Symptoms of interstitial cystitis
The disease has a rapid onset and progresses quickly, but after the onset of typical symptoms the disease usually remains stable without further exacerbation. Even without treatment, more than half of patients will experience spontaneous remission, only to have another episode soon after.
The symptoms can be divided into two symptom groups: bladder irritation and painful symptoms. The main symptoms are severe bladder irritation such as urinary frequency, urgency, painful urination and pain in the suprapubic area, but also urethral pain, perineal and vaginal pain, and painful intercourse in 60% of patients. The pain is very intense and is associated with bladder filling, and the symptoms may be relieved after urination. In some atypical patients, the symptoms may be manifested as lower abdominal cramping or pressure, and the symptoms are aggravated before menstruation or during ovulation. Physical examination usually has no abnormal findings. Some patients have pressure pain in the suprapubic area and tenderness in the bladder on vaginal finger examination.
Patients may have both bladder irritation and pain symptoms, or only one symptom may predominate. The symptoms are similar to other inflammatory bladder conditions but are more persistent and longer lasting.
Causes of interstitial cystitis
Although interstitial cystitis (IC) has been known for a century, the etiology and pathogenesis of IC is still unclear, and according to current research progress, there are several hypotheses.
1, occult infection: Although no clear pathogens have been detected from patients, there is evidence that microorganisms (including bacteria, viruses, and fungi) are significantly higher in the urine of IC patients than in normal controls. Most people now believe that infection may not be the main cause of IC development, but it may act in conjunction with other pathogenic factors.
2, genetic factors: the incidence of IC in North Americans is significantly higher than in Japanese, the incidence in Jewish women is much higher than in other races, while blacks rarely suffer from IC, suggesting that IC may be related to race.
3, neurogenic inflammatory response: stress states such as cold, trauma, toxins, drugs, sympathetic excitation, release of vasoactive substances, causing local inflammation and nociceptive hypersensitivity; vasoactive substances can also further activate mast cells, causing vasodilation, bladder mucosal damage caused by inflammatory response.
4, mast cell activation: mast cell activation and aggregation is the main pathophysiological changes of IC. Mast cells are mostly aggregated around the nerves. Under acute stress, mast cells are activated and degranulated, releasing a variety of vasoactive substances such as histamine, cytokines, prostaglandins, trypsin, etc., which can cause a severe inflammatory response. There is activation of mast cells in the bladder in 20% to 65% of patients.
5, autoimmune disease: IC is an autoimmune disease for the following reasons.
(1) It is mostly seen in women ;
(2) A high percentage of patients have other autoimmune diseases at the same time;
(3) Patients are allergic to drugs in 26% to 70% of cases, and antinuclear antibodies can be detected in many patients;
(4) Histological examination is accompanied by lesions of connective tissue;
(5) Application of immunosuppressive therapy has some efficacy.
6, bladder mucosal barrier damage: the amino polysaccharide layer (glycosaminoglycans, GAG) on the migrating epithelial cells has a protective layer that prevents urine and its harmful components from damaging the nerves and muscles under the mucosa. Damage to the bladder mucosal barrier results in epithelial cell dysfunction and altered permeability, with the result that potentially toxic substances in the urine enter the bladder muscles, depolarizing the sensory nerves and causing clinical symptoms such as urinary frequency and urgency. This potentially toxic substance is mainly potassium ions, potassium ions do not damage or permeate the normal urinary epithelium, but have a toxic effect on the bladder muscle layer.
7. Toxic effects of urine: There are specific toxic substances in the urine of IC patients that cause damage to the bladder, such as antiproliferative factor (APF).
Diagnosis of interstitial cystitis
The diagnosis of interstitial cystitis is an exclusionary diagnosis that requires the exclusion of many diseases with similar symptoms. Thus, the diagnosis is difficult. And different physicians may have different criteria for diagnosis, which results in diagnostic confusion. For this reason, the NIADDK (National Institute of arthritis, diabetes, digestive and kidney diseases) developed diagnostic criteria for IC in 1987 and revised them in 1988.
The NIADDK’s diagnostic criteria for IC in the United States are
Required conditions: ① pain in the bladder area or lower abdomen, suprapubic with urinary frequency; ② submucosal punctate bleeding or Hunner’s ulcer seen after aqueous dilatation under anesthesia.
