urgency, frequency, and/or dysuria may pose a diagnostic dilemma. They may have bladder-related symptoms or they may have nonbladder related symptoms. It is beneficial for the urologist to distinguish between these patients. This study outlined a modified urodynamics test to discriminate between bladder-related and nonbladder-related patients. Consecutive IC patients (bladder-related and nonbladder-related patients) and stress incontinent controls underwent modified urodynamics. Testing consisted of an epithelial leak test, a filling cystometrogram, bladder emptying and instilling lidocaine intravesically, and repeat cystometrogram after bladder emptying. The epithelial leak test and lidocaine test predict reliably if a patient has bladder-related or nonbladder-related symptoms. Modified urodynamics permits a logical stratification of IC patients, and may predict treatment response.

Adult