Interstitial cystitis

Interstitial cystitis (IC) often is considered to be an enigma. Many urologists believe it is an autoimmune disorder, and others consider it an infectious disease, a syndrome of multiple symptoms, or a psychological problem that should be included with other "hysterical women's diseases" (ie, conditions suffered mostly by women that are frequently dismissed as exaggerated or diagnosed as psychiatric disorders).(1) This variety of opinion may be justified, given the difficulty in both diagnosing and treating the disorder. To date, there is no definitive cure for IC, and the treatments are palliative and administered primarily to treat symptoms. Diagnosis usually is determined by exclusion (ie, ruling out "real disease" conditions), and the criteria for the diagnosis varies widely among institutions.(2)

Patients with IC typically present with a variety of symptoms, including chronic superpubic or infrapubic pain, urinary urgency or frequency, and nocturia. Although these symptoms also are indicative of acute or chronic cystitis, IC symptoms tend to be more severe. Acute or chronic cystitis usually affects only the internal bladder surface, whereas IC may affect all layers of the bladder wall. Ninety percent of patients with IC are women, and the condition is most common in women 40 to 60 years of age; 25% of patients with IC are under the age of 25.(3) It may affect as many as 450,000 people in the United States; however, only 20,000 to 40,000 cases have been diagnosed. Women who have IC may report voiding up to 60 times per day and every 20 to 30 minutes during the night.(4) As with other diseases that primarily affect women, IC often is misdiagnosed as a psychiatric disorder, and treatment with psychotropic medication is not uncommon.

Stress often is cited as the underlying cause of the disorder, and relaxation is the first treatment option--regardless of the fact that neither stress nor psychological factors has been show to cause IC.(5) On average, people with IC spend 4.5 years and visit five physicians before achieving a correct diagnosis.(6) An average 50% of patients with IC are unable to work full time, and those who do work earn an average of $3.41 or less per hour. Quality-of-life scores for patients with IC are lower than those of patients on renal dialysis, and 60% of patients with IC report having such severe pain during sexual intercourse that they are forced to abstain.(7) Chronicity also is a factor; thus, this disorder often is characterized by periods of exacerbation and remission.(8)

ANATOMY AND PHYSIOLOGY

The renal system contains the kidneys, ureters, bladder, and urethra. The kidneys are located high and retropentoneal in the abdominal cavity, usually between the upper border of the 12th thoracic and the third lumbar vertebrae. The tube-shaped ureters convey urine from the kidneys through the abdominal cavity to the urinary bladder. Each ureter tube is 25 cm to 30 cm in length and approximately 4 mm to 5 mm in diameter.(9) The tubes enter the posterior side of the bladder and run approximately 2 cm downward through the bladder wall before opening into the bladder itself. The bladder is a hollow, muscular organ situated deep in the pelvic cavity behind the ureter tubes. In the male, the bladder is anterior to the rectum, and in the female, it is situated anterior to the front wall of the vagina and neck of the uterus. It is a freely movable organ, held in place by folds of peritoneum and fascia. The urethra connects the bladder to the urinary meatus. In the female, the urethra is approximately 3 cm to 5 cm in length and may be found anterior to the wall of the vagina.(10) This article focuses on the bladder and urethra in the female.

When empty, the bladder is located deep in the pelvis. When slightly distended, the bladder is rounded, and when greatly distended, it is oval in shape. It has four muscle layers. The serous coat is an extension of the peritoneum, and it covers only the superior and upper lateral surfaces. The muscular coat has three layers: the outer longitudinal, the middle circular, and the inner longitudinal layers. The inner longitudinal layer is attached at the inferior surface of the bladder and ascends upward to the superior surface, over the top, and then downward along the fundus. At the lateral edges, the fibers interconnect and form the detrusor urinae muscle. This muscle thickens near the urethra to form the internal and external sphincters.(11)

