Nonbladder related symptoms in patients with interstitial cystitis.

PURPOSE: Clinical experience and epidemiological studies suggest that patients with interstitial cystitis have multiple nonbladder related symptoms. However, to our knowledge this finding has not been tested with a validated questionnaire and matched controls. With the University of Wisconsin scale, we compare the scores for patients with interstitial cystitis to those for control subjects. This validated questionnaire includes 7 bladder and 18 reference symptoms not related to the bladder. MATERIALS AND METHODS: A total of 35 female patients with interstitial cystitis and 35 age matched female controls completed the University of Wisconsin questionnaire. RESULTS: For the 7 bladder symptoms the difference between interstitial cystitis and control groups was extremely significant (p = 0.0001). Patients with interstitial cystitis had higher scores than controls for 2 reference symptoms, including other pelvic discomfort, backache, dizziness, chest pain, aches in joints, abdominal cramps, nausea, heart pounding and headache (p <0.01). However, they did not have higher scores for blind spots and/or blurred vision, numbness and/or tingling in fingers or toes, swollen ankles, feeling of suffocation, sore throat, cough, flu, nasal congestion and ringing in ears. The majority of patients with interstitial cystitis had a 0 score for all but 2 of the reference symptoms. CONCLUSIONS: Patients with interstitial cystitis had increased scores for 9 reference symptoms but did not indiscriminately report high scores for generalized complaints. This result suggests that in some cases of interstitial cystitis the pathophysiology may affect other organ systems besides the bladder. Alternatively, some of these symptoms may result from changes in sleep pattern or other factors associated with interstitial cystitis.

Urine markers of interstitial cystitis.

This article describes the current state of the art with regard to urine markers of interstitial cystitis (IC), and describes the areas that need continuing research. Articles referenced in MEDLINE that describe urine alterations in IC were reviewed. Additional articles were identified by cross-referencing. The different marker alterations were tabulated. The relevant articles were discussed, considering different purposes for urine markers including: (1) diagnosing IC; (2) confirming a specific pathophysiology for IC; and (3) predicting or following response to a specific treatment. Currently, 2 markers (glycoprotein-51 and antiproliferative factor [APF]) clearly separate IC and control subjects, with minimal overlap. Markers that correlate with specific bladder biopsy features include 1,4-methylimidazole acetic acid and eosinophil cationic protein (ECP), which correlate with mast cell density, and interleukin (IL)-6, which correlates with mononuclear inflammation. Markers that changed after treatment were as follows: (1) nitric oxide synthase and cyclic guanosine monophosphate increased with oral L-arginine; (2) ECP decreased with subcutaneous heparin; (3) prostaglandin E(2) and kallikrein decreased after bladder distention; (4) neutrophil chemotactic activity decreased after dimethyl sulfoxide; (5) IL-2 inhibitor decreased after oral nifedipine; (6) IL-2, IL-6, and IL-8 decreased after bacille Calmette-Guérin (BCG) vaccine; and (7) APF and heparin-binding epidermal growth factor changed to or toward normal levels after bladder distention or sacral nerve stimulation. A larger number of urine alterations have been reported, and a few are being pursued further by correlating with bladder biopsy findings or treatment responses. Further research is needed.

Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis.

We previously determined that the urine of interstitial cystitis (IC) patients specifically contains a factor (antiproliferative factor [APF]) that inhibits primary bladder epithelial cell proliferation, and that it has significantly decreased levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF) compared with urine from asymptomatic controls and patients with bacterial cystitis. We sought to confirm the specificity of these findings for IC using a larger patient population, including control patients with a variety of urogenital disorders. Clean catch urine specimens were collected from 219 symptomatic IC patients, 113 asymptomatic controls without bladder disease, and 211 patients with various urogenital diseases including acute bacterial cystitis, vulvovaginitis, chronic nonbacterial prostatitis, overactive bladder, hematuria, stress incontinence, neurogenic bladder, benign prostatic hyperplasia, bladder or pelvic pain without voiding symptoms, bladder cancer, prostate cancer, or miscellaneous diagnoses including anatomic disorders. APF activity was determined by (3)H-thymidine incorporation into primary normal adult human bladder epithelial cells. HB-EGF and EGF levels were determined by enzyme-linked immunosorbent assay. APF activity was present significantly more often in IC than control urine specimens (P <0.005 for IC vs any control group; sensitivity = 94%, specificity = 95%, P <10(-82) for IC vs all controls). HB-EGF levels were also significantly lower and EGF levels significantly higher in IC urine than in specimens from controls (P <10(-84) and P <10(-36), respectively). These findings confirm the utility of APF, HB-EGF, and EGF as markers for IC. Understanding the reasons for altered levels of these markers may lead to understanding the pathogenesis of this disorder.

