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Hemorrhagic Cystitis - An overview

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Hemorrhagic cystitis is caused due to anticancer chemotherapy and malignancies. Read this article to know more.

Written byDr. Kavya

Medically reviewed byDr. Samer Sameer Juma Ali Altawil

Published At October 10, 2022
Reviewed AtJune 10, 2024

Introduction

Hemorrhagic cystitis is most commonly caused by bacterial infections, and neglect may be life-threatening. It has a broad spectrum of possible treatment approaches with a satisfactory prognosis that provides a better standard of living.

What Is Hemorrhagic Cystitis?

It is an inflammatory condition of the urinary bladder caused by infectious or non-infectious conditions leading to bleeding of the bladder mucosa and hematuria (blood in urine).

What Are the Symptoms to Look Out For?

  • The individual may feel a burning sensation while passing urine.

  • The individual may have a frequent urge to urinate.

  • Unable to control the urge to urinate.

  • Nocturia (an urge to pass urine throughout the night).

  • The patient may feel a sense of fatigue and may also experience abdominal pain.

What Causes Hemorrhagic Cystitis?

The etiology can be of two types: infectious and noninfectious.

1. Infectious Causes:

  • Viral: Adenovirus, BK virus, herpes simplex virus, cytomegalovirus.

  • Bacterial: E.coli, Proteus mirabilis, Klebsiella.

  • Fungal: Cryptococcus neoformans, Aspergillus fumigatus and Candida albicans.

  • Parasite: Toxoplasma gondii.

2. Non-infectious Causes:

3. Drug-induced:

  • Ifosfamide.

  • Cyclophosphamide.

  • Busulfan.

  • Thiotepa.

  • Temozolomide.

  • 9-nitrocamptothecin.

  • Penicillin and its derivatives like Methicillin, Carbenicillin, Ticarcillin, and Piperacillin.

  • Danazol.

  • Tiaprofenic acid.

  • Allopurinol.

  • Methaqualone.

  • Methenamine mandelate.

  • Gentian violet.

  • Acetic acid.

Chemotherapy medications, such as Cyclophosphamide and Ifosfamide, are commonly used, leading to a high risk of acquiring hemorrhagic cystitis. Busulfan and Thiotepa are the lesser common drugs. During the excretion of these drugs, the bladder lining can undergo irritation and, in severe cases, may even lead to ulceration, ultimately leading to hematuria.

Environmental Toxins:

  • Aniline dyes.

  • Toluidine.

  • Chlordimeform.

  • Ether.

Systemic Conditions:

  • Amyloidosis: Amyloidosis is a condition in which an abnormal protein (amyloid) is built up that interferes with normal functioning.

  • Systemic Lupus Erythematosus: Systemic lupus erythematosus is an autoimmune disease where the immune system attacks its tissues. The organs usually affected are kidneys, blood cells, skin, joints, brain, heart, and lungs.

  • Rheumatoid Arthritis: Rheumatoid arthritis is an autoimmune disease that mainly affects the joints, causing inflammation of the joints.

  • Crohn's Disease: Inflammatory bowel disease affecting the digestive system, leading to pain, discomfort, and diarrhea.

  • Boon's Disease.

  • Radiation therapy for pelvic malignancies.

What Is the Pathophysiology of Hemorrhagic Cystitis?

Hemorrhagic cystitis occurs when toxins, viruses, radiation, drugs (especially chemotherapeutic drugs), bacterial infections, or other disease processes damage the bladder's transitional epithelium and blood vessels. On a histological level, the bladder wall shows nonspecific findings, including intense inflammatory infiltrates, chronic inflammation, and fibrosis.

What Are the Risk Factors of Hemorrhagic Cystitis?

  • Individuals undergoing chemotherapy or pelvic radiation therapy, especially for prostate, cervix, and bladder cancers, are at an elevated risk for HC.

  • Chemotherapeutic drugs such as Cyclophosphamide and Ifosfamide, used in treating various cancers like lymphoma, breast, and testicular cancers, increase the risk of HC.

  • The highest risk for HC is observed in individuals requiring bone marrow or stem cell transplants, often necessitating a combination of chemotherapy and radiation therapy. This treatment regimen can also compromise the body's resistance to infections, further increasing the risk of HC.

  • People undergoing chemotherapy are at high risk, followed by people requiring stem cell and bone marrow transplants.

What Is the Grading of Hemorrhagic Cystitis?

The grading system proposed by Droller et al. is used for hemorrhagic cystitis.

0 - No symptoms of bladder irritability or hemorrhage.

1 - Microscopic hematuria.

2 - Macroscopic hematuria.

3 - Massive macroscopic hematuria with small clots.