Blood supply for the bladder and urethra originates at the uterine and vaginal arteries. Innervation (ie, the distribution of nerves) begins at the pelvic splanchnic (ie, bladder wall and interior sphincter) nerves and the pudendal (ie, external sphincter) nerve. Micturition (ie, urination) usually is voluntary and initiated with relaxation of the external sphincter and muscles in the pelvic floor. It also may be initiated reflexively when the bladder fills beyond the usual volume present at voluntary micturition. Pressure receptors in the bladder respond to the increased urine and contract the detrusor muscle, causing the internal sphincter to relax. The average capacity of a normal bladder is 700 mL to 800 mL.(12)

ETIOLOGY

There are two types of IC: ulcerative and nonulcerative. Ulcerative IC, which is less common and found primarily in postmenopausal women, is characterized by Hunner's ulcers (ie, star-shaped ulcers that may bleed when the bladder wall is distended during cystoscopy or hydrodistention treatment).(13) Nonulcerative IC, which is more common and generally found in younger, premenopausal women, is characterized by petechial hemorrhages and signs of chronic inflammation within the bladder wall.(14) The cystitis seen in IC is extensive and involves hyperemic mucosa, edema, and frequently submucosal inflammatory cell infiltration, particularly of mast cells, resulting in injury to the interior protective glycosaminoglycan (GAG) layer of the bladder.(15)

Researchers have investigated relationships between IC and a number of causal entities, including allergies, reflex sympathetic dystrophy, and toxic urinary agents.(16) The three areas that have received the most research efforts are infectious disease, GAG layer alteration, and autoimmune responses.

INFECTIOUS DISEASE

The process of infection has been investigated as the primary cause of IC. The presenting symptoms of IC can include chronic inflammation, mucosal irritation or ulceration, lymphocyte or mast cell infiltrates, and long-term fibrosis--all of which are characteristic of an infectious process. Interstitial cystitis was first presented as an infectious disease in 1907, and in 1915, Hunner's ulcers were added to the criteria for diagnosis.(17)

Approximately 10% of patients with IC will exhibit "classic" IC lesions, characterized by reddened mucosal patches with central ridges (ie, Hunner's ulcers). Microscopic examination usually reveals

* variable epithelial cell size,

* areas denuded of epithelium,

* branching microvillae,

* increased intercellular spaces,

* increased bladder wall permeability, and

* an increased number of mast cells and T lymphocytes in the granulation tissue around the ulcers and in the detrusor muscle.(18)

The majority of patients (ie, 90%) will present without these classic symptoms. These patients will present with petechial hemorrhages or glomerulations that appear to be epithelial ruptures with some submucosal hemorrhages. These glomerulations are detected with bladder cystoscopy and hydrodistention procedures. The glomerulations may be fibrin covered and may exhibit reduced inflammatory responses. Squamous hyperplasia may be present in the epithelium of the bladder. Although T lymphocytes may be found, mast cell involvement may be reduced or not present at all. Edema typically is detected, and approximately 25% of patients with IC may have concurrent vasculitis. In both the ulcerative and nonulcerative forms, a cystoscopy procedure may reveal a thickened bladder wall and infiltrated perivesicular tissues. In addition, the procedure may detect that the bladder is fixed to surrounding structures.(19)

These clinical findings are consistent with an infectious process; however, both high- and low-dose antibiotic therapies have failed to produce relief of IC symptoms. Furthermore, tissue and urine cultures fail to show an elevation in microorganisms, bacteria, fungi, or viruses in patients with IC, and no microorganisms have been identified as causes for IC.(20)

GLYCOSAMINOGLYCAN LAYER ALTERATION

The GAG layer lines the epithelium in the bladder. It acts as a protective barrier, shielding the bladder wall from microorganisms, toxins, and urine components that may adversely affect the tissues. Deficiency or injury to this layer is a leading explanation for the etiology of IC. Increased permeability of the bladder wall found in patients with IC may be the result of alterations in this layer.(21)

