Interstitial Cystitis (IC)

This web page is created for an undergraduate class at Davidson College

Overview of IC

Intersititial Cystitis (IC) is a disease characterized by inflamation of the bladder wall. The primary symptoms (varrying in severity) are bladder pain, frequent and urgent urination, and abdominal pain. While this disease is not new, it has only been recognized by western physicians for the last 30 years. Previously it was often lumped with other "bladder pain" conditions and said to be caused by the antiquated concept of 'general female anxiety'. IC has been diagnosed in ~700,000 patients in the US, but because it is difficult make a positive diagnosis, many feel that there are many more unreported cases. Ninety percent of the cases occur in women with an average onset at age 40, while 25% of the patients are under the age of 30. IC affects different patients in different ways. Some patients feel more pain when their bladders are full and others become unable to retain normal amounts of urine in their bladder. It is not uncommon in a severe case for a patient to urinate up to 60 times in one day. Many women experience additional abdominal and bladder pain during menstruation and for many sufferers sexual intercourse is painful. Patients suffering from IC are more likely experience a number of other conditions including irratable bowel syndrome, allergies, and sensitve skin (ICA).

What causes IC?

The cause of IC is has not been completely determined. It is widely believed that there may be a number of different causes for IC. I will discuss some of these further below. The damage that causes the symptoms of IC is a degradation of the glycosaminoglycan (GAG) component of the mucin layer of the bladder (Metts 2001), and an increased number of activated mast cells in the bladder lining is thought to play a role in causing the symptoms of IC (Theoharides 1998). The mucin layer acts as a buffer for the bladder by blocking access of many potentially toxic or inflamatory substances to the lining of the bladder. One of the functions of GAG is to retain a water layer between the bladder lumen and the endotheliul cells. Without this layer toxins (from drugs, food, drink, etc) and lymphocytes and their byproducts have access to the lining of the bladder and can lead to the symptoms of IC. Below is a 3D structure of heparin, a molecule very similar to the GAG's lost in IC patients (also used as a replacement therapy).

Figure 1: 3D structure of glycosaminoglycan molecule heparin. Provided by PDB.

In addition to the above structure, go to the online version of Metts 2001 and check out the diagram of the bladder with labled mucin layer. (I was unable to recieve permission to use this figure on my webpage). While you're there check out the cystoscopy photographs.

Activated mast cells in the bladder lining cause damage by releasing inflamatory molecules and additionally by releasing proteases. Theoharides (1998) discuss the role that lymphatic cells can play in activating neurons to relase neurotransmitters. Apparently certain neurotransmitters (ACh and Sp) can further activate mast cells. Furthermore, bladder mast cells have estrogen receptors and the presence of estrogen increases their activation (perhaps explaining the increased pain during ovulation and menstruation). The final conclusion of Theohardies is that stress can play a role in activating blader mast cells (they showed this possiblity in a rat model). Therefore we see that immune, nueral, and endocrine factors affect IC.

We have discussed the role of activated mast cells in bladder lining damage, and we can now examine furthur research into the possible autoimmune causation of IC. It has been known for many years that IC patients have novel autoantibodies (Ochs 1997). A autoimmune causation model for IC has been shown in rats (Luber-Narod et. al. 1996). They were able to induce IC in rats by injecting them with Freund's adjuvant containing bladder homogenate. Following this injection the rats had doubled urination frequency and venular congestion (a histological change in the bladder) suggesting IC. They also noted two important details. First, there wasn't a significant change in bladder capacity, and second the number of mast cells was not signifcantly higher in the rats that had induced IC. However, there was a large variation in the number of mast cells from different sections taken from the bladders, and thus mast cell numbers are not a good indicator of IC. They were also able to induce IC disease in healthy syngenic rats simply by transplanting splenocytes from rats with IC. They therefore conclude that they have discovered an autoimmune model for IC.

This same group of researchers (Sankar 1999) followed up this discovery with another publication. I should point out that the second time around they refer to the induced IC as EAC (experimental autoimmune cystitis). They have since learned that EAC progresses with at least two cycles of "exacerbation and remission". This important feature of this paper is the discovery of an autoantigen (in rats remember) present in the bladder that is associated with EAC. In fact they showed that 9 of 10 EAC rats had serum Ab's for this 12 kDa antigen, while 12 of 13 'sham injected' rats did not have these Ab's. It is also worth noting that the Ab's were absent in the rats that did not develop EAC when injected with Freund's adjuvant and bladder homogenate (though they give no numbers to back this up). They have thus explained that urination frequency increases cyclically in EAC (and thus perhaps also in IC) and that there is a12 kDa antigen in rat bladders that may be responsible for the disorder. Unfortunalty I can find no follow up to this work that identifies this supposed autoantigen, nor is there similar work being performed in humans.

Some physicians have noticed that many patients who suffer from IC have a higher rate of other autoimmune disorders. Kimio (2002) investigate the genetic role of the ß2 gene, the interleukin (IL)-4 gene and its receptor gene in IC patients. They chose these genes because they are often associated with immune disorders. They studied five polymorphisms per gene. They found significantly higher prevalence of one of the polymorphisms for ADRB2, ADRA1d, and for the IL-4 genes in IC vs. non-IC patients. There was no significant difference in the IL-4 receptor or the ADRB3 genes. They conclude that ADRB2, ADRA1d, and Il-4 genes may play a role in predisposing certain patients to IC.

