Biomarkers for patients with interstitial cystitis/bladder pain syndrome

Interstitial cystitis or bladder pain syndrome (IC/BPS) is a disease of unknown etiology manifested with bladder pain and frequency urgency symptoms. Although several pathophysiologic mechanisms have been proposed, the underlying mechanism of IC/BPS is still unclear. Accumulated evidence supports that IC/BPS is actually a spectrum of clinical phenomena that involves several different genes and environmental factors. Heterogeneous syndromes are seen in patients with IC/PBS, which suggests that the disease should be classified into different subtypes. Abnormal expressions of several bladder epithelial markers, including mast cells, epithelial differentiation proteins, cell membrane proteins, neurotransmitters, and cytokines, are present in IC/BPS. This review discusses the possible biomarkers that may play crucial roles in IC/BPS, and especially focuses on those that have the potential to be used as biomarkers for prognosis and for the determination of the best treatment for patients.     

Lymphocyte function in patients with interstitial cystitis.

To determine whether there is a primary immunological disorder involved in the etiology of interstitial cystitis, we compared the in vitro function of peripheral blood lymphocytes from 10 patients with interstitial cystitis to those from 10 healthy female controls. The lymphocytes were isolated and incubated in either cell culture medium alone, cell culture medium supplemented with the mitogen phytohemagglutinin or cell culture medium with autologous sterile filtered urine, the latter to detect any immunogenic potential of urine in this disease. We studied the relative proliferation of the phenotypes CD2, CD4, CD8, CD19, CD14 and CD56 by immunofluorescence and flow cytometry. To detect activation of T lymphocytes we also studied expression of HLA-Dr and interleukin-2 receptors. There was no difference in the rate of proliferation of the various lymphocyte phenotypes between the 2 groups in any of the culture media. Similarly, there was no difference between the 2 groups in the degree of lymphocytic activation after incubation. Furthermore, incubation in the presence of autologous urine caused no increase in activation above that seen in control cultures. We also assessed the production of the lymphokines interleukin-1, interleukin-2 and interferon-gamma in the supernatant fluid of the cell cultures. There was no difference in the production of these immunoregulatory cytokines between the control and patient groups, and again urine did not act as a mitogen in either group. We conclude from this study that there is no primary immunological disorder evident in patients with interstitial cystitis, and that the urine does not act as a stimulant to the immune system. This finding casts severe doubt on any theory suggesting that interstitial cystitis is an autoimmune disease or that urine contains an autoantigen causing the disease.     

Bladder necrosis following hydrodistention in patients with interstitial cystitis

PURPOSE: Bladder hydrodistention is used to diagnose and treat patients with interstitial cystitis. This procedure has been shown to have minimal morbidity and provide symptomatic relief in a subset of patients with interstitial cystitis. We report our experience with almost total bladder necrosis after hydrodistention at 2 institutions. To our knowledge this rare complication has not been previously reported in the literature. We also reviewed the literature regarding complications of hydrodistention and discuss their possible etiology. MATERIALS AND METHODS: We report 3 cases of bladder necrosis after therapeutic hydrodistention for interstitial cystitis at 2 institutions. All records were reviewed, and the clinical presentation, findings and treatments are discussed. A literature review was performed to evaluate the effectiveness and complications of hydrodistention for interstitial cystitis. RESULTS: There were 2 female and 1 male patient between ages 29 and 46. All patients had a previous diagnosis of interstitial cystitis and had been previously treated with hydrodistention. All patients presented with severe abdominal pain and had necrosis of the entire bladder wall with sparing of the trigone. Two patients were treated with supratrigonal cystectomy. A review of the literature revealed little data on the effectiveness of hydrodistention for interstitial cystitis. CONCLUSIONS: Vesical necrosis is a rare but devastating complication of hydrodistention. It can occur in young patients in the absence of a contracted bladder and it usually presents as severe postoperative abdominal pain. At exploration bladder necrosis with sparing of the trigone was observed. All patients required enterocystoplasty.     