Cystoscopy should be performed after filling the bladder with water under general or even rigid anesthesia to a pressure of 80-100 cmH2O and holding it for 1 to 2 minutes for a total of two times, and should reveal diffuse submucosal punctate hemorrhage with a range of more than three quadrants, more than 10 in each quadrant, and not at the site where the cystoscope passes.
Diffuse punctate hemorrhage seen after filling with water
Cloudy hemorrhage seen on drainage
Conditions that should be excluded.
1. bladder volume greater than 350 ml in the awake state;
2.No urination at 30-100ml/min water injection to 150ml;
3, Periodic involuntary contractions during bladder perfusion;
4.No symptoms for more than 9 months;
5.No increase in nocturia;
6.Antibiotics, antimicrobial agents, anticholinergic or antispasmodic treatment is effective;
7. Urination less than 8 times a day when awake;
8.Prostatitis or bacterial cystitis within 3 months;
9, bladder or lower urinary tract stones;
10, active genital herpes;
11.Uterine, vaginal and urethral tumors;
12.Urethral diverticulum;
13, Phosphamide or other chemical cystitis;
14.Tuberculous cystitis;
15.Radiation cystitis;
16, Benign and malignant bladder tumors;
17, Vaginitis;
18, age less than 18 years.
The diagnostic criteria are too strict, making 60% of patients clinically unable to meet the diagnostic criteria of NIADDK. Hanno et al. analyzed a group of IC patients and found that only 32%-42% of 269 patients met the diagnostic criteria of NIADDK. Schuster, on the other hand, concluded that pediatric IC patients are not uncommon. The commonly used cystoscopy, aqueous dilatation of the bladder under anesthesia, as the “gold standard” for diagnosis, is not absolute. In a prospective study, the sensitivity of this test was 42% in IC, compared with a positive rate of 45% in normal controls. Even if a patient has typical IC symptoms, the typical petechiae may not be detected by dilatation of the bladder under anesthesia.
Thus, the diagnosis clinically relies on a comprehensive assessment of history, physical examination, voiding diary, urinalysis, urine culture, urodynamics, cystoscopy and pathological histology.
Based on the hypothesis that bladder mucosal barrier disruption is the pathogenesis of interstitial cystitis, Parsons proposed a method for screening and diagnosing IC, the potassium sensitivity test (PST), by performing bladder perfusion with sterile water and 0.4 mmol/L potassium solution, respectively, and recording the degree of urinary tract irritation symptoms. Normal individuals do not show symptoms due to the protection of the intact GAG layer, while patients with IC have irritation and toxic reactions due to the defective GAG layer, where potassium ions pass through the migrating epithelium and reach deeper tissues.
PST has a positive rate of 75%, is simple and almost non-invasive, and has a large application value, but it is still undetectable in 25% of patients and has a high false positive rate, thus its application value is much controversial. Patients with both acute cystitis and radiation cystitis have increased permeability of the bladder epithelium, which can produce a positive reaction.
There is also interest in finding markers for IC similar to tumor markers, and Erickson et al. tested multiple urinary markers in the same population and concluded that currently only glycoprotein 51 (GP51) and antiproliferative factor (AFP) can completely distinguish IC from normal controls. GP 51 and AFP have high sensitivity and high specificity in patients with IC who meet the diagnostic criteria of NIDDK, but further studies are needed in patients who do not clinically meet the diagnostic criteria of NIDDK. GP51 and AFP have the potential to be diagnostic markers for IC.
Parsons designed the pelvic pain (pelvic pain) and urinary urgency (urgency) and frequency (frequency) symptom scoring system (PUF), and the positive rate of PST was 74% for PUF 10-14 and 91% for PUF ≥ 20, so PUF can also be a valid tool for IC screening.
Treatment of interstitial cystitis
1, antihistamines: Since interstitial cystitis has a tendency to increase mast cells in the bladder wall and release inflammatory substances that cause pain, it can be inhibited with antihistamines. Antihistamines are usually used in the early stages of the disease, or in the severe acute phase, to obtain rapid relief of pain.
Hydroxyzine (hydroxyzine trade name atarax, vistaril) is an H1 receptor blocker that inhibits the secretion of mast cells and nerve cells, and has sedative and anxiolytic effects. Adverse effects include general weakness, drowsiness, and acute urinary retention. This drug is not used for pregnant women and people who are depressed. The symptoms disappear after a few days or a month after stopping the drug can be relapsed, so you should take 25mg every night as a maintenance dose.