A new direct test of bladder permeability.

PURPOSE: A proposed cause of interstitial cystitis is increased bladder permeability but to our knowledge this theory has not been proved by direct testing. We developed a safe, relatively painless, direct test of bladder permeability. MATERIALS AND METHODS: The original permeability test involved placing 4% lactulose and 1% rhamnose intravesically, then drawing blood to assay for these sugars. Initial feasibility studies were performed in rabbits with bladder epithelium that was intact or disrupted by a 50% acetone rinse. In humans the initial goal was to distinguish intact bladders from those known to have increased permeability. Since distention is known to increase permeability temporarily, we studied patients with interstitial cystitis immediately after distention. RESULTS: Neither sugar was absorbed from intact rabbit bladders, while each was absorbed from acetone rinsed bladders at 10, 20 and 30 minutes. We used 100 ml. of solution in the initial 8 humans, including 6 with interstitial cystitis and 2 controls. At 30 minutes each sugar was absorbed from interstitial cystitis bladders but neither was absorbed from intact bladders. The test solution was then changed to 5% rhamnose. Mean rhamnose absorption plus or minus standard deviation was much greater in the 6 patients with interstitial cystitis than in 8 controls (26.3 + or - 26.1 versus 0.78 + or - 0.87 nmol. /ml. serum, p = 0.008). With 1 exception interstitial cystitis serum levels were at least 4-fold higher than the highest control level. CONCLUSIONS: This new permeability test clearly distinguishes intact versus distended bladders. It may be performed to test whether bladder permeability is increased in interstitial cystitis.

Characterization of the rabbit homolog of human MUC1 glycoprotein isolated from bladder by affinity chromatography on immobilized jacalin.

The urinary bladder is lined by transitional epithelium, the glycocalyx on the luminal surface has interesting properties and is implicated in protective functions. Glycoconjugates are major components of the glycocalyx, but their biochemical nature is not well understood. Previous studies on rabbit bladder indicated the presence of significant levels of sialoglycoproteins compared to glycosaminoglycans in the epithelium. In this study, rabbit explant cultures were radiolabeled by precursor sugars or amino acids and a major lectin-reactive glycoprotein of rabbit bladder mucosa was isolated by affinity chromatography on jacalin-agarose. The radiolabeled glycoprotein was purified to homogeneity by a second cycle on the lectin column, followed by gel filtration and density gradient centrifugation. The average molecular mass of the glycoprotein was estimated to be 245 kDa and 210 kDa by gel filtration and SDS-PAGE, respectively. Its buoyant density was 1.40 g/ml, suggesting a carbohydrate content of approximately 50%. The percent distribution of glucosamine-derived tritium label in sialic acid, galactosamine, and glucosamine was 30, 52, and 18, respectively. The glycoprotein consisted entirely of small sialylated and neutral oligosaccharides O-glycosidically linked to serine and threonine residues. The same glycoprotein could be immunoprecipitated with an antibody against the carboxy terminal 17 amino acid peptide of human MUC1 mucin glycoprotein. This suggests that this mucin glycoprotein is the rabbit homolog of MUC1 glycoprotein, which has been previously established to be a component of human bladder urothelium and has been purified from human urine and biochemically characterized.

Interstitial cystitis: update on etiologies and therapeutic options.

Interstitial cystitis (IC) is a syndrome of pelvic and/or perineal pain, urinary urgency, and frequency. It is now agreed that IC is a multifactorial syndrome, not a single condition. A variety of etiologies for IC have been proposed, but none has been definitively proven. Since the etiologies for IC remain unknown, the current treatments are empiric. This article will review the major theories of etiology for IC and discuss the current treatment options with relevance to the proposed etiologies. No single treatment is effective for all IC patients. Therefore, the approach is to try different treatments, alone or in combination, until symptom relief is satisfactory. In some cases, none of the empiric IC treatments are successful. These patients require adjunctive pain management, and a small minority of IC patients resort to surgery if all other options fail.

In vitro ligation of ureters and urethra modulates fetal mouse bladder explants development.