Diurnal cortisol variations and symptoms in patients with interstitial cystitis

PURPOSE: Little attention has focused on systemic factors that may allow a state of chronic bladder inflammation to be established and maintained in interstitial cystitis cases. Abnormalities of the hypothalamic-pituitary-adrenal feedback system result in poorer regulation of the inflammatory response and are present in many chronic inflammatory and pain conditions, of which some have high co-morbidity with interstitial cystitis. MATERIALS AND METHODS: A total of 48 patients with interstitial cystitis and 35 healthy, age matched controls collected 24-hour urine samples and 3 days of salivary samples at 7 to 8 a.m., 4 to 5 p.m. and 8 to 9 p.m. for cortisol analysis. In addition, they completed a concurrent symptom questionnaire. Prospective symptom diaries also were completed in the month before sampling. RESULTS: Mean urinary or salivary cortisol did not differ in patients and controls. However, patients with interstitial cystitis and higher morning cortisol had significantly less pain and urgency, while those with higher urinary free cortisol reported less overall symptomatology (p <0.05). Relationships with morning cortisol were also observed when controlling for co-morbid conditions known to be affected by the hypothalamic-pituitary-adrenal axis, such as fibromyalgia, chronic fatigue and rheumatoid arthritis. Patients with morning cortisol less than 12.5 nmol./l. were 12.8 times more likely to report high urinary urgency than those with values above this cutoff. CONCLUSIONS: These findings imply that regulation of the hypothalamic-pituitary-adrenal axis may be associated with interstitial cystitis symptomatology and there may be different diurnal hypothalamic-pituitary-adrenal patterns in patients with interstitial cystitis who do and do not have co-morbid conditions. These findings may have treatment implications for patients with interstitial cystitis who have early morning cortisol deficiencies.     

Skin reactions to urine in patients with interstitial cystitis

Eight of 11 patients with interstitial cystitis had positive skin reactions to patch tests with urine (delayed type IV or irritant reactions). The positive reactions were seen to tests with the patients' own urine, but also, although less frequently, to tests with foreign urine as well. Immediate reactions (type I reactions; prick tests, scratch patch tests, and 20-minute patch tests) were not observed. The clinical morphology and the histology of the positive patch tests suggest a toxic rather than an allergic reaction, although the latter could not be totally excluded. The positive skin reactions may be relevant in the pathogenesis of interstitial cystitis suggesting a mucosal hyperreactivity to some component of urine.     

Abnormal urinary potassium metabolism in patients with interstitial cystitis

PURPOSE: If most patients with interstitial cystitis (IC) have epithelial leakage allowing urinary K to penetrate the interstitium and provoke symptoms, urinary K should be lower in untreated patients than in healthy subjects and it should increase with successful heparinoid treatment. This study tested these hypotheses. MATERIALS AND METHODS: Na, K and creatinine (Cr) were determined in spot urine samples from new, symptomatic, untreated patients with IC meeting all National Institute of Diabetes and Digestive and Kidney Diseases clinical diagnostic criteria, returning patients with IC reporting 50% or greater symptom improvement after 4 or greater months of oral heparinoid therapy and control subjects, and in 24-hour urine samples from new untreated patients and controls. RESULTS: In spot urine specimens of 37 new patients with IC K-to-Cr ratios were significantly lower than in 18 controls (0.51 vs 0.88 mg/mg Cr, p = 0.001). A total of 50 successfully treated patients with IC had significantly higher K-to-Cr ratios than those in 37 new patients (0.66 vs 0.51 mg/mg Cr, p = 0.025). Na-to-Cr ratios in the 3 groups were not significantly different. In 24-hour urine specimens 30 new patients had lower average K (31.0 vs 46.2 mEq/l, p = 0.01) and lower K-to-Cr ratios (0.43 vs 0.52 mg K/mg Cr, p = 0.01) than in 47 controls, while Na was not significantly different. CONCLUSIONS: Our finding of lower urinary K in new, untreated patients supports the concept of abnormal epithelial permeability and K absorption in IC. Higher urinary K in successfully treated vs untreated patients may reflect decreasing urinary K absorption due to mucosal repair and a resulting decrease in epithelial permeability. K/mg Cr appears accurate for normalizing urinary K.     

