Unit Two : Etiopathogenesis
The morphology of bladder in patients with bladder pain syndrome appears to range from that of end stage bladder, which is a small capacity fibrotic bladder resulting from prolonged inflammation of all layers of bladder (Pan cystitis) to absolutely normal bladder. This is the biggest challenge in description of this clinical entity and hence it has been accepted that it is a heterogenous conglomeration. For the sake of convenience of description, we may look at the practical classification of this clinical entity as inflammatory or non-inflammatory IC/BPS
A) Inflammatory IC/BPS
The bladder is a target organ for inflammation and the effects of mediators of inflammation are evident on the histological studies. Histological evidence of inflammation in all the layers of urinary bladder have been documented with preponderance of mast cells in the detrusor layer of bladder. There has been attempt to label the diagnosis based upon the number of mast cells seen per high power field, but it has been given up due to poor sensitivity and specificity.
Etiopathogenesis of this group (inflammatory) of patients have various possible mechanisms as discussed in the following passages
- Infections with non-culturable organisms have been one of the earliest and the foremost theories considered. The organisms without definite cell wall like mycoplasma were implicated. Electron microscopic studies and polymerase chain reaction have failed to document any evidence of microorganisms in the layers of urinary bladder. Various clinicians have used cyclical courses of broad-spectrum antibiotics like doxicycline, macrolides etc. over periods ranging from few weeks to months. However they have not been successful.
- Autoimmunity The fact that many of these patients have associated disorders like bronchial asthma. The presence of sheets of plasma cells, T lymphocytes and aggregates of B lymphocytes in the layers of detrusor is at the best a circumstantial evidence of auto immune phenomenon working to generate pan cystitis.
- Defective urothelium. Urothelium is a multilayered epithelial barrier, which separates the hypertonic urine with all its constituents on one side and normal physiological tissues on other. The ability to store hypertonic solution (urine) without damaging the normal tissues is because of the unique structure of urothelium, which is a multilayered transitional epithelium covered with a layer of complex molecules called proteoglycans. These molecules have a proteinaceous end and a carbohydrate end. These are collectively known as GlycosAminGlycan or GAG layer. Naturally occurring GAG include heparin, chondroitin sulfate, hyaluronic acid, and keratin sulfate among others. Injury to this urothelial barrier results in percolation of urinary solutes into the sub urothelial and detrusor layers resulting in inflammation and resultant painful irritative symptoms. Damage to the urothelial barrier is evident by the loss of GAG layer as seen by electron microscopic studies. There is either a deficiency or difficulty in repairing this GAG layer, which results in the pathogenesis of IC/BPS. Porous urothelium could also be due to impaired proliferation of urothelial cells causing gaps in the tight junctions of the most superficial layer. Increased concentration of Anti Proliferative factor (APF) have been identified in the urine of these patients
- Urinary Toxins. It has been postulated that these patients excrete some urinary toxins, which are responsible for initiating and perpetuating inflammation in the layers of bladder. A heat labile low molecular weight substance has been isolated, but as of present day knowledge it’s role has not been validated.
- Neurogenic inflammation. Usually it is the inflammation that causes pain, but in this situation, it is the pain, which causes inflammation. Afferent nerves carrying pain can have antidromic conduction and these fibres can release substance P and neurokinin A, which are initiators of inflammation
- Dietary constituents. Certain dietary items might have an adverse effect on the urothelium. This may result in exacerbation of preexisting urothelial insult. It is possible that some dietary constituents, when taken over along time can deplete the healthy urothelial layer.
B) Non inflammatory IC/BPS
- Neuroplasticity. The afferent nerves carrying the pain sensation (C fibers) pass through the dorsal horn of the spinal cord from where the information is transmitted through the ascending pathways to the cerebral cortex as unpleasant sensation. If the painful sensation is repetitive, as might occur due to infective cystitis, the dorsal horn cells happen to replicate the messages to cortex without actually receiving any input from peripheral afferent nerves. These processes are mediated through specific neurotransmitter known as N-methyl -D aspartate (NMDA). This perception of pain, based on prior sensitization, in the absence of any peripheral afferent input is called neuroplasticity.
- Cross sensitization. Several visceral organs are innervated by same spinal segment. As a result there are viscera visceral referred pain sensation. This happens with large bowel, uterus and adnexa, and the urinary bladder.
- Pelvic floor dysfunction. Spasm of pelvic floor due to anxiety, behavioral disorder, substance abuse, past traumatic experience etc. can result in dis-coordinated or dysfunctional voiding. This may cause pain due to spasm of trigone and skeletal sphincter. The pattern flow of urine is like that of a straining against obstruction. The overall clinical picture may be similar to inflammatory IC/BPS
- Stress. People who are constantly under some kind of stress have been found to have pain perceived to be originating from the urinary bladder. The bladders of these people have been found to increase density of sympathetic nerve fibers.
Lets now learn about epidemiology