小龍醫師館

認識間質性膀胱炎

　　間質性膀胱炎病因不明，好發中年女性，典型表現包括嚴重頻尿、尿急、夜尿增多，伴恥骨上膀胱區脹痛。間質性膀胱癌的診斷是症狀及排除其他相似症狀所引起的疾病。 　　間質性膀胱炎(Interstitial cystitis，IC)或稱 bladder pain syndrome，是一種膀胱和盆腔周圍不適的疾病，以女性患者占多數，2009年RAND研究報告指出，在美國，就有3~8百萬患有IC(In 2009, new research (now known as the RAND study) revealed that in the U.S alone, between 3 and 8 million people have interstitial cystitis)。病因不明，大部份專家認為是由許多不同原因所造成的，包括肥大細胞活力增加(an increase in mast cell activity)、毒性物質滲入膀胱上皮下(an abnormality in the bladder lining causing leakage of toxic elements in the urine through to the underlying layers)、神經病變(neurological,ie (C-fiber upregulation, central pain sensitisation)、自體免疫疾病(autoimmunity)、過敏(allergy/hypersensitivity)、感染(infection)、遺傳(heredity or genetics)。

　　典型表現包括嚴重頻尿、尿急、夜尿增多，伴恥骨上膀胱區脹痛(pain associated with the bladder, dysuria, urinary frequency, urgency, or pressure in the bladder or pelvis during the day and night lasting more than 3 months)至少3個月以上，而尿檢無任何白血球或細菌感染。在診斷本病前必須先排除膀胱炎、膀胱腫瘤、尿道結石與阻塞、膀胱過動症(overactive bladde)等所引起相似症狀的疾病(Exclusion of any identifiable infection, disease or disorder)。 　　談到病因各家說法紛紜，包括可能病因如下：

理論	內容
Anxiety and stress theory	研究顯示，可能與 anxiety, stress, hyperresponsiveness, and panic 有關
Genes theory	尿中某種物質引起膀胱產生抗增值因數，抑制膀胱上皮細胞增殖(An antiproliferative factor(APF) secreted by the bladders of IC patients which inhibits bladder cell proliferation, thus possibly causing the missing bladder lining)
Autoimmune theory	Oravisto 觀察 54 名女性患者中，85% 抗核抗體(ANA)陽性
Leaky Bladder Lining theory	研究顯示(leaky lining theory)，患者的膀胱黏膜 GAG 層(glycosaminoglycan layer)遭受某因素破壞後損傷，進一步刺激黏膜下神經，引起膀胱疼痛，或急尿症狀(a defect in the bladder epithelium lining allows irritating substances in the urine to penetrate into the bladder；Deficiency in this glycosaminoglycan layer on the surface of the bladder results in increased permeability of the underlying submucosal tissues)。GAG 層中的 GP51 是一種醣蛋白，可防止尿中有毒物質及鉀離子滲入膀胱上皮粘膜下，據研究指出，間質性膀胱炎時，GP51 明顯下調(GP 51 is a urinary glycoprotein that functions as a protective barrier to the bladder wall. A study evaluated urinary GP 51 levels in patients with and without interstitial cystitis and found that these levels are significantly reduced in patients with the disease)
Mast cells theory	患者的膀胱組織病理結果顯示肥大細胞大量聚集，提示 IC 疾病與過敏反應有關(Biopsies on the bladder walls of people with IC usually contain mast cells. Mast cells gather when an allergic reaction is occurring. 肥大細胞可釋放組織胺，引起腫脹、疼痛，抑制傷口癒合(Histamine causes pain, swelling, scarring and prevents healing)
Nerve damage theory	可能是某些毒素造成膀胱神經受損後，釋放神經多肽物質，引起一系列瀑布放大後之疼痛反應(An unknown toxin or stimulus causes nerves in the bladder wall to fire uncontrollably. When they fire, they release substances called neuropeptides that induce a cascade of reactions that cause pain in the bladder wall)

　　間質性膀胱炎具有三大特徵：

1. 有長期進行性頻尿、尿急、夜尿增多；偶見血尿；
2. 在膀胱漲尿時感覺恥骨上區疼痛及觸痛，有時有尿道和會陰部疼痛，而排尿後症狀緩解；
3. 尿檢正常，無任何明顯的白血球或是細菌； 血尿偶可出現，在膀胱過充充盈擴張時明顯，有的患者在病史中可能有過敏性疾患。

　　間質性膀胱癌的診斷是症狀及排除其他診斷為主(Diagnosis of IC is essentially based on symptoms and exclusion of other painful bladder conditions)。但完整診斷應包括各項：

- Physical examination

- Laboratory tests including dipstick urinalysis, routine and special cultures, urine cytology