The GAG layer comprises mucopolysaccharides and protein. It is extremely hydrophilic because of the ionic charge, and it functions by placing a layer of water between the bladder epithelium and the internal bladder environment. The GAG water barrier protects the bladder wall by not allowing urinary solutes, bacteria, and toxins to contact or adhere to the bladder surface.(22)

Research had been contradictory regarding the role of the GAG layer in IC. One study found increased bladder permeability in patients with IC as a result of a significant reduction of the barrier function of the GAG layer.(23) Later research finds increased bladder permeability to be characteristic of any bladder injury or inflammation.(24) Some studies indicate a possible toxin is present in the urine of patients with IC that is capable of bladder epithelial injury.(25) These studies find that this toxin--in combination with a GAG layer deficiency--may illustrate the true method of epithelial injury in IC.

AUTOIMMUNE RESPONSE

Autoimmune disorders can be generalized or organ specific. One hypothesis for the etiology of IC is that it is an organ-specific autoimmune response similar to Grave's disease, myasthenia gravis, or insulin-resistant diabetes mellitus.(26) The theory that IC may be caused by an autoimmune response relies heavily on the finding of increased numbers of mast cells in the bladder walls of patients with IC. Mast cells store histamines and proteoglycans and can produce leukotrienes. Mast cells also have been reported to have high affinities for estrogen, which could account for the predominance of female patients with IC.(27) Studies of electron microscopy of bladder biopsies of patients with IC and patients with bladder carcinoma revealed mast cell activation in 80% of patients with IC studied.(28) In contrast, mast cell involvement was detected in 20% of patients with bladder carcinoma.

To date, there is conflicting evidence regarding the designation of IC as an autoimmune disorder.(29) One researcher proposes that an infectious disease agent may alter the GAG layer barrier, causing increased bladder wall permeability and the patient's exposure to antigens previously found only in the urinary tract.(30) The immune system acts on these antigens as "new" and elicits an inflammatory and immunologic response.

This researcher suggests that examining other inflammatory diseases may help scientists understand the pathogenesis of IC.(31) For example, symptoms of chronic gastritis--a condition characterized by chronic pain in a luminal organ--are similar to those of IC. Patients with chronic gastritis often experience epithelial damage, inflammatory response in the lamina propria, and epithelial ulcerations. Many cases of gastritis are believed to be caused by Helicobacter pylori. Achieving a microbiologic diagnosis of chronic gastritis requires performing a mucosal biopsy by a combination of special culture techniques and histological staining. Numerous antibiotics have been unsuccessful at treating this disease, and at times, double and triple antibiotic administration is recommended for therapy. In light of the similarities between chronic gastritis and IC, the researcher proposes that causes of both conditions may be similar, as well.(32)

DIAGNOSIS

Diagnosis of IC remains difficult. In 1987 and 1988, the National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) established baseline criteria for diagnosing IC.(33) Based on this, patients who have IC must present

* 10 glomerulations per quadrant,

* pain associated with the bladder, or

* urinary urgency.

The exclusion method of diagnoses, however, remains in the NIDDK criteria, as it outlines 18 conditions that exclude IC diagnoses (eg, bladder capacity [is greater than] 350 mL, experiencing symptoms for less than nine months, absence of nocturia, voiding less than eight times per day). Patients presenting with symptoms of IC--but without the cystoscopic findings to confirm the diagnosis--often are diagnosed with idiopathic reduced bladder storage.(34) Cystoscopy and hydrodistention procedures remain the primary tools for diagnosing IC.

TREATMENTS

With the cause of IC unknown, recommended therapies are palliative and primarily administered to treat symptoms. Pain relief is a major focus of treatment.(35)

A diagnostic tool, hydrodistention also relieves symptoms in approximately 28% of patients with IC who have a bladder capacity of less than 600 mL; therefore, it is the first-line treatment of IC.(36) Two types of hydrodistention are used: simple and the Helmstein balloon procedure. Both procedures act to increase the bladder capacity. Simple hydrodistention involves filling the bladder by passive gravity at a pressure of 60 cm to 80 cm of water for two to three minutes. The Helmstein balloon procedure increases the bladder capacity by inflating a balloon inside the bladder and maintaining an inflated pressure for several hours. This procedure involves the use and risks of anesthetics and the cost of hospital facilities.(37)