The above information regarding the causes of IC leaves one feeling perhaps a bit confused and definitly more than a little disapointed. While we have come a long way from lumping IC in with 'female hysteria', we are still a long way from assigning specific causations of the disease. From available evidence it appears that an autoimmune causation is most likely, but we must remember that there are likely mulitple events that can lead to IC. It is also important to remember that as researchers we are upset by the lack of evidence, yet it is the patients diagnosed with IC that are really left in dark with regards to this disease.

How is IC treated?

One of the most difficult aspects of treating IC is diagnosing IC. Currently the requirements for diagnosis involve ruling out all other causes, such as STDs, bladder cancer, infections, and kidney disease (ICA). Additionally a cystoscopy must be performed in which the bladder is distended (filled with fluid) and tiny hemorrhages must be identified. Saban (2002) are currently workig to identify gene expression differences in acute vs. chronic bladder inflamation. During acute inflamation the primary infiltrate is neutrophils and this leads to certain profile of expression/repression. They also identified profiles for acute to chronic transition and for chronic inflamation, at which point the priamry infiltrate are macrophages. This data may eventually lead to microarrays being used to more quickly diagnose IC and other chronic bladder conditions.

In order to reduce the affects of mast cell degranulation an antihistamine Hydroxyzine is often prescribed. It is interesting to note that allergies are often correlated with IC in many patietns. This drug will help with both of these. (ICA)

One of the most promising treatments developed to treat IC is the drug Elmiron. The goal of treatment with Elmiron is to rebuild a synthetic GAG layer in the bladder. This was the first FDA approved oral treatment for IC and has proven quite effective. Patients are told that it may take up to six months of Elmiron therapy before results can be noticed. As the new GAG layer is rebuilt pain can be eliminated, but it often takes longer to lessen urination frequency. (ICA)

DMSO is used to treat IC because it has analgesic properties and is believed to limit free-radical production (and therefore will reduce some of the agents that will irritate exposed bladder endothelium).

Surgery can be used to treat IC, however it is only recomended in the most severe cases after all other options have been exhausted. One of the more drastic treatments used to treat frequent urination urge associated with IC is called InterStim Therapy. This is not yet a common IC treatment. It involves inserting an electrical stimulation device near the sacral nerves in the back. The sacral nerves influence bladder control and thus manipulation of these impulses can have an affect on the frequency of urination. (InterStim Therapy Fact Sheet)

Another very important way to deal with IC is to drastically alter your diet. Patients are told to keep a diary of foods they eat so they can correlate them with pain or lack of pain. Foods and drinks high in acid can lead to flare ups and are thus avoided. This means no coffee, cokes, caffeine, alcohol, spicy food, vingegar, soy sauce, and no MSG! Over time patients learn what causes their flare ups and they learn to avoid them (or not avoid them).

Living with IC

IC is a chronic disorder that can have debilitating effects on patient's lives. With some patients having to go to the bathroom as many as sixty times in one day, it is not difficult to image how having IC could change your life. I have recently learned through personal interactions with a person dealing with IC just how important the diagnosis of IC can be. As mentioned above physicians must rule out a number of other diseases and perform invasive procedures before assigning IC as the cause of a patient's discomfort. What I didn't mention is that for many patients go through months or years of misdiagnosis (and thus no proper treatment) and often times painful and expensive treatments that are not directed at one disorder. This leads to confusion and frustration in the patient and often their family. However, 2003 is a pretty good time to be diagnosed with IC because it is a disease that is gaining more and more attention due to better knowledge and diagnosis. For example, as soon as you know you have IC, you suddenly are given handouts, videos, webpages, etc that will explain your disease and tell you how to best live with your symptoms. More importantly you can start targeted treatments such as Elmiron and you can begin to modify your diet so as to prevent flare ups. There are also many IC support groups in most large towns that patients can attend and learn from others how they deal with the disease. Learning that you are not 'crazy' or facing the disease alone is very important because there is quite a stigma attached to excretory diseases, at least in the US.


ICA Frequently Asked Question. Accessed April 24, 2003.

Julius Metts. Interstitial Cystitis: Urgency and Frequency Syndrome. Amer. Fam. Physician. October 1, 2001. Available at

Theoharides Theoharides, Xinzhu Pang, , Richar Letourneau, Grannum Sant. Interstitial Cystitis: A Neuroimmunoendocrine Disorder. Annals of the New York Academy of Sciences 840:619-634 (1998)

Ochs RL. Autoantibodies and interstitial cystitis. Clin Lab Med 1997 Sep;17(3):571-9

Luber-Narod J, Austin-Ritchie T, Banner B, Hollins C 3rd, Maramag C, Price H, Menon M. Experimental autoimmune cystitis in the Lewis rat: a potential animal model for interstitial cystitis. Urol Res 1996;24(6):367-73

Saban MR, Nguyen NB, Hammond TG, Saban R. Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. Am J Pathol 2002 Jun;160(6):2095-110.

Kimio Sugaya; Saori Nishijima; Tetsuo Yamada; Minoru Miyazato; Tadashi Hatano; Yoshihide Ogawa. Molecular Analysis Of Adrenergic Receptor Genes And Interleukin-4/Interleukin-4 Receptor Genes In Patients With Interstitial Cystitis. The Journal of Urology 2002; 168(6):2668-2671.

Sankar Mitra, Abraham Dagher, Reinhard Kage, Rifaat K. Dagher, Judith Luber-Narod. Experimental autoimmune cystitis: further characterization and serum autoantibodies. Urological Research. Volume 27 Issue 5 (1999) pp 351-356

The Interstitial Cystitis Association. Interstitial Cystitis Treatment Fact Sheets. 1999.

MedLine Page on Interstitial Cystitits (IC)

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