If you have read part 1 and 2 of this series, “What causes interstitial cystitis?”, you understand by now that interstitial cystitis, although considered a condition all on its own, can really be viewed as just one symptom of a body system that is out of balance
So far, I have gone over nine contributing factors involved in the development of interstitial cystitis and today, I will go over five of the lesser known abnormalities and contributing factors that could be related to your IC.
A word of caution: There may be some new words in here that you are not familiar with because a lot of it is taken from scientific papers on IC. However, after a few careful reads of this post and a few dictionary searches, you’ll be able to understand the material.
I first came across these lesser known causes of IC while performing research on IC for my pathology class while studying nutrition. It really helped me to gain a deeper understanding of the multi-faceted nature of IC and how all of these processes of dysfunction and imbalances that occur in someone with IC are intricately connected.
Here are 5 lesser known contributing factors of interstitial cystitis
1. GAG layer defect
One of the factors at play in the chronic inflammatory process of IC, is a dysfunctional urothelium. The urothelium is covered by a layer of glycosaminoglycans (GAG layer) that consists of chondroitin sulfate, hyaluronate sodium, glycoproteins, and mucins to protect the bladder.
In IC, damage occurs to the mucous or GAG layer, causing altered permeability of the urothelium to various urinary cations such as potassium. Think leaky gut, leaky brain and now, leaky bladder!
Initial insult or damage can occur from exposure to toxins, allergens, injury, infection (viral, fungal, bacterial), etc. Damage also occurs to the urothelium after the initial insult, followed by an inflammatory process of cytokine production, leading to the proliferation and activation of mast cells.
Influx of potassium ions causes up-regulation of sensory afferent nerves, which further activates the mast cells, thus initiating a vicious, self-reinforcing cycle.
In addition, studies have suggested that the urothelium releases a number of neuropeptides (e.g. nerve growth factor) neurotransmitters and anti-proliferative factor (APF), which activates submucosal afferent nerves and mast cells during this process, resulting in hyperalgesia (increases sensitivity to pain) in patients with IC.
APF induces increased permeability of normal urothelium and regulates expression of other cytokines, such as up-regulating heparin-binding epidermal growth factor and down-regulating epidermal growth factor, by the urothelium. These cytokine abnormalities could mediate increased bladder sensation and pain (Grover 5).
2. Mastocytosis and mast cell activation
A second factor is mastocytosis and mast cell activation. An increased number of mast cells, both in submucosa and detrusor layers, can be seen particularly in classic IC with Hunner’s ulcers. A study using immunocytochemical demonstrated a 6 to 10-fold increase in mast cells in classic/ulcerative IC compared with a 2-fold increase in patients with non-ulcerative IC (Grover 5).
Mast cells are activated by numerous mediators such as: (1) cytokine-like stem cell factors (SCF) that are released by damaged urothelium or nerve growth factor (NGF), which is also increased in patients with IC; (2) bacterial and viral super antigens; (3) immunoglobulin aggregates; (4) neuropeptides, such as substance P (SP); (5) acetylcholine (ACh) and (6) neurotensin.
Once activated, mast cells undergo degranulation to release vasoactive, inflammatory, and nociceptive mediators, such as histamine, kinins, proteases (e.g. tryptase), cytokines, leukotrienes (e.g. IL-6 and IL-8), prostaglandins, and nitric oxide.
For example, vascular endothelial growth factor (VEGF), a mast cell mediator, is over-expressed in 58% of IC bladders, while IL-6 and IL-8 are also over-expressed. The release of vasoactive and inflammatory mediators from mast cells may explain many IC symptoms and characteristics like hypervascularity and glomerulations.
Studies have also shown an association between increased VEGF and severity of IC-associated pain. Usually, these mediators have shorter half-life, but in IC, the noxious stimulus persists for a longer duration resulting in increased secretion of inflammatory mediators even when the stimulus is removed.
This causes angioedema, leading to vasculitis and neuroinflammation, which promote neuritis and secretion of neurotransmitters that further stimulate mast cells. Therefore, a vicious circle of events begins, causing persistent inflammation and urothelial re-injury, which clinically manifests as hyperalgesia leading to dysuria, urgency and lower urinary tract symptoms (Grover 6).
Tryptase, another inflammatory mediator from mast cells, can cause microvascular leakage and stimulate protease-activated receptors (PARs), in turn leading to widespread inflammation and neuronal hyper-excitability.
Mast cell-derived tumour necrosis factor-a (TNF-a), activates the nuclear transcription factor-kB, which is a key regulator of inflammatory gene expression, causing further urothelial inflammation.
3. Neurogenic inflammation
A third factor in this vicious cycle of inflammation is neuronal inflammation and nerve up-regulation. It is believed that IC also represents a visceral neuropathic pain syndrome mediated by up-regulation of nerves in the pelvis, spinal cord, and brain.