The compliance of the bladder which accommodates the holding and voiding of urine is influenced by the amount and type of collagen deposited as well as the packing and organization of collagen fiber bundles. During fetal development, the accumulation of urine within the bladder lumen is associated with the maturation of the bladder's wall. Fetal mouse bladders can undergo maturation as organ cultured explants in defined medium. Polarized light optics of Sirius red-stained sections of fetal mouse bladders in organ culture for 4 days showed that the ligation of both ureters and urethra promoted more orderly packing of collagen fiber bundles within the luminal edge of the lamina propria compared to unligated bladder explants. It is proposed that ligation causes differences in the development and organization of the collagen fiber bundles within the bladder wall. These differences are due to either increases in intravesical pressure, the accumulation of growth factors within the lumen or a combination of both.

Interstitial cystitis.

Interstitial cystitis (IC) is a multifactorial syndrome with symptoms of pelvic or perineal pain, urinary frequency and urgency. The etiologies are unknown, but several theories have been proposed. Diagnosis is often delayed because most of the conventional evaluation is normal. Pelvic examination is normal except for bladder tenderness. Urodynamics are normal except for increased bladder sensitivity and low capacity. Urinalysis, urine culture and office cystoscopy are also normal. The diagnostic test is cystoscopy under anesthesia with bladder distension. Small submucosal hemorrhages (glomerulations) or ulcers appear after distension. Many empiric treatments have been proposed for IC. None is universally effective, and so treatments are tried sequentially until good symptom relief is achieved. Bladder distension gives excellent (but transient) relief in some patients, especially those with severe bladder inflammation (who also tend to be older). A variety of oral, intravesical and adjunctive treatments are also described.

Increased urinary hyaluronic acid and interstitial cystitis.

PURPOSE: We compared urinary levels of hyaluronic acid in patients who met the National Institute for Diabetes, and Digestive and Kidney Diseases criteria for interstitial cystitis and in age matched healthy female controls. MATERIALS AND METHODS: Urinary hyaluronic acid was measured by solid phase radiometric assay using hyaluronic acid binding protein. Hyaluronic acid and symptom scores were compared in interstitial cystitis patients who gave multiple urine samples during treatment. Since hyaluronic acid changed with treatment in some patients, 17 samples from untreated interstitial cystitis patients were selected and compared with 17 control samples. RESULTS: Mean plus or minus standard deviation urinary hyaluronic acid concentrations were similar in the 2 groups (interstitial cystitis group 574 +/- 496, controls 512 +/- 324 ng./ml., p = 0.77). When normalized to creatinine urinary hyaluronic acid was significantly higher in interstitial cystitis patients (interstitial cystitis group 674 +/- 220, controls 446 +/- 220 ng./mg. creatinine, p = 0.0019). Urinary creatinine concentrations did not differ significantly (interstitial cystitis group 842 +/- 715, controls 1,162 +/- 516 mg./l., p = 0.12). CONCLUSIONS: Urinary hyaluronic acid was higher in interstitial cystitis patients than healthy controls. Since bladder hyaluronic acid is below the epithelium, this finding may indicate leakage across the epithelium into the urine in interstitial cystitis patients.

Inflammatory cell types and clinical features of interstitial cystitis.

PURPOSE: We tested whether the types of inflammatory cells seen on bladder biopsies were associated with other clinical features and urinary markers of interstitial cystitis. MATERIALS AND METHODS: Bladder biopsies from 30 interstitial cystitis patients were evaluated by immunohistochemical staining for T cells, B cells, macrophages and human leukocyte antigen-DR positive cells. These findings were tested for associations with clinical features and urinary markers of interstitial cystitis using alpha = 0.01 because multiple tests were performed. RESULTS: Overall severity of inflammation was significantly associated with age at symptom onset, symptom relief after bladder distention and urinary interleukin-6 levels. Patients with severe inflammation had trends toward smaller bladder capacity under anesthesia, increased bladder vascularity and mucosal cracks, lower urinary MUC-1 glycoprotein levels and absence of bloating as a symptom. B cell staining was significantly associated with severe inflammation, symptom relief after distention and absence of bloating as a symptom. T cell staining was significantly associated with severe inflammation and age at symptom onset. Human leukocyte antigen-DR staining had trends with symptoms, including presence of bloating, constant urge to void and absence of burning. Macrophage staining did not associate with any features tested at the alpha = 0.05 level. CONCLUSIONS: Interstitial cystitis patients with severe inflammation have different age, treatment response and urinary marker levels than those with mild inflammation. These findings suggest that the 2 patient groups have different underlying pathophysiologies. The significant associations for T and B cell staining were similar to those for overall inflammation.