- Serum PSA in male patients over the age of 40 years

- Flowmetry and post-void residual urine volume measure by ultrasound scanning

- Cystoscopy with biopsy

1. 從前，確定間質性膀胱炎診斷，必須進行膀胱鏡下以水擴張檢查(gold standard test for IC was the use of hydrodistention with cystoscopy)。近年來，二種簡化方法加入使用，一種是幫助醫師診斷間質性膀胱炎所用的的簡易問卷調查(The Pelvic Pain Urgency/Frequency (PUF) Patient Survey is a short questionnaire that will help doctors identify if pelvic pain could be coming from the bladder)；二是氯化鉀試驗(The KCl test , also known as the potassium sensitivity test, uses a mild potassium solution to test the integrity of the bladder wall)，雖後者特異性不高，但卻可以知道使用 pentosan polysulphate 治療患者是否有效而確定診斷。
2. 尿常規多正常，有時可見血尿；當膀胱纖維化，導致膀胱輸尿管返流或梗阻時，腎功能檢查可出現異常。
3. 放射學及影像學檢查：在膀胱輸尿管返流時，排泄性尿路造影可見腎盂積水，膀胱容量減少等表現。超音波可測排尿後殘餘尿量的多寡(Ultrasound scanning may be carried out to see how much urine is left in the bladder afterurination (post-void residual urine)。
4. 尿路動力學檢查(urodynamics)：可用於評估how much urine the bladder can hold以及任何原因的尿滯留尿道梗阻、膀胱排空情況any kind of urinary retention or obstruction and either unable to empty the bladder at all or only able to partially empty it)。
5. 膀胱鏡檢查(cystoscopy)：可見膀胱容量縮小，施行膀胱擴張後，可見膀胱頂部小片狀瘀斑、出血，甚至裂隙。

　　間質性膀胱炎是一個謎樣的疾病，雖然不會致命，但它對我們身心、家庭事業影響相當的大，早期發現症狀就應及早就醫。根據病因，口服藥可包括以下各類：Antidepressants/anti-inflammatory drugs/ antispasmodics and anticholinergics/anticonvulsants (Gabapentin (Neurontin®)) /histamine-receptor antagonists/immunosuppressive agents (Cyclosporine A)/ painkillers (analgesics)/ pentosan polysulfate sodium/prostaglandins，僅重點介紹：

方法	內容
avoid diet	Food or drink containing caffeine Citrus fruit and juices acidic food such as tomatoes, vinegar etc. Artificial sweeteners Alcoholic drinks Carbonated drinks/soda hot pepper food
Rescue instillations	使用 pentosan polysulfate or heparin, sodium hyaluronate, lidocaine and sodium bicarbonate 所組成的溶液灌注到膀胱內，約有 90% 患者在頻尿及急尿感均可有明顯改善，增加膀胱容量。pentosan polysulfate 類似膀胱黏膜細胞分泌的 GAG，可有效修補膀胱表皮保護膜缺損。灌入此種藥物後需在膀胱內表留約 2hr 不排出，使膀胱表皮得到完全修護。一週治療 2~3 次，持續 12 週。若效果不佳，也可改在膀胱內將超強辣素 Resiniferatoxin(a diterpenoid stimulator of substance P release，RTX)藥物灌注，可讓膀胱神經釋放大量神經傳遞物質，使症狀得到 3~6 個月的緩解，治療膀胱過動及膀胱區疼痛(treat overactive bladder and hypersensitive painful bladder)。灌入此種藥物後需在膀胱內保留約 1/2~1hr 不排出
Elmiron	若嫌上述灌注膀胱太過麻煩，可口服用一種類似 heparin 藥，稱為 Elmiron(pentosan polysulphate sodium)，100 mg tid，但只 20~30% 有效(Oral pentosan polysulfate is believed to provide a protective coating in the bladder, but studies show it is not statistically significant compared to placebo)
Bladder coatings	對膀胱擴張療法(Bladder distension)或將 DMSO 灌注膀胱內無效患者，可以嘗試換 Cystistat(sodium hyaluronate)及 Uracyst(chondroitin)灌注膀胱內，可讓藥物彌補 GAG 層缺失。患者需臥床 20~40min，每 10min 翻身一次以讓藥物滲入膀胱內皮下，起更加保護作用 (this treatment may require the patient to lie for 20 ~40 min, turning over every 10 min, to allow the chemical to soak in and give a good coating)
DMSO	50ml DMSO(Dimethyl sulfoxide)注入膀胱，每週 2 次，每次保留 15min，可減少尿頻症狀方面取得良好效果。 【註】 The DMSO cocktail (6-8 weekly cycles)： -- 50% DMSO 50cc -- Triamcinolone 40mg -- Heparin sulfate 10,000-20,000 IU -- Sodium bicarbonate 44 meq -- (+/-) Gentamicin
肉毒桿菌毒素 (Botulinum toxin A)	膀胱壁注射或以膀胱以水擴張後，使膀胱壁出現裂隙時，再灌入肉毒桿菌毒素溶液，作用於膀胱壁上的膽鹼神經末稍，釋放神經傳遞物質有助於膀胱放鬆、容量增大、減少膀胱疼痛
Bladder distension (gold standard test)	膀胱鏡下以水擴張檢查法(gold standard test for IC) 除可以當作診斷方法，亦有治療效果。將生理沿水灌住到膀胱內，當膀胱內壓 > 80cmH 2 O ，可見膀胱黏膜有裂隙現象，當把水放流後，除了膀胱可出現明顯的出血點、出血斑、片狀出血之外，可暫時性減輕尿頻或尿痛症狀數週或數個月(success in reducing urinary frequency and giving pain relief to patients；Recent studies showing that pressure on pelvic trigger points can relieve symptoms may be connected)
Neuromodul-ation	可以使用 TENS、PTNS stimulators、Percutaneous sacral nerve root stimulation (PNS)治療以減輕疼痛致狀
Surgery	間質性膀胱炎末期，患者膀胱容量可 < 250 ml，若進一步下降 100 ml 以下的膀胱容量，則有明顯膀胱疼痛，此時可考慮做膀胱部份切除(cystectomy)，以小腸或大腸來做膀胱擴大整形手術，術後可增加膀胱容量，改善尿急、尿痛，這是最後不得已的手段(a treatment of last resort when all other treatment modalities have failed and pain is severe)

間質性膀胱炎、嚴重頻尿、神經病變、尿道結石、膀胱鏡、血尿、膀胱脹痛、臨床醫學資訊館