Painful bladder syndrome/interstitial cystitis (PBS/IC) is a heterogeneous clinical
syndrome of multifactorial aetiology. It is considered to be a consequence of different
pathophysiologic processes. An illustrative representation of the events in the
pathogenesis of IC and PBS is shown in [Figure 1].1
Theories of IC
Although the direct causes of IC are unknown, several theories explaining the pathophysiology
exist.
Defect in the glycosoaminoglycans layer
In a healthy bladder, large negatively charged molecules called glycoproteins and
glycosoaminoglycans (GAGs) line the epithelium(figure 2). This hydrophilic mucous
lining protects the underlying tissues of the bladder from harmful elements such
as proteins, ions, microcrystals and bacteria within the urine. A stable layer of
water is maintained in between the bladder lumen and the urothelium. One popular
theory is that the epithelial layer in the urinary bladder is deficient. It is also
stated that the defect in the GAG layer is the cause for IC. A defective GAG layer
leads to the leakage and absorption of urinary solutes, mainly potassium into the
underlying tissues resulting in damage. Ongoing exposure of the bladder wall to
potassium causes inflammation, tissue irritation and injury, mast cell degranulation,
and sensory nerve depolarisation. This process results in symptoms associated with
PBS/IC including urinary frequency, urgency and pain. The exposure of the bladder
wall to irritating substances in the urine causes chronic inflammation, injury,
tissue irritation, mast cell degranulation and depolarisation of nerve fibres. Over
a period of time, there is progressive damage to the bladder wall. This results
in the clinical symptoms of urinary urgency, frequency and chronic pelvic pain seen
in patients with IC.1-3
There is a lower ratio of urinary potassium to creatinine and GAG excretion in the
urine of patients with IC. The treatment of IC with GAG replacements such as sodium
pentosan polysulphate, heparin and hyaluronic acid is based on the hypothesis of
a defect in the GAG layer.3
Activation of Mast Cell
Another theory in the aetiology of IC is based on the degranulation of mast cells,
which are found in increased numbers in patients with IC. Acetylcholine, stress
and hormonal fluctuations can cause a stimulation of mast cells. The release of
histamine, leukotreins and prostaglandins on antigenic exposure of the mast cells
plays a role in the flares and episodic symptoms seen in IC. These pharmacologically
active mediators have a significant effect on smooth muscle, vascular epithelium
and inflammation. This theory is based on the hypothesis that the activation of
mast cells leads to degranulation into the nearby tissues. The resulting inflammatory
response causes local tissue damage and stimulation of nerve fibres. When the insult
continues over a prolonged period, the GAG layer is damaged.1-3
Role of Autoimmunity
One of the hypothesis for IC is based on the involvement of the immune system. The
chronic symptoms, exacerbations, remissions and the response to immunosuppressants
resemble dysregulation of the immune system complex. It shows an unexplained association
with other autoimmune diseases and chronic pain syndromes. Few of the associated
conditions seen with IC are irritable bowel syndrome, fibromyalgia, thyroiditis
and allergies.
A study to ascertain the local immunopathological mechanisms was undertaken in patients
with clinically proven IC. Urinary bladder and skin biopsies were studied by histological
and immunopathological mechanisms. Deposition of immunoglobulin and complement components
was observed in the bladder vessel walls. This was suggestive of involvement of
the complement system and local vascular immunological mechanisms in the pathogenesis
of IC.1,3
Neural Involvement
An alternate hypothesis is based on the role of substance P, present within sensory
nerves, in the pathogenesis of pain and local inflammation seen in IC. There is
an increased amount of substance P-containing nerve fibres in patients with IC.
An initial stimulus such as urinary tract infection which causes insult to the bladder
wall results in excitation of sensory nerves. The resulting neurogenic inflammation
causes the release of substance P, which further activates the release of mast cell
mediators. This results in local inflammatory changes, causing cell and tissue damage.
Alternatively, substance P is released on nerve stimulation due to mast cell degranulation.
Substance P causes sustained inflammation locally and increases activation of the
nerve endings. This prolonged activation of substance P on the nerve endings leads
to a decrease in the threshold needed for neural stimulus to induce symptoms of
IC. Over a period of time, neuroplasticity occurs in the nerves accompanied by visceral
allodynia resulting in sensations of pain being transmitted beyond the bladder.1,2
Role of Antiproliferative Factor
Antiproliferative factor (AFP) is a protein found in the urine of patients with
IC. AFP causes inhibition of the normal growth of epithelial cells and also decreases
the amount of epithelial growth factor within the urine. This causes a defect in
the regeneration of the damaged bladder epithelium. Improper regeneration increases
the future risk of infection and injury. In a study by Keay et al, urinalysis in
94% of patients diagnosed with IC showed the presence of AFP. However, there is
a lack of data to support the use of AFP as a diagnostic tool in the definitive
diagnosis of IC.1,2