Dyspareunia and chronic pelvic pain in patients with interstitial cystitis/bladder pain syndrome

ObjectiveA previous study established that interstitial cystitis/bladder pain syndrome (IC/BPS) patients had significantly more dyspareunia and fear of pain than healthy controls. We evaluated the relationships between lower urinary tract symptoms and dyspareunia in IC/BPS patients.Materials and methodsA total of 156 IC/BPS female patients were included in this study. The diagnosis was made on the consensus of IC/PBS proposed by the Society for Urodynamics and Female Urology criteria in 2008. All women completed measures of pain severity (visual analog scale) and bladder symptom severity [IC Symptom Index, IC Problem Index, and the Pelvic Pain and Urinary/Frequency (PUF) scale]. Respondents were asked to recall if they experienced any sexual pain during or after sexual intercourse in the past 1 year. Cystoscopic hydrodistension during general anesthesia was performed for 5 minutes and maximal bladder capacity was also measured. Bivariate analyses were performed using chi-square and independent Student t tests.ResultsOf the women with a current sexual partner, 61% (96/156) reported dyspareunia during or after sexual intercourse. Of the 96 dyspareunia respondents, 46% (44/96) reported pain in the bladder only, 43% (41/96) in the vagina only, and 11% (11/96) in both the bladder and the vagina. Patients with dyspareunia complained of more severe urological pain (p = 0.02), a higher PUF scale score (p < 0.01), and larger anesthetic maximal bladder capacity (p = 0.04) than patients without dyspareunia. However, patients with dyspareunia at the bladder only had more severe urgency sensation (p < 0.01) but no differences in pain, PUF scale, severity of glomerulation, and maximal bladder capacity than those with dyspareunia at the vagina only.ConclusionIC/BPS women with dyspareunia have significantly more severe urological pain and a higher PUF scale score than women without dyspareunia. Physicians should consider sexual pain disorder in the management of patients with IC/BPS and use the PUF scale to evaluate not only IC-specific lower urinary tract symptoms, but also sexual pain disorder.     

Voiding urges perceived by patients with interstitial cystitis/painful bladder syndrome

AIMS: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a symptom-based diagnosis. We studied the IC/PBS symptom commonly referred to as "urgency" and its relationship to IC/PBS pain in a group of women with recent onset of the disease. METHODS: As part of a case control study to identify risk factors for IC, cases completed a questionnaire including two statements regarding the perceived cause of their urge to void. One was related to fear of incontinence and the other was linked with relief of pain. A Likert scale indicating level of agreement/disagreement comprised the response options. RESULTS: Most respondents (65%) agreed with the statement linking urge with pain relief. A minority (21%) concurred with the fear of incontinence statement. Disagreement for both was found in 19%. A substantial proportion (46%) agreed with pain relief but also disagreed that urge is related to fear of incontinence. Those who reported urge to relieve pain were significantly more likely to report worsened pain with bladder filling and/or improved pain with voiding. There were no such associations with urge to prevent incontinence. Overactive bladder or diabetes prior to IC onset did not confound these results. CONCLUSIONS: At least two distinct experiences of urge to urinate are evident in this population. For most, urge is linked with pain relief and is associated with bladder filling/emptying. About 1/5 reported urge to prevent incontinence. A similar portion did not agree with either urge, indicating that they may experience something altogether different, which requires further inquiry.     

Depressive symptoms and quality of life in patients with interstitial cystitis

PURPOSE: Previous research suggests that patients with interstitial cystitis have poorer quality of life and higher levels of depressive symptoms. However, most studies to date have been limited by the lack of standard measures to describe the experience of living with interstitial cystitis. In addition, to our knowledge no study has used a structured interview to assess depressive symptomatology. We investigated the extent of depressive symptoms and impaired quality of life in a sample of female patients with interstitial cystitis compared with healthy controls. Relationships among physician rated symptom severity, quality of life and depressive symptoms were also examined. MATERIALS AND METHODS: At a clinic visit 65 female patients previously diagnosed with interstitial cystitis and 40 age matched, healthy controls completed questionnaires on depressive symptoms (Beck Depression Inventory) and quality of life (Medical Outcomes Study 36-Item Short Form), and a structured interview on depressive symptoms (Hamilton Rating Scale for Depression) with trained interviewers. RESULTS: Patients reported compromised quality of life compared with healthy controls across various domains, including physical functioning, ability to function in one's normal role and vitality. They also had more severe depressive symptoms on the 2 depression measures. In patients, greater interstitial cystitis severity was associated with greater compromise in physical and social functioning, and mental health but not in other quality of life domains or depressive symptoms. CONCLUSIONS: A diagnosis of interstitial cystitis is related to poorer functioning in various life domains. Decrements increase with disease severity.     

