Urine is normally sterile due to the low pH and unidirectional flow of urine that does not allow bacteria to grow and invade the urinary tract. Cystitis occurs when the normally sterile lower urinary tract (urethra and bladder) is either infected by bacteria or rarely a fungus, which leads to irritation and inflammation. Irritation followed by inflammation can also occur in response to trauma, chemicals or foreign bodies. Females are more prone to the development of cystitis because of their relatively shorter and straighter urethra. Bacteria does not have to travel as far to enter the bladder, which is in part due to the relatively short distance between the opening of the urethra and the anus. The pathogenesis of complicated cystitis include obstruction and stasis of urine flow. Normal flow of urine washes away the pathogens and clears the tract. Obstruction leads to overdistension and bacterial growth is facilitated by the residual urine. Stasis of urine flow allows entry of pathogens into the urinary tract.

• Acute uncomplicated cystitis is an inflammation of the urinary bladder that occurs in the absence of any structural or functional pathology. In women, vaginal colonization of the uropathogens leads to the development of a urinary tract infection.
• Cystitis occurs when the normally sterile lower urinary tract (consisting of urethra and bladder) is infected by bacteria and becomes irritated and inflamed.
• Once bacteria enter the bladder, they are normally removed through urination. When bacteria multiply faster than they are removed by urination, it results in their accumulation leading to an infection.^[1][2]

Cystitis is rare in males but when occurs, is predominantly found in homosexual or uncircumscribed individuals.

• Females are more prone to the development of cystitis because of their relatively shorter urethra.
• Bacteria do not have to travel as far to enter the bladder, which is in part due to the relatively short distance between the opening of the urethra and the anus.^[3][4]

The pathogenesis of complicated cystitis include obstruction and stasis of urine flow.

• Complicated cystitis is usually a result of an abnormality in the structure or function of the urinary tract.
• This abnormality can result from various causes like foreign bodies such as:
  • kidney stones
  • Urinary catheters or other draining devices
  • Structural defects
  • renal failure
  • pregnancy
  • immunosuppression.
• Any process leading to the obstruction leads to over distension and so bacterial growth is facilitated by the residual urine.
• Stasis of urine flow allows entry of pathogens into the urinary tract and also hinders the natural preventive mechanism by which urine flushes away the pathogens and prevents colonisation in the urinary tract.^[1][5][6][7]

Recurrent inflammation of the bladder that is usually due to an infection, needs intensive investigation. Recurrent urinary infections may result from:

• Immunodeficiency
• contraceptive device
• Sexual intercourse
• Structural defecct
• genetic defect

The most common pathogen involved in recurrent infections resulting in inflammation of the bladder is E.coli.

• Chronic inflammation of the urinary bladder can cause alterations in the functional mechanisms and may lead to structural changes.
• It is understood that recurrent or chronic cystitis can lead to changes in the expression of the neuropeptides like substance P and calcitonn gene-related peptide (CGRP).
• This manifests as altered sensation of bladder filling called allodynia and hyperreflexia of the urinary bladder due to defect in the agents responsible for regular sensing ability of the bladder. ^{[8][9][10][11][12]}

The pathogenesis of Interstitial cystitis also known as bladder pain syndrome, includes:^{[13][14][15][16]}

• Epithelial dysfunction
• Mast cell activation
• Bladder sensory nerve up-regulation
• Organ cross talk

Certain foods have been associated with the interstitial cystitis, some of these include:

• Spicy foods
• Citrus fruit
• Tomatoes
• Carbonated and alcoholic drinks
• Coffee or tea
• Vitamin C

The urothelium acts as a barrier against damage to the bladder. The urothelium produces a mucous layer which regulates the entry of potassium in the bladder interstitium.

• Damage to the urothelium results in the production of cytokines which activate mast cells in the interstitium.
• Mast cell activation is further triggered by the diffusion of excess potassium into the bladder interstitium.^[17]

Chronic irritation from infection, calculi or even tumors results in metaplasia of the urothelium, which proliferates into buds, which grow down into the connective tissue beneath the epithelium in the lamina propria.

• In the case of cystitis cystica, the buds then differentiate into cystic deposits.
• The pathogenesis of cystitis cystica follows a positive feedback mechanism where with each infection there is a greater chance of subsequent changes in the bladder mucosa.
• Long term chemoprophylaxis and transurethral resection of the bladder are amongst the possible treatment options for cystitis cystica.^{[18][19][20][21]}

Inflammation of the urinary bladder by infiltration of eosinophils is the core of the process.

• Schistosoma haematobium is strongly associated with the development of eosinophilic cystitis.
• Infection with Schistosoma haematobium is generally associated with excessive presence of eosinophilic leukocytes and cytokines.
• Eosinophiliac cystitis can also be caused by certain medications that can have allergic manifestation and thus increase the number of eosinophils.
• Eosinophilic cystitis is sometimes confused with invasive bladder carcinoma and can be differentiated by demonstrating the presence of eosinophilia. ^[22]

Hemorrhagic cystitis is associated with hematuria.