Hydrodistention typically involves the use of one medication or a combination of medications instilled into the bladder via a catheter and retained for a specified time before being drained. The most common medications used in intravesical therapy are dimethyl sulfoxide (ie, DMSO), heparin, steroids, sodium bicarbonate, silver nitrate, or pentosan polysulfate sodium (Elmiron). Dimethyl sulfoxide and pentosan polysulfate sodium are the only medications approved by the US Food and Drug Administration for intravesical therapy; all others should be considered experimental.(38) If there is no relief of symptoms, intravesical sodium oxychlorosene (Clorpactin) therapy is the next possible option.

Although DMSO and sodium oxychlorosene cannot be administered outside of the health care setting, patients can be taught how to perform other medication therapies, such as heparin and corticosteroid instillations, at home. Bladder instillation therapy regimes are described in Table 1.

Table 1

BLADDER INSTALLATION THERAPY REGIMES

Self-care treatments are common in patients with IC; however, little is in the literature to help patients identify self-care therapies. Most self-care strategies reported were developed by individual patients or are based on suggestions from other patients with IC. The Internet has provided new sources of information and methods for patients with IC to share effective self-care treatments (Table 2). Over-the-counter medications and herbal therapies, diet changes, and physical comfort measures are some of the most common self-care therapies.(39)

Table 2

GLOSSARY OF AORN STRUCTURAL DATA ELEMENTS

In extreme cases, surgical interventions, such as a cystectomy and ileocystoplasty procedure, have been used. In this procedure, the surgeon removes the diseased bladder and replaces it with a pouch of intestinal tissue formed into a reservoir. The histologic changes found in the original bladder, however, sometimes recur in the intestinal tissue. Other surgical interventions involve diverting the urine and leaving the bladder in place.(40)

RESEARCH

With the NIDDK criteria in 1987 came the structure necessary for IC research to achieve greater prominence. Shortly after 1987, the National Institutes of Health added IC to its list of funding areas, and IC research expanded. Today, the Interstitial Cystitis Association and other private organizations also provide additional funding for research.

One recent study indicates that an antiproliferative peptide specifically present in the urine of patients with IC inhibits bladder epithelial cell proliferation and regeneration.(41) Another study reveals that patients with IC have alterations in certain growth factors normally found in urine; urine samples of patients with IC show low concentrations of HB-EGF, a contributor to epithelial cell growth, when compared to normal urine samples.(42)

Other ongoing projects that explore the role of glycoconjugates in maintaining and repairing the bladder lining may provide additional information on effective therapies using other glycoconjugates, such as heparin and hyaluronic acid, to repair the injured bladder lining.(43) Moreover, one researcher has established a company to develop a diagnostic test for IC.(44)

EFFECTS ON LIFESTYLE

After discussing the disorder on a single appearance on a national television show, one physician received 10,000 letters in two weeks from individuals who suffer from IC--each looking for information and telling stories illustrating the emotional and physical toll taken by IC.(45)

One patient provided the following description of IC:

In an interview, Ms P, a 34-year-old female nurse who is newly diagnosed with IC, said,

Patients with IC often have to perform their own research.(48) Ms P said,

Initial hydrodistention procedures typically relieve some of the disorder's symptoms; however, many patients reports that the pain returns. Ms P said,

The pain of IC is a recurrent theme for patients with IC. One patient said, "I am told I have to learn to live in pain without medication."(51)

Another patient said,

Ms P said,

Patients with IC may feel isolated and may not want to talk to family members and friends about what they are experiencing. Ms P said,

She also said,

Diet and sleep pattern changes are common. One patient described

Ms P said, "[The physician] really didn't mention [dietary changes]. Most of the diet changes I found, I got from reading."(57)

Relationships also are affected by IC. One patient said, "This condition has caused all kinds of trouble between me and my wife, I am kind of useless now."(58)