Incidence of Helicobacter pylori in patients with interstitial cystitis.

OBJECTIVE: Chronic gastritis has compelling similarities to interstitial cystitis (IC). It is characterised by chronic pain in a tubular organ. Histologically, epithelial damage, inflammatory response in the lamina propria and epithelial ulcerations are seen. An infective cause was rarely considered until the emergence of Helicobacter pylori over the past 15 years. We have had experience of patients with bladder pain and irritability reporting improvement with antihistamines. It has also been reported that IC symptoms improved dramatically after treatment for H. pylori infection. Previous studies have determined the incidence of H. pylori antibodies in women with IC but we examined bladder material histologically and performed the Campylobacter-like organism (CLO) test on the biopsy specimens. MATERIALS AND METHODS: A prospective controlled study was performed. Patients with urinary symptoms fulfilling the National Institute of Diabetes and Digestive and Kidney Diseases criteria for IC underwent GA cystoscopy at which the macroscopic appearance of the bladder was noted and biopsies were taken. The biopsy material underwent histological examination and CLO test. Control patients who were undergoing cystoscopy for reasons other than investigation of IC also had biopsy taken and the CLO test was performed on these specimens. RESULTS: Five of 15 patients with symptoms and signs of IC had a positive CLO test. Three of 15 patients of the control group had a positive CLO test. With the 2-sided chi(2) test there was no statistical difference between the 2 groups. CONCLUSION: Our small prospective control study does not support the hypothesis that H. pylori is an important component in the pathogenesis of interstitial cystitis.     

Role of serum immunoglobulin E in patients with interstitial cystitis/bladder pain syndrome

ObjectiveThe actual pathophysiology of interstitial cystitis (IC)/bladder pain syndrome (BPS) is still uncertain. Immune or hypersensitivity mechanisms may play an important role in the pathogenesis of IC/BPS. This study was designed to investigate and analyze serum immunoglobulin E (IgE) levels in patients with IC/BPS.Materials and methodsPatients with IC/BPS who were admitted for cystoscopic hydrodistention were enrolled in this study. Blood samples were obtained to investigate their serum IgE levels. A serum IgE level more than 200 IU/mL was considered abnormal. The patients' symptoms, visual analog scale (VAS) scores, O'Leary–Sant symptom (OSS) scores, cystometric bladder capacity (CBC), maximal bladder capacity (MBC), and grading of bladder glomerulation hemorrhage during cystoscopic hydrodistention were recorded. Serum IgE levels were also investigated in women with stress urinary incontinence, who served as the control group.ResultsTwo hundred patients with IC/BPS and 35 controls were investigated. In total, 22 IC/BPS patients (11%) had abnormal serum IgE levels. No abnormal serum IgE levels were detected in the controls. The mean serum IgE level in IC/BPS patients and controls were 102.37 IU/mL ± 250.68 IU/mL and 74.21 IU/mL ± 88.62 IU/mL, respectively (p = 0.204). The VAS, OSS, CBC, MBC, and grading of glomerulations were not significantly correlated with serum IgE levels (p = 0.317, 0.587, 0.774, 0.559, and 0.309, respectively). The serum IgE levels were slightly higher in men than in women, although the difference was not significant (152.98 IU/mL ± 201.73 IU/mL vs. 94.87 IU/mL ± 262.54 IU/mL, p = 0.183).ConclusionIn this study, 11% of patients with IC/BPS had IgE level more than 200 IU/mL, but the mean serum IgE level was not higher than the controls. Aggravating factors such as food or environmental substance should be carefully investigated in IC/BPS patients with elevated serum IgE levels.