• The hematuria results from rupture of the small mucosal blood vessels that are damaged due to:
  • Radiation exposure
  • Medications such as:
    • cyclophosphamide
    • ifosfamide
    • penicillin G
  • Viruses such as:
    • adenovirus
  • Accumulation of metabolites from chemotherapeutic drugs
• Treatments targeting eradication of the causative viruses, drugs or metabolites and intravenous hydration that flushes the urinary tract are very effective in treating hemorrhagic cystitis.^[23]
• Several adenovirus serotypes have been associated with an acute, self-limited hemorrhagic cystitis, which occurs primarily in boys.
• It is characterized by hematuria, and virus can usually be recovered from the urine.^{[24][25][26][27][28][29]}

Traumatic cystitis is caused by trauma to the bladder.

• Damage to the bladder predisposes it to invasion by pathogens that are normally not able to infect the bladder.
• Traumatic cystitis is a common phenomenon in females and follows invasion of a bruised bladder that follows an abnormally forceful sexual intercourse.
• Absence of circumcision increase chances of the normal pathogen in the skin to be lodged into the urinary tract, though the evidence is not convincing.
• Traumatic cystitis can also occur postoperatively in children.
• Trauma can also lead to stricture formation which in turn leads to stasis of urine and growth of bacteria or viruses in the bladder. ^[30][31]

Foreign bodies like kidney stones, indwelling catheters, and contraceptive devices can either result in:

• Mechanical damage to the epithelium leading to inflammation or
• Cause stasis of urine due to adhesion formation leading to pathogen invasion and ultimately cystitis
• Foreign bodies like catheters can grow bacteria like E.Coli, pseudomonas and staphylococcus saprophyticus leading to cystitis.

Removal of the foreign body and flushing the urinary tract with fluids are very effective treatment options.

• Polypoid/Papillary cystitis is caused by obstruction of the bladder by a benign tutor that leads to stasis leading to infection and inflammation of the bladder.^{[32][33][34][35][36][37]}

Gas production inside the bladder is the key feature to diagnose emphysematous cystitis. Diabetes has been strongly associated with this emphysematous cystitis.

• Though the pathogenesis is not exactly understood, high tissue glucose content in a patient with diabetes mellitus and fermentation of glucose in urine are considered to be important mechanisms that facilitate invasion of gas forming bacteria.
• E.Coli and Klebsiella are amongst the found pathogens.
• Another important aspect in the pathogeneses of emphysematous cystitis is the imbalance between the accumulation of gas and its clearance.
• Emphysematous cystitis can be an incidental finding on abdominal imaging done for abdominal pain or any other suspected pathology.
• Abdominal pain and hematuria can be seen in patients with this disease due to damage caused by gas forming bacteria.
• Since air accumulation interferes with normal oxygenation of the tissues, provision of hyperbaric oxygen has been associated with improvement of symptoms in patients with emphysematous cystitis.^{[38][39][40][41][42]}

Cystitis glandularis is considered a premalignant condition. The following are some significant aspects in the pathogenesis of cystitis glandularis:

• This abnormal disorder of proliferation involves glandular metaplasia of transitional cells in the bladder epithelium.
• Cystitis glandularis has two types, the typical, involving the urinary bladder and the intestinal/colonic type.
• Cystitis glandularis is considered to be a precursor of bladder adenocarcinoma.
• The intestinal component is considered to be more premalignant of the two types.
• Tumor necrosis factor alpha is considered a mediator of chronic inflammation.
• TNF-a causes induction of nuclear localisation of beta-catenin which is a component of adherents junction. This pathway is similar to the pathogenesis of barret’s esophagus. ^{[43][44][45][46]}

Ketamine cystitis is a complication of procedures where ketamine is used as anaesthetic agent. Ketamine cystitis differs from other drugs that cause cystitis like cyclophosphamide, ifosfamide and penicillin G, in that it does not cause haemorrhage. The pathogeneses of ketamine cystitis includes urothelial dysfunction by the following mechanisms:^[47]

• Inflammation mediated by mast cells
• Increased expression of M3
• Increased expression of B3-AR
• Decreased expression of ZO-1 and E-cadherin in bladder mucosa
• Increased TUNNEL expression and high Tryptase activity in the mucosa
• Increased cell apoptosis in the urothelium

Though the genetics of cystitis have not been studied extensively. It is understood that family history of urinary tract infection is a strong risk factor recurrent urinary infections in relatives. This risk is stronger in closer than distant relatives suggesting the role of a genetic component.^[8][48]

The following conditions can be associated with cystitis.^{[1][4][49][50]}

• Immunodeficiency
• Diabetes
• Pregnancy
• Benign prostatic hyperplasia
• Renal Stones
• Post menopausal status
• Toxoplasmosis
• HIV

The gross pathology of cystitis does not yield any findings.

The microscopic pathology helps to confirm the diagnosis and to differentiate different types of cystitis.^[51][52]

• 
  Cystitis Cystica. Source: Libre Pathology^[51]
• 
  Cystitis Glandularis. Source: Libre Pathology^[52]