The Interstitial Cystitis Data Base Study: concepts and preliminary baseline descriptive statistics.

OBJECTIVES: To describe the design, patient population, and data and specimen collection aspects of the interstitial Cystitis Data Base (ICDB) Study and to provide preliminary descriptive statistics and inferential results from an interim analysis. METHODS: All 424 study participants successfully enrolled in the ICDB Study prior to December 31, 1995, were selected for an interim analysis and were classified into 1 of 3 symptom severity subgroups. Statistical tests for associations among these symptom severity subgroups and a broad range of baseline characteristics were conducted using Mantal-Haenszel procedures to adjust for variation among clinical centers. RESULTS: ICDB Study patients are predominantly female (91.5%), white (91.0%), with an average age at enrollment of 44.3 years. Nearly 45% of these patients underwent a cystoscopy at baseline screening, among whom there was an overall prevalence of 10.5% for Hunner's patch and 90% for glomerulations. Urodynamic evaluation for the entire 424 patients demonstrated that volumes at first sensation and at maximal capacity were inversely associated with symptom severity subgroups. A broad range of symptoms were analyzed, indicating that nearly 40% of patients reported urinating 15 times or more during awake hours, and more than 20% reported voiding at least 4 times per night. Almost half (47.9%) reported constant urgency and 23.6% reported having severe pain. Patients in the severe symptom subgroup reported greater limitations in selected quality-of-life indicators than those with less severe symptoms. CONCLUSIONS: This interim analysis of the ICDB Study data was compared to previous epidemiologic studies of IC and provides an essential foundation for further analytic investigations of baseline associations and longitudinal trends.

An investigation of the nature of bladder mucosal glycoconjugates and their role in interstitial cystitis.

The long-term objective of this study is to elucidate the role of bladder mucosal glycosaminoglycans and mucin glycoproteins in the development of interstitial cystitis and other bladder diseases. Bladder biopsies and urine samples from patients and healthy controls were analyzed for glycoconjugates by biochemical and immunochemical methods. Due to the limited availability of human bladders for research purposes, detailed analysis of rabbit bladders glycoconjugates were also carried out. Biochemical analysis of rabbit bladders indicate that while the major portion of the glycoconjugates in the urothelium is sialoglycoprotein, low levels of heparan sulfate and chondroitin sulfate are also present. The correlating immunohistochemical data show very weak staining of the rabbit bladder epithelium by antiglycosaminoglycan antibodies. In contrast, the lamina propria and muscle layers stained intensely for chondroitin sulfate and hyaluronic acid. Thus, the quantity of glycosaminoglycans associated with the bladder epithelial layer, particularly as extracellular matrix components on the luminal surface of the bladder, appears insignificant. On the other hand, several lectins and anti-epitectin (a MUC1 sialoglycoprotein) antibodies showed strong staining of the luminal surface of rabbit and normal human bladders. Further, preliminary results with anti-epitectin antibodies reveal a weaker and patchy staining of biopsy specimens from interstitial cystitis patients compared to controls. The urinary levels of glycosaminoglycans and epitectin, in interstitial cystitis patients and healthy controls were determined by chemical or immunoassays. Urinary epitectin, but not glycosaminoglycans, was decreased in interstitial cystitis patients.

Urinary chondroitin sulfates, heparan sulfate and total sulfated glycosaminoglycans in interstitial cystitis.

PURPOSE: We compared urinary glycosaminoglycan levels in patients with interstitial cystitis and healthy controls. MATERIALS AND METHODS: Total sulfated glycosaminoglycans assayed by dimethylmethylene blue binding and individual glycosaminoglycans analyzed by cellulose acetate electrophoresis were compared in patients with interstitial cystitis and healthy controls. Also, multiple urine samples were obtained from healthy female controls for 2 months to assess the relationship of urinary glycosaminoglycan and creatinine concentrations, and to determine whether glycosaminoglycan excretion changes during the menstrual cycle. RESULTS: Total sulfated glycosaminoglycan and creatinine concentrations correlated well in random voided samples. Menstrual cycle day did not affect total sulfated glycosaminoglycan levels. Cellulose acetate electrophoresis revealed 3 bands corresponding to chondroitin sulfates, heparan sulfate and acidic glycoprotein. Patients with interstitial cystitis had decreased urinary concentrations of each of these individual components and total sulfated glycosaminoglycans. However, glycosaminoglycan-to-creatinine ratios were similar in interstitial cystitis and control urine. CONCLUSIONS: Using these assays total and individual urinary glycosaminoglycan levels normalized to creatinine were not altered in interstitial cystitis.

