This document summarizes the pathogenesis of interstitial cystitis (IC). It discusses how IC was originally described in the 1800s and defines how it is currently classified. The pathogenesis is multifactorial and may involve infection, inflammation, autoimmunity, mast cell involvement, defects in the bladder surface, and neurobiological factors. The document also reviews diagnostic criteria, epidemiology, associated disorders, potential etiologies, and pathological findings of IC.

1. Pathogenesis of
Interstitial Cystitis
Dr Rohan Sharma
Urology Resident
MPUH
NADIAD

2.  Interstitial cystitis (IC) is a clinical diagnosis
primarily based on symptoms of
urgency/frequency and pain in the bladder

3.  Joseph Parrish (1836) –
“tic doloureux of the bladder.”
 Skene (1887) used the term interstitial
cystitis to describe an inflammation that has
“destroyed the mucous membrane partly or
wholly and extended to the muscular
parietes.”

4. ICS Definition
 Painful bladder syndrome (PBS) - “the
complaint of suprapubic pain related to
bladder filling, accompanied by other
symptoms such as increased daytime and
night-time frequency, in the absence of
proven urinary infection or other obvious
pathology”

5.  The ICS reserves the diagnosis of IC for
patients with “typical cystoscopic and
histological features,” without further
specifying these.
 Recent international consultations have
agreed that the nomenclature of “interstitial
cystitis” be revised to “painful bladder
syndrome/interstitial cystitis.”

6. NIDDK Diagnostic Criteria for
Interstitial Cystitis
 To be diagnosed with interstitial cystitis, patients
must have either glomerulations on cystoscopic
examination or a classic Hunner ulcer, and they
must have either pain associated with the bladder
or urinary urgency.
 An examination for glomerulations should be
undertaken after distention of the bladder under
anesthesia to 80 to 100 cm H2O for 1 to 2 minutes.
The bladder may be distended up to two times
before evaluation.

7.  The glomerulations must be diffuse—
present in at least three quadrants of the
bladder—and there must be at least 10
glomerulations per quadrant.
 The glomerulations must not be along the
path of the cystoscope.

8. Exclusion criteria
1. Bladder capacity of greater than 350 mL on
awake cystometry
2. Absence of an intense urge to void with the
bladder filled to 100 mL of gas or 150 mL of
liquid filling medium
3. The demonstration of phasic involuntary
bladder contractions on cystometry
4. Duration of symptoms less than 9 months
5. Absence of nocturia

9. 6. Symptoms relieved by antimicrobial agents,
urinary antiseptic agents, anticholinergic agents,
or antispasmodic agents
7. A frequency of urination while awake of
less than 8 times per day
8. A diagnosis of bacterial cystitis or prostatitis
within a 3-month period
9. Bladder or ureteral calculi
10. Active genital herpes

10. 11. Uterine, cervical, vaginal, or urethral cancer
12. Urethral diverticulum
13. Cyclophosphamide or any type of chemical
cystitis
14. Tuberculous cystitis
15. Radiation cystitis
16. Benign or malignant bladder tumors
17. Vaginitis
18. Age younger than 18 years

11. EPIDEMIOLOGY
 Prevalence estimates per 100,000 persons
United States: 35-24,000
Netherlands: 7
Finland: 10.6-450
Japan: 1.2
 An accurate country-by-country
determination of PBS/IC prevalence and
incidence is difficult to perform at the
present time

12. EPIDEMIOLOGY
 Female to male ratio = 5:1
 Median age at onset is 40 years.
 Late deterioration in symptoms is unusual.
 There is a 50% temporary spontaneous
remission rate, with a mean duration of 8
months.

13.  The incidence of childhood bladder
problems is 10 times higher in IC patients
versus controls.
 The incidence of a history of urinary tract
infection is twice that of controls.
 IC patients have a lower quality of life than
dialysis patients

14. ASSOCIATED DISORDERS
 Allergies - 40% -MC
 Irritable bowel syndrome - 30%
 Fibromyalgia
 Systemic lupus erythematosus
 Inflammatory bowel disease - 7%
 Focal vulvitis/vulvar vestibulitis
 Sjögren's syndrome

15. Etiology and Pathogenesis
 PBS/IC has a multifactorial etiology that
may act predominantly through one or more
pathways resulting in the typical symptom-
complex

17. Infection
 The symptom-complex looks to the patient
and physician like an infectious process
 Diagnosis of PBS/IC is made only after a
patient has been treated with antibiotics for
presumed urinary tract infection without
resolution of symptoms

18.  The epidemiology of urinary tract infection
and its predominance in women mirror the
IC data
 Infectious etiology could not be identified

19. Inflammation/Autoimmunity
 Immune/neuroimmune mechanisms may
have an important role in the pathogenesis
of PBS/IC.
 Excessive release of sensory nerve
neurotransmitters and mast cell
inflammatory mediators is thought to be
responsible for the development and
propagation of symptoms .

20.  Inflammation results in altered nerve growth
factor and in morphologic changes in
sensory and motor neurons
 Such neuroplasticity may explain the
long-term symptoms and pain after
inflammation subsides

21.  Oravisto (1980) provided strong circumstantial
evidence of autoimmunity
- Chronic course of disease
- Absence of infection
- Pathologic findings
- Occurrence of antinuclear antibodies
- Responses to corticosteroids
But the paucity of activated lymphocytes is
against an autoimmune process.