4 - Massive macroscopic hematuria requiring instrumentation for clot evacuation or causing urinary obstruction.

How Can Hemorrhagic Cystitis Be Prevented?

People receiving chemotherapy are usually on high doses of commonly used chemotherapy drugs such as cyclophosphamide, and ifosfamide can be recommended for saline diuresis and mesna. Mesna helps to inline the bladder mucosa and prevents irritation and bleeding. It can be given orally, intravenously, or subcutaneously. Mesna can have side effects such as diarrhea, pain, and headaches.

What Is the Treatment for Hemorrhagic Cystitis?

Identification and elimination of the cause of irritation if the cause is drug-induced and the drugs stopped or tapered down to a lower dose. If it is not possible to stop the drug, it should be substituted with an alternative drug. Toxicity can be reduced by providing hydration to the patient and using forced diuresis. Continuous bladder irrigation is also one method to reduce toxicity.

For radiation-induced hemorrhagic cystitis, there is a lack of treatment options. However, ongoing trials suggest that using hyperbaric oxygen therapy may show the desired outcome to a certain extent. The treatment involves the administration of 100 percent oxygen at a pressure of 1.4 atm to 3.0 atm (standard atmosphere) at intervals of 60 to 120 minutes. Conjugated estrogens also show an impressive prognosis for radiation-induced hemorrhagic cystitis. Studies have shown that hyaluronic acid is one of the treatment modalities that can be used. In cases of viral hemorrhagic cystitis treatment, studies have shown the use of the following drugs:

General modalities involved in hemorrhagic cystitis treatment include:

  • Pentosan polysulfate sodium can help in reducing inflammation.

  • Decompressing the bladder is done by inserting a Foley catheter and starting saline irrigation.

  • Cystoscopy can be used to evaluate the bladder for bleeding and malignancies.

1. Medical Treatment:

The drugs that can be used are:

  • Epsilon- Aminocaproic Acid: It is given at a maximum dose of 30 grams per day, and the loading dose is 5 grams. It is given orally, parentally, or intravesically. Side effects involve clot formation.

  • One Percent Alum (Aluminum Ammonium Sulfate or Aluminum Potassium Sulfate): It is an astringent given at 250 ml per hour. It helps in the resolution of hematuria. Side effects involve microcytic anemia, osteomalacia, dementia, encephalopathy, metabolic acidosis, and coagulopathy.

  • Silver Nitrate (0.5 percent to 1 percent): 10 to 20 minutes. There can be bladder spasms. Side effects involve renal failure.

  • Phenol: 100 percent phenol with 30 ml glycine.

  • Prostaglandins: 0.8 mg/dL to 1.0 mg/dL.

  • Formalin: 1 percent to 2 percent formalin. It helps in fixing the bladder mucosa.

2. Surgical Modalities:

  • Nephrostomy: It is a procedure in which an opening is created between the kidney and the skin to create a diversion in the upper part of the urinary bladder.

  • Cystectomy: It is the surgical removal of the entire or portion of the urinary bladder.

  • Ileal Loop Diversion: A segment of the small intestine is used to divert the urine from the kidney.

  • Ureterosigmoidostomy: Diversion of the ureters to the sigmoid colon.

  • Cutaneous Ureterostomy: A procedure in which the surgeon detaches the ureters and brings either one or both towards the abdomen.

  • Open Packing of the Bladder: It is a catheterization procedure of the bladder, where one end of the catheter is left open for urine drainage.

  • Ligation of Hypogastric Arteries: The hypogastric arteries are ligated to prevent massive bleeding.

What Is the Prognosis for Hemorrhagic Cystitis?

The prognosis for hemorrhagic cystitis varies depending on its stage and cause. In cases of HC caused by infection, the outlook is generally good, as many individuals respond well to treatment and do not experience long-term issues. However, HC resulting from cancer treatment may have a different prognosis. Symptoms can manifest weeks, months, or even years after treatment and may persist over the long term.

There are numerous hemorrhagic cystitis treatment options available for HC induced by radiation or chemotherapy. In most instances, HC can be effectively managed with treatment, and symptoms typically improve following cancer therapy. In cases where other treatments prove ineffective, cystectomy may offer a cure for HC. Following cystectomy, reconstructive surgery options are available to restore urine flow. It is important to note that the need for cystectomy due to this condition is exceedingly rare.

Conclusion:

Hemorrhagic cystitis is caused due to anticancer chemotherapy and malignancies. Among the varying causes of hemorrhagic cystitis, the leading causes involve radiation-induced cystitis and the usage of chemotherapy drugs such as cyclophosphamide. It is an inflammatory condition of the urinary bladder caused by infectious or non-infectious conditions leading to bleeding of the bladder mucosa and hematuria. With the ever-evolving hemorrhagic cystitis treatment modalities and approaches to treatment planning, the main aim is to improve the quality of patient care and provide a satisfactory prognosis.