2, antidepressants: antidepressants are helpful in relaxing the bladder and reducing bladder tension, so patients can get relief from emotional and inflammatory bladder reactions.
Amitriptyline (amitriptyline) is a tricyclic antidepressant used to treat interstitial cystitis, with the following mechanisms of action.
(i) blocking the reuptake of norepinephrine and 5-hydroxytryptamine by pre-synaptic nerve endings and blocking their receptors, which can achieve analgesia;
②Blocking H1 receptors has a sedative and anti-inflammatory effect;
③ anticholinergic and excitatory β receptors, can reduce bladder forcing muscle tone. The initial dose is 25mg, taken at bedtime, gradually increased to 75mg (once a night) within 3 weeks, the maximum can be up to 100mg.
3, calcium channel blockers: calcium channel blockers can relax the bladder forceps and vascular smooth muscle, improve the blood supply to the bladder wall.
The starting dose of nifedipine is 10mg, 3 times a day; if tolerated, it can be slowly increased to 20mg, 3 times a day. People with normal blood pressure take the slow-release form, blood pressure is not easy to fall and fluctuate, the course of treatment is 3 months, the efficacy of treatment will appear after about 1 month.
4, opioid receptor antagonist: sodium meperidine hydrochloride is a new opioid receptor antagonist, which can inhibit the release of histamine, 5-hydroxytryptamine, leukotriene and cytokines from mast cells degranulation. The initial dose was gradually increased from 0.5 mg twice a day to 60 mg twice a day. Initially, the dose is increased by 2mg per week, and after 3 months, it can be increased by 10mg per week.
5.Pentosan polysulfate sodium (PPS, trade name elmiron): It is a drug with a structure similar to GAG, which is partially excreted in the urine after oral administration and helps to restore the structure and function of the bladder epithelium. The recommended dose is 100 mg, 3 times/d; the maximum can be 600-900 mg/d. Most of the symptoms improve significantly within 3 months of taking the drug, and can last for 3 years, and studies have shown that the longer you take it, the better the efficacy, the more severe the symptoms are than those with mild symptoms. There are few adverse reactions, mainly gastrointestinal reactions, with alopecia, abdominal pain, diarrhea and nausea occurring in about 5% of patients.
6, methanesulfonate (suplatast tosilate): inhibit adjuvant (sexual) T cell-mediated allergic reactions. 300mg per day for 12 months significantly increases bladder capacity and reduces symptoms such as urinary frequency and pain.
7, other drugs: there are glucocorticoids, antiepileptic drugs, anticholinergic drugs, narcotics, antispasmodic sedatives, etc.. Generally used in combination to increase the therapeutic effect.
8, intravesical drug infusion: the advantages of intravesical infusion are: the direct action of the bladder drug concentration is higher; not easily absorbed through the bladder, less systemic adverse reactions; and not through the liver, gastrointestinal, renal absorption or excretion, so less drug interactions. The disadvantage is that there are complications of catheterization, such as pain and infection. Commonly used drugs are.
(1) dimethyl sulfoxide and heparin: dimethyl sulfoxide (DMSO) has anti-inflammatory, analgesic and antibacterial effects, and can quickly penetrate the cell membrane. Heparin (heparin) can enhance the protective effect of the GAG layer, and also has an inhibitory effect on cell proliferation and anti-inflammatory and anti-adhesive effects. aTP is a bladder injury neurotransmitter, which is activated and released to transmit bladder sensation by epithelial cell stretching after bladder expansion. in interstitial cystitis, the release of ATP increases, and this process can be blocked by dimethyl sulfoxide with heparin. Therefore, the therapeutic effect of dimethyl sulfoxide and heparin on the hypersensitivity symptoms of interstitial cystitis can be explained, and heparin has a more pronounced dose-dependent effect than dimethyl sulfoxide.
50 ml of 50% dimethyl sulfoxide with 50 ml of saline was infused every 2 weeks for 15 minutes for more than 8 weeks. Data from a group of studies showed that after 2 months of treatment followed by a 1-month interval, 93% of the test group showed objective improvement and 53% subjective improvement, corresponding to 35% versus 18% with saline instillation only. The relapse rate was 35% to 40% when treatment was stopped, and then continued treatment was effective and should be performed after the urinary tract infection had been controlled and the bladder biopsy had been performed at intervals with no adverse effects other than the garlic smell of breathing.
These drops are mixed together for bladder instillation, commonly known as cocktail therapy.