Another patient added, "One by one, doctors, friends, and relatives have concluded that my problems must be imaginary."(59)

Ms P's relationships also were affected by the disorder:

The uncertainty of the disease progression and the chronicity are issues that remain on the minds of patients with IC. Ms P concluded,

CONCLUSION

Interstitial cystitis is not a well-known disease, and it has profound effects on the people suffering with it, affecting almost every aspect of their lives. The uncertainty of the prognosis, constant pain, taboos associated with urinary disorders, and the lifestyle changes make this a difficult disease with which to live. Research now is being funded for IC through the National Institutes for Health and the Interstitial Cystitis Association. Results of these studies may make a vast difference in the lives of people who have experienced a difficult time and may face an uncertain future.

NOTES

(1.) D C Webster, T Brennan, "Use and effectiveness of physical self-care strategies for interstitial cystitis," Nurse Practitioner 19 (October 1994) 55-61.

(2.) M Barger, B Woolner, "Primary care for women: Assessment and management of genitourinary tract disorders," Journal of Nurse Midwifery 40 (March/April 1995) 231-245; P M Hanno, "Diagnosis of interstitial cystitis," The Urologic Clinic's of North America 21 (February 1994)63-66; Webster, Brennan, "Use and effectiveness of physical self-care strategies for interstitial cystitis," 55-61.

(3.) V Ratner, D Slade, G Greene, "Interstitial cystitis: A patient's perspective," The Urologic Clinics of North America 21 (February 1994) 1-5.

(4.) Barger, Woolner, "Primary care for women: Assessment and management of genitourinary tract disorders," 231-245; Webster, Brennan, "Use and effectiveness of physical self-care strategies for interstitial cystitis," 55-61.

(5.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5; Webster, Brennan, "Use and effectiveness of physical self-care strategies for interstitial cystitis," 55-61.

(6.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5;

(7.) Ibid.

(8.) G R Sant, D R LaRock, "Standard intravesical therapies for interstitial cystitis," The Urologic Clinics of North America 21 (February 1994) 73-83.

(9.) D C Kimber, C E Gray, C E Stackpole, Anatomy and Physiology, 15th ed, L C Leavell, M A Miller, eds (New York: The Macmillan Co, 1969) 676-700.

(10.) Ibid; K L McCance, S E Heuther, Pathophysiology: The Biologic' Basis for Disease in Adults and Children, third ed (St Louis: Mosby, Inc, 1998) 1227-1228; R Rhoudes, R Pflanzer, Human Physiology, third ed (Philadelphia: Saunders College Publishing, 1996) 705.

(11.) Ibid.

(12.) Ibid.

(13.) Barger, Woolner, "Primary care for women: Assessment and management of genitourinary tract disorders," 231-245; T L Ratliff, C G Klutke, E M McDougall, "The etiology of interstitial cystitis," The Urologic Clinics of North America 21 (February 1994) 21-30.

(14.) Ibid.

(15.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5,

(16.) F Haab, P E Zimmern, "New concepts in the etiology and diagnosis of interstitial cystitis," Journal of Infectious Urology 9 no 3 (1996) 79, 82-83; M A Pontari, "Interstitial cystitis update," Journal of Infectious Urology 10 no 3 (1997) 75-80; Ratliff, Klutke, McDougall, "The etiology of interstitial cystitis," 21-30.

(17.) Ibid; J W Warren, "Interstitial cystitis as an infectious disease," The Urologic Clinics of North America 21 (February 1994)31-39.

(18.) Warren, "Interstitial cystitis as an infectious disease," 31-39.

(19.) Ibid; Hanno, "Diagnosis of interstitial cystitis," 63-66.

(20.) Haab, Zimmem, "New concepts in the etiology and diagnosis of interstitial cystitis," 79, 82-83; F Haab, P E Zimmem, "Current concepts in the etiology and diagnosis of interstitial cystitis," Primary Care Review: Update on Urology 3 (Fall 1997) 5-7; Warren, "Interstitial cystitis as an infectious disease," 31-39.