Urethral obstruction after anterior colporrhaphy: correction by simple vaginoplasty.

OBJECTIVES: Bladder outlet obstruction is a well-known complication of anti-stress incontinence procedures including retropubic suspensions, needle suspensions, and slings. Relief of obstruction after these procedures usually requires freeing the urethra from its superior attachments. Because the anterior colporrhaphy does not involve suspension above the urethra, obstruction can be relieved by a simple plastic procedure involving the anterior vaginal wall. METHODS: We describe 2 cases in which a simple plastic procedure was used to correct urodynamically confirmed obstruction after anterior colporrhaphy. RESULTS: One patient became completely asymptomatic. The other had subjective and urodynamic resolution of her obstructive symptoms, but persistent detrusor instability. CONCLUSIONS: A simple plastic procedure can be used to correct urethral obstruction after anterior colporrhaphy.

Urinary epitectin (MUC-1 glycoprotein) in the menstrual cycle and interstitial cystitis.

PURPOSE: We compared interstitial cystitis and control urine specimens for epitectin (MUC-1 glycoprotein), an epithelial mucin. MATERIALS AND METHODS: Urinary epitectin was measured in 28 patients with interstitial cystitis and 26 healthy controls. Ten controls provided multiple urine samples to determine whether urinary epitectin changes with the menstrual cycle. RESULTS: Epitectin levels were stable throughout the menstrual cycle. Interstitial cystitis cases had decreased urinary epitectin-to-creatinine ratios (mean 3.89 versus 6.38 micrograms./mg. creatinine for controls, p = 0.0035) and epitectin concentrations (mean 1.96 versus 4.30 micrograms./ml., respectively, p = 0.0005). CONCLUSIONS: Decreased mean urinary epitectin levels may reflect a cause (epithelial mucin deficiency) or a consequence of interstitial cystitis.

Characterization and immunohistochemical localization of the glycoconjugates of the rabbit bladder mucosa.

An impairment of the mucosal glycoconjugates could be an important factor in the development of bladder disorders such as interstitial cystitis. However, very little definitive biochemical information is available on the glycoco-jugate components of the mammalian bladder mucosa. In this-study, the mucosa from metabolically radiolabeled rabbit bladder was separated, delipidated, and digested with protease, and the released glycosaminoglycans and glycopeptides were fractionated. About 80 and 36% of the nondialyzable tritium and 35S activities, respectively, was associated with the sialoglycopeptide fractions. The balance of the total tritium activity in the protease digest was in glycosaminoglycans identified as hyaluronan, chondroitin sulfates, and heparan sulfate. Immunohistochemical examination using anti-heparan sulfate antibodies, including one against mouse syndecan-1, indicated the presence of heparan sulfate proteoglycan in the epithelium. In contrast, there was no significant staining of the bladder epithelium with anti-chondroitin-4- and 6-sulfate antibodies or hyaluronan-binding protein. The lamina propria and muscle layers showed strong staining with anti-chondroitin-4-sulfate antibody and hyaluronan-binding protein and weak staining with anti-chondroitin-6-sulfate antibody. The insignificant levels of glycosaminoglycans in the glycocalyx of bladder mucosa epithelium suggest that glycosaminoglycans may be less important than other glycoconjugates in maintaining normal epithelial function and in bladder disorders such as interstitial cystitis.

Transitional cell bladder carcinoma with presentation mimicking ovarian carcinoma.

In the case described here, the patient's initial presentation suggested ovarian carcinoma. She had recurrent ascites, a pelvic mass, elevated CA-125, and extensive peritoneal carcinomatosis with transitional cell histology. The presence of hematuria prompted a cystoscopy, which revealed the true site of origin to be the urinary bladder rather than ovaries. This presentation is extremely rare for bladder cancer. Since transitional cell tumors from the bladder have a much worse prognosis than those of ovarian origin, it is important to identify the primary site correctly. Therefore, cystoscopy is essential for patients with hematuria, and should be considered in cases of apparent primary peritoneal carcinoma with transitional cell histology.