Heparin 25,000 U in 10 ml of saline is administered by bladder irrigation and kept for 1 hour three times a week. Many patients were treated for 4 to 6 months before the efficacy appeared, and no adverse effects, especially no coagulation disorders, occurred. Now we advocate the use of “cocktail therapy”, the solution consists of 50 ml of 50% DMSO, 10 ml of NaHCO3 (concentration 75 mg/ml), 40 mg of trenbolone, and 10,000-20,000 units of heparin. The bladder is perfused with 30-50rnl of the solution and kept for 30-60 minutes and then emptied.
(2) Sodium hydroxychlorophyllin (clorpactin): This drug was previously used to treat bladder tuberculosis by the mechanism of partial destruction of the bladder surface by its oxidative effect. The healing process of the bladder surface induced by the infusion of sodium hydroxychlorophyllide can alleviate the patient’s symptoms. 0.4% solution is the commonly used concentration and it is advisable to prepare it when used because painful irritation often requires treatment under anesthesia. The method is to administer 0.4% sodium hydroxychlorophyllide in an amount of about 50% of the bladder volume, instill it and leave it for 5 to 7 minutes and then withdraw it, and so on 3 to 4 times, and finally rinse the bladder repeatedly with saline, and the patient’s urinary pain and frequency will worsen a few hours or days after instillation. Various authors suggest that treatment should be spaced out over several weeks or months. The effectiveness rate is about 50% to 70% and the disappearance of symptoms lasts for 6 to 12 months.
(3) BCG: BCG causes significant mucosal exfoliation, and the mechanism of action is still not fully understood, but may be achieved by strengthening the immune system. Double-blind and controlled trials have shown a 60% remission rate at 6 months (compared to 27% in the control group), and 89% of patients who responded still maintained remission at 2 years.
(4) Hyaluronic acid: Hyaluronic acid can be used to temporarily repair defective epithelial mucosa (GAG) and has a chemical structure similar to that of heparin. Bladder perfusion has been reported to relieve the symptoms of IC. It is currently undergoing double-blind controlled trials in the US and Canada with low adverse effects.
(5) Silver nitrate: treats IC with its bactericidal, astringent, and corrosive effects and is contraindicated in those with ureteral reflux and those with recent bladder biopsies. The concentration varies from 1/2000, 1/1000, 1/100, 2/100, more than 1% need to use anesthesia, each time the amount of about 50-80 ml, stay 2-10 minutes, interval of 6-8 weeks. This treatment is still effective in 50% of the cases with one year follow-up.
(6) Capsaicin and botulinum toxin: In recent years, it is believed that the use of capsaicin or RTX to inhibit C nerve afferent fibers in the bladder can help reduce the inflammatory response in the bladder, which in turn can improve the symptoms of bladder muscle inflammation and bladder contracture. However, because capsaicin and RTX are still quite irritating to the bladder, instillation can be uncomfortable and may be unacceptable to some patients. Therefore, the painful bladder response can be suppressed by instilling anesthetics into the bladder, followed by further C nerve fiber desensitization with capsaicin or RTX. The concentration used is preferable to a lower concentration (8-10 mmol/L), but multiple treatments are required.
Botulinum toxin has been used in the past for overactive bladder disorders, where it is injected inside the muscles of the bladder to inhibit the unstable contraction of the muscles, resulting in an increase in bladder capacity. However, in some patients, the contraction of the detrusor muscle may be reduced as a result, thus also producing a short-term sequelae of more difficulty in urination. The use of botulinum toxin injections into the submucosa of the bladder has recently been reported and has been found to be effective in suppressing bladder sensation and increasing bladder capacity.
However, there is still an inhibitory effect on the contractility of the detrusor muscle, leaving patients with complications of dyspareunia even after treatment. Interstitial cystitis often occurs in middle-aged women and is characterized by fibrosis of the bladder wall. It is accompanied by a reduction in bladder capacity, with frequency, urgency, and distension of the bladder area as its main symptoms.
Traditional Chinese medicine treatment.
Chinese medicine treatment should be chosen to clear heat and detoxification, dampness and laxative mainly, supplemented by tonifying the kidney and consolidating the root, activating blood circulation and eliminating blood stasis, supporting the righteousness and eliminating evil, and improving the immunity of the body as the method of formula. The author has contacted many such patients in the clinic and has gained a lot of insights. If the evidence is properly identified, immediate results can be seen.