The vasoactive and inflammatory molecules, such as SP and NGF, secreted by mast cells, potentially increase proliferation of the nerve fibers. Studies have shown that there is an increase in nerve fibers in IC, particularly those containing the neuropeptide SP in patients with untreated IC.
Perivascular sensory nerve terminals have been found to have enhanced sensitivity to SP, leading to a local cascade of neurogenic inflammatory responses, which is responsible for the patho-physiological changes of IC. This potentially explains the flaring of symptoms in female patients with IC before menses due to an estrogen surge that induces histamine release from mast cells with subsequent secretion of SP.
Likewise, stress may exacerbate IC symptoms due to release of corticotropin-releasing factor (CRF) and subsequent activation of mast cells. The increased levels of NGF and morphological changes (neuroplasticity) in sensory and motor neurons may be responsible for continued pain, frequency, and urgency even after the initial inflammatory stimulus has subsided (Grover 7).
4. A History of Bladder Trauma
A trauma to the bladder can weaken the bladder and set the stage for urine (which contains toxins and is usually overly acidic in IC patients) to damage the bladder lining, leading to inflammation and an increase in mast cell activation.
Simone explains that bladder trauma can be from surgery in and around the bladder area, such as a hysterectomy, removal of ovarian cysts and fibroids, tubal ligations, or relating to endometriosis.
Trauma to the bladder can occur during pelvic surgery or during childbirth. It could even be from an unrelated surgery, as there have been some cases of IC development after dental surgery.
A spinal cord trauma could affect the nerves in the bladder. Some women have reported the onset of IC after their first sexual experience or after a sexual trauma, such as a rape. Repeated UTIs can also cause trauma or damage to the bladder and set the stage for IC (Simone, To Wake In Tears 29).
5. Urine abnormalities
A unique protein, APR (anti-proliferative factor) has been isolated in the urine of IC patients. It is not found in the urine from patients without urologic symptoms or those who have acute UTIs or other urologic conditions.
This protein may be directly responsible for preventing repair of the damaged epithelial lining in IC patients. In addition, it has been discovered that heparin-binding epidermal growth factor (HB-EGF), known to be important for epithelial cell proliferation and wound healing, is significantly decreased in IC patient urine specimens (Willis 31).
Dr. Gillespie, who has treated thousands of patients with IC, found that her patients’ urine in the bladder was alkaline, with a higher pH. She attributes a higher urine pH to the fact that the cells in the bladder leak bicarbonate to compensate for the bladder tissues being burned by acidic urine. She confirms that her IC patients actually had a low urine pH because the urine she evaluated by catheterization from the kidneys was 5.5, which is acidic (Willis 31).
The urine of IC patients sometimes contains red blood cells, which may result in pink-tinged or brownish urine. Reddish-coloured urine indicated some amount of active bleeding from injured bladder epithelium, or from other areas of the urinary tract, such as the prostate.
White blood cells can sometimes be in the urine of patients with IC, although not usually concentrated enough to indicate infection.
Patients with IC also have greater levels of histamine and substance P (an inflammatory neurotransmitter) in their urine than non-IC patients. The elevated levels of histamine may indicate an allergic component to IC (Cohan 37-38).
Do you have to understand all of the above to heal your IC?
You do not have to fully comprehend all of the processes explained in this post to heal your IC, but I do think it is important to have a general idea of what is going on inside of you. Why? It allows you to be a better advocate for your own health and well-being.
No matter what healing route you decide to take, you will undoubtedly visit more than one practitioner to get help with some aspect of your IC. The more you know about your own condition and the more you can understand the connections between the various imbalances in your body, the more likely you are to receive appropriate and helpful treatment options for your particular “brand” of IC.
When you can speak intelligently about your condition to the practitioners that you approach for help and you are able to guide them to important information and resources on IC, you can develop a beneficial healing relationship based on trust and an understanding that your input matters and it is a two way street between you and your practitioner.
I hope I have not overwhelmed you with this information and that these posts on what causes interstitial cystitis will be of help to you on your journey!
Comments or questions? Feel free to reply below or send me an email directly.
Cohan, W. (2011). The Better Bladder Book: A Holistic Approach to Healing Interstitial Cystitis & Chronic Pelvic Pain. Alameda: Hunter House, Inc.
Grover, S. et. al. (2011). Role of inflammation in bladder function and interstitial cystitis, Therapeutic Advances in Urology, 3(1),19-33. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126088/ (accessed July 7, 2013).
Simone, C.M. (1998). To Wake in Tears: Understanding Interstitial Cystitis. Cleavland: IC Hope, Ltd.
Willis, A.K. (2003). Solving the Interstitial Cystitis Puzzle: A Guide to Natural Healing. Beverly Hills: Holistic Life Enterprises.