22. Anderson and colleagues (1989)
 Although IC patients demonstrated a nonspecific
increase in antibody formation, this was not
significantly different from a similar group of other
urologic patients.
 The lack of specificity indicates the immunologic
findings are likely secondary to inflammation
rather than a primary etiology

23.  The exact role of autoimmunity in IC
remains controversial
 Although the immune system remains a
target for therapy, no clear indication of a
primary role for autoimmunity as the cause
of IC has been observed

24. Mast Cell Involvement
 Simmons (1961) was the first to suggest mast
cells as a cause of IC
 Mast cells have frequently been reported to
be associated with IC, both as a
pathogenetic mechanism and as a
pathognomonic marker

25.  Mast cells may serve as the final common
pathway through which the symptomatic
condition is expressed.
 Mast cells produce histamine.
 Histamine release in tissue causes pain,
hyperemia, and fibrosis, all notable features
of IC

26.  Mast cells are strategically localized in the
urinary bladder close to blood vessels,
lymphatics, nerves and detrusor smooth
muscle
 Mast cells are not specific for IC
 IC is a syndrome with neural, immune, and
endocrine components in which activated
mast cells play a central, although not
primary, pathogenetic role in many patients

27. Bladder Glycosaminoglycan Layer and
Epithelial Permeability
 Parsons(1990) hypothesized and popularized
the concept that IC in a subset of patients is
the result of some defect in the epithelial
permeability barrier of the bladder surface
glycosaminoglycans

28.  The GAG layer functions as a permeability and
antiadherence barrier
 In the absence of this protective layer in the
urinary bladder, its susceptibility to infection
would increase and the production of nitric oxide
and substance P increases.
 Consequently, the permeability of both the
urothelium and the blood vessels in the mucous
membrane increases and the blood flow slows due
to vasodilatation

29.  Parsons reported a lower excretion of
urinary uronic acid and glycosaminoglycans
in IC patients than in normal volunteers
 Hypothesized that a leaky transitional
epithelium might be absorbing these
substances to its surface

30.  Parsons placed 0.4 M potassium chloride
(KCl) intravesically into normal volunteers
and IC patients.
 KCl provoked the symptom in 4.5% of
normal individuals and 70% of IC patients.
 Symptomatic responses were reduced in
patients on heparinoid therapy.

31.  Increased mucosal permeability is
nonspecific and a consequence of bladder
inflammation (cyclophosphamide-induced
bladder injury, bacterial infection, and
cystitis /aging)
 Whether increased mucosal permeability
represents a primary cause of IC or the
result of an unidentified source of
inflammation is unclear

32. Neurobiology
 Inflammatory painful stimuli, especially if
repeated, can chronically alter innervation,
central pain-processing mechanisms, and
tissue responses

33.  Sensory nervous system can generate some of the
manifestations of inflammation
 Activation of sensory nerves trigger neurogenic
inflammation through release of neuropeptides
such as substance P, neurokinin A and CGRP
 Also cause degranulation of mast cells with release
of potent mediators of inflammation and lead to
injury and increased permeability of epithelial
surfaces
 An increase in nerve fibers within the
suburothelium and detrusor muscle in ulcerative
IC has been noted

34.  Nervous system itself contributes to the chronic
nature of this pain syndrome, regardless of
initiating etiology
 Repetitious stimulation of a peripheral nerve -
persistent NMDA receptor activation - trophic
changes spinal cord cells
 Pain resulting from subsequent stimulation
becomes exaggerated and prolonged.
 This “pain memory” in the spinal cord causes IC
patients to become refractory to different therapies

35. Urine Abnormalities
 Access of a component of urine to the
interstices of the bladder wall, resulting in
an inflammatory response induced by toxic,
allergic, or immunologic means

36. Antiproliferative Factor (APF)
 Keay (1996) discovered antiproliferative
factor (APF)- produced by the urothelium of
IC patients
 APF was found to be a sensitive and
specific biomarker for IC
 APF is associated with decreased production
of heparin-binding epidermal growth factor–
like growth factor (HB-EGF)

37.  PBS/IC may result from an inhibition of
bladder epithelial cell proliferation caused
by the APF
 Injuries to the bladder (infection, trauma,
and overdistention) in a susceptible
individual may result in PBS/IC if APF is
present

38.  APF was found to be a sensitive and specific
biomarker for IC
 APF can differentiate chronic pelvic pain
syndrome in men/chronic nonbacterial
prostatitis from PBS/IC

39. Other Potential Causes
 Stress-
There are no data currently to suggest that
stress initiates the chronic syndrome of IC
 Estrogen –
- 5:1 female to male preponderance makes
the role of the hormone potentially
important
- Estradiol augments mast cell secretion
 Pelvic floor dysfunction

40. PATHOLOGY
 There is no microscopic picture
pathognomonic of this syndrome
 The role of histopathology in the diagnosis
of IC is primarily to exclude other possible
diagnoses

41.  Although earlier reports described a chronic,
edematous pancystitis with mast cell
infiltration, submucosal ulcerations and
involvement of the bladder wall, and chronic
lymphocytic infiltrate
 These cases were taken from patients with
severe disease and not representative of the
majority of cases currently diagnosed.

42.  The pathologic findings in IC are not
consistent
 Ulcerative IC- Pancystitis ,mucosal
ulceration and hemorrhage, granulation
tissue, intense inflammatory infiltrate,
elevated mast cell counts, and perineural
infiltrates

43. Hunner’s ulcer

45.  IC is a diagnosis of exclusion, excluding
other diseases that are pathologically
identifiable is the primary utility of bladder
biopsy in this group of patients.

46. THANK YOU