(21.) Haab, Zimmem, "New concepts in the etiology and diagnosis of interstitial cystitis," 79, 82-83; Haab, Zimmem, "Current concepts in the etiology and diagnosis of interstitial cystitis," 5-7; Ratliff, Klutke, McDougall, "The etiology of interstitial cystitis," 21-30.

(22.) Ibid.

(23.) M Ruggieri et al, "Current findings and future research avenues in the study of interstitial cystitis," Urologic Clinics of North America 21 (February 1994) 163-176.

(24.) Ratliff, Klutke, McDougall, "The etiology of interstitial cystitis," 21-30.

(25.) Haab, Zimmem, "New concepts in the etiology and diagnosis of interstitial cystitis," 79, 82-83; Haab, Zimmem, "Current concepts in the etiology and diagnosis of interstitial cystitis," 5-7; Ratliff, Klutke, McDougall, "The etiology of interstitial cystitis," 21-30.

(26.) Ratliff, Klutke, McDougall, "The etiology of interstitial cystitis," 21-30.

(27.) Haab, Zimmem, "New concepts in the etiology and diagnosis of interstitial cystitis," 79, 82-83; Haab, Zimmem, "Current concepts in the etiology and diagnosis of interstitial cystitis," 5-7;

(28.) G R Sant, T C Theoharides, "The role of mast cells in interstitial cystitis," The Urologic Clinics of North America 21 (February 1994) 41-53.

(29.) Haab, Zimmem, "New concepts in the etiology and diagnosis of interstitial cystitis," 79, 82-83; Haab, Zimmem, "Current concepts in the etiology and diagnosis of interstitial cystitis," 5-7; Ratliff, Klutke, McDougall, "The etiology of interstitial cystitis," 21-30.

(30.) Warren, "Interstitial cystitis as an infectious disease," 31-39.

(31.) Ibid,

(32.) Ibid.

(33.) Hanno, "Diagnosis of interstitial cystitis," 63-66.

(34.) Ibid; Pontari, "Interstitial cystitis update," 75-80.

(35.) Webster, Brennan, "Use and effectiveness of physical self-care strategies for interstitial cystitis," 5561.

(36.) Pontari, "Interstitial cystitis update," 75-80.

(37.) Ibid; Sant, LaRock, "Standard intravesical therapies for interstitial cystitis," 73-83.

(38.) Sant, LaRock, "Standard intravesical therapies for interstitial cystitis," 73-83.

(39.) Webster, Brennan, "Use and effectiveness of physical self-care strategies for interstitial cystitis," 55-61.

(40.) Warren, "Interstitial cystitis as an infectious disease," 31-39.

(41.) Two Breakthrough Discoveries in Interstitial Cystitis (news release, Baltimore: University of Maryland, December f997). Available from http://www.medscape.com/UMD/ 1997/dec/UMPR. 1223.IC9.html. Accessed 27 Jan 1998.

(42.) Ibid.

(43.) "Interstitial cystitis is getting easier to diagnose," (Current Affairs) Urologic Nursing 18 (June 1998) 139.

(44.) Ibid.

(45.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5.

(46.) Ibid.

(47.) Patient interview by Lesley Henderson, transcript, Rome, Ga, February 1998.

(48.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5.

(49.) Patient interview by Lesley Henderson, 1998.

(50.) Ibid.

(51.) Rather, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5.

(52.) Ibid.

(53.) Patient interview by Lesley Henderson, 1998.

(54.) Ibid.

(55.) Ibid.

(56.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5.

(57.) Patient interview by Lesley Henderson, 1998.

(58.) Ratner, Slade, Greene, "Interstitial cystitis: A patient's perspective," 1-5.

(59.) Ibid.

(60.) Patient interview by Lesley Henderson, 1998.

(61.) Ibid.

Lesley J. Henderson, RN, MSN, CNOR, is a nursing instructor at Floyd College Department of Nursing, Rome, Ga.

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