Deficient glycosaminoglycan layer
Glycosaminoglycans are a constituent of the mucin layer that protects the urothelium and prevents urine components from coming
into direct contact with the bladder mucosa. One hypothesis suggests a deficiency of the glycosaminoglycan protective layer
exposes the urothelium to these components, causing tissue damage and a leaky urothelium. Tissue injury exposes and stimulates
pain-sensitive fibers (C fibers), causing the release of substance P (a neurotransmitter), mast cell activation and degranulation,
inflammation, and edema, which further affect the bladder urothelium, C fibers, and afferent neurons.12,13 This cascade of events, known as neurogenic inflammation, may account for the vicious cycle of pain and dysuria.
Histologic examination of bladder wall samples from cats with FIC reveals increased numbers of C fibers, mast cells, and substance
P receptors.13 In addition, low rates of glycosaminoglycan excretion and increased bladder wall permeability are present in both people
and cats with interstitial cystitis.14-17 There is, however, some indication that abnormalities present in people with idiopathic cystitis, such as decreased glycosaminoglycans
and increased mast cells, can be present in nonidiopathic cystitis disease, suggesting that these abnormalities are not a
cause but a result of idiopathic cystitis.18,19
Central nervous system involvement in the development of iFLUTD has been suggested in several studies. Areas in the brain
(locus ceruleus, paraventricular nucleus) that provide excitatory input in response to bladder distention have been shown
to have higher activities of an enzyme, tyrosine hydroxylase, involved in catecholamine synthesis, and significantly higher
plasma catecholamine concentrations have been documented in cats with iFLUTD compared with controls.20,21 Alpha2-adrenoreceptors, which normally inhibit catecholamine release and pain input to the brain, appear to be desensitized in cats
with iFLUTD, possibly because of chronically elevated catecholamine concentrations.22 Alpha2-adrenoreceptors are also found in the bladder and may play a role in blood flow.5 In these studies, cats were evaluated in both stressful and environmentally enriched conditions. Some of the parameters
measured, such as catecholamine concentrations and bladder permeability, decreased during the enrichment phase.
Other evidence that suggests these cats function abnormally under stress is smaller adrenal glands and a suboptimal response
to synthetic ACTH in cats with iFLUTD compared with controls.23
SIGNALMENT, HISTORY, AND PHYSICAL EXAMINATION FINDINGS
Cats with iFLUTD are typically between 4 and 7 years of age.6 No breed predisposition exists. Castrated males have an increased risk, while intact females have a decreased risk.6
Owners of cats with iFLUTD report one or more of the following signs: periuria, hematuria, pollakiuria, stranguria, or an
inability to urinate.24 Cats may present in their first episode or have a chronic, recurrent history.
On physical examination, affected cats appear normal and active unless they have a urethral obstruction or are in extreme
pain. It is important to assess bladder size in cats with a history of stranguria that have become depressed or obtunded or
that have other systemic signs such as vomiting and anorexia. Palpation may reveal a large, turgid bladder that cannot be
expressed. Steps must be taken to relieve the obstruction as quickly as possible. In contrast, the bladders of cats with nonobstructive
iFLUTD are small. Even minimal palpation can result in urination because of the irritated, inflamed bladder wall. Often, no
other relevant physical examination findings related to the urinary signs will be present.
The LUTS that are present with iFLUTD can be attributed to other causes (Table 1), so a thorough work-up is imperative. These possible causes of LUTS, urolithiasis in particular, should guide the work-up
of cats suspected of having iFLUTD.
Table 1 Differential Diagnoses and Diagnostic Tests to Consider in Cats with LUTS
Periuria is a common clinical sign, occurring in 93% of cats with iFLUTD.24 However, periuria can also be purely behavioral and should prompt questioning about the cat's environment, such as the introduction
of a new cat or other pet, arrival of a new baby or household member, a recent move or change to the living environment (e.g. new carpeting, a new addition), or a change in litter or food. The roles of environment and stress in iFLUTD will be discussed
Hematuria can be caused by UTIs, urolithiasis, neoplasia, thrombocytopenia, clotting disorders, and trauma.25 UTIs are uncommon in cats < 10 years old (< 2%),5,6 but cats > 10 years of age are more likely to develop UTIs.6 Since dilute urine increases the susceptibility of animals to UTIs, concurrent illness, such as chronic renal failure, may
be responsible.26,27 This age group is also more likely to have bladder tumors such as transitional cell carcinoma that can serve as a nidus
of infection.6 Inherited coagulopathies are uncommon in cats.28,29 Factor XII deficiency (Hageman trait) in cats rarely results in clinical hemorrhage.
Pollakiuria and stranguria
Pollakiuria and stranguria are reported in 79% and 70% of iFLUTD cases, respectively.24 These signs can result from UTIs, urethral plugs, cystic or urethral stones, neoplasia, and iFLUTD. In one large retrospective
study, urolithiasis and urethral plugs accounted for LUTS in 10% of cats, while iFLUTD accounted for 63% of cases.6 Other studies have reported ranges of 13% to 28% for urolithiasis and 55% to 69% for iFLUTD.5
Keeping in mind that FLUTD is a constellation of diseases and that iFLUTD is a diagnosis of exclusion, each cat presenting
with stranguria, pollakiuria, hematuria, periuria, or partial or complete urethral obstruction should be approached similarly.
In addition to a history and physical examination, a typical work-up includes a urinalysis, urine bacterial culture, complete
blood count, serum chemistry profile, and radiographic examination. Ultrasonography, double-contrast cystourethrography, and
cystoscopy are included as needed. In addition, consider evaluating platelets and, in rare cases, clotting factors when hematuria
is present. Clotting factor assays, such as prothrombin time and activated partial thromboplastin time, are necessary if there
is evidence of bleeding elsewhere or systemic illness, such as hepatic disease or neoplasia.30
Cystocentesis is preferred to obtain a urine sample but may be difficult to perform because affected cats often have small,
irritated bladders. A comparison of samples obtained free-catch and by cystocentesis may be useful in cases of urethral disease.
With urethral transitional cell carcinoma, for example, there may be few cytologic abnormalities in a sample obtained by cystocentesis,
but transitional cells may be present in a free-catch sample. The mean urine specific gravity in cats with iFLUTD is 1.052,
urine pH is usually acidic, and microscopic hematuria is present in 95% of cases.24 Pyuria may be present if inflammation is severe, but bacteriuria is uncommon.24
Urine bacterial culture
UTIs occur most commonly in cats > 10 years of age.6 Urolithiasis, neoplasia, previous urethral catheterizations, and urethrostomies also predispose cats to UTIs. A negative
culture result can confirm sterile urine when pyuria caused by inflammation rather than infection is present. Interpret positive
culture results from free-catch samples with caution. In cats, growth of > 10,000 CFU/ml from a midstream free-catch sample
is highly suggestive of a true UTI.31 Despite the difficulty in obtaining and interpreting urine bacterial cultures, it is an important diagnostic step, given
a recent study suggesting that UTIs may be more common in cats with iFLUTD than previously thought.7