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Frequently Asked Questions

Hemorrhagic cystitis occurs due to inflammation of the bladder lining. An individual can contract the condition either by a bacterial or viral infection or by bone marrow transplant, chemotherapy, occupational exposure to chemicals, or radiation therapy around the bladder. It is not very common in the general population but is seen in about 10 percent to 35 percent of patients under cancer therapy.
Hemorrhagic cystitis can be caused by a bacterial, fungal, or viral infection. It is also common in patients under cancer therapy as radiation, and chemotherapeutic drugs severely deplete the immune system, which opens up the body to various opportunistic infections. Hemorrhagic cystitis is usually caused by Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis and Klebsiella species, Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus and Torulopsis glabrata, and Polyomavirus.
Hemorrhagic cystitis can be, rarely, fatal. Severe forms may be characterized by clots and persistent hemorrhage. Fatality with hemorrhagic cystitis is mostly seen secondary to chemotherapy or bladder radiation.
Hemorrhagic cystic has a multi-modal treatment approach. Based on the causative organism, antibiotics, antifungals, or antivirals are prescribed to treat the infection. Additionally, intravenous fluids are administered to increase urine output and flush the bladder. A catheter may be placed to remove the clots from the ureter, or the bleeding areas may be cauterized with a cystoscopic view. The patient might require blood transfusions based on the amount of blood loss. Sodium hyaluronidase medications, silver nitrate, alum, phenol, and formalin can be administered intravesical to decrease or arrest bleeding. The patient may be kept in a hyperbaric chamber with a cent percent oxygen daily for up to 40 sessions. The last resort, if all fails, is cystectomy, where the surgeon removes the bladder.
Cystitis treatment lasts for a few days. Along with antimicrobial or intravesical therapy, the individual can drink plenty of water and pee frequently to flush out the bladder. The person must avoid intercourse and drinks that irritate the bladder, like fruit juices, coffee, and alcohol. If the symptoms do not reduce in a few days, it is advisable to follow up with a specialist.
Chemotherapeutic drugs Cyclophosphamide and NSAIDs (non-steroidal anti-inflammatory drugs) like Tiaprofenic acid have been reported to cause cystitis. Cyclophosphamide caused cystitis within 48 hours of treatment. Other drugs that have been observed to cause hemorrhagic cystitis are Penicillins, Danazol, Temozolomide, Bleomycin, Tiaprofenic acid, Allopurinol, Methaqualone, Methenamine mandelate, ether, gentian violet, Nonoxynol-9 suppositories, and intravesical acetic acid.
Uncomplicated cystitis lasts for a week in about 30 to 50 percent of affected women. Mild infections last for a few days, even without treatment, while the symptoms may persist for about a week. In compromised individuals (cancer patients), the infection may last longer and cause life-threatening complications, requiring rigorous interventions.
Microscopic hematuria may occur in the initial stages of cystitis and can only be observed under microscopic analysis. In the second stage, urine may be blood-tinged, which may show up as clots in the third stage. In the most serious cases, the clots may be so big that they block the urinary flow. The bleeding arrest might be made with cauterization, and clots may require removal by a catheter.
Some steps that can be taken to cure cystitis naturally are:
- Mixing bicarbonate soda in drinking water to dilute the urine.
- Unsweetened cranberry juice consumption.
- Increase hydration and pee frequently.
- Increase intake of foods rich in vitamin C.
- Take probiotics.
- Take extracts like D-mannose, cranberry extract, and garlic extract.
Commonly used antimicrobial drugs against cystitis are Trimethoprim-Sulfamethoxazole, Trimethoprim, Beta-lactams (Amoxicillin-Clavulanate), Fluoroquinolones (Levofloxacin, Ciprofloxacin, Norfloxacin), Nitrofurantoin (Macrobid and Macrodantin), Fosfomycin, and Tromethamine.
An individual with cystitis must follow a strict dietary regimen to hasten recovery. The dietary plan includes the following:
- Fruits like bananas, blueberries, melons, pears, apples, etc.
- Vegetables like asparagus, avocados, celery, black olives, cucumber, green beans, bell peppers, etc.
- Avoid milk or dairy products like chocolate ice cream, processed cheese, soy products, yogurt, etc.
- Include dairy products like cheeses, eggs, milk, sherbet, etc.
- Drink water, blueberry juice, pear juice, tea, etc.
- Avoid alcohol.
Chronic psychological stress can affect urinary tract health and induce infection, especially in patients with predisposing conditions like overactive bladder and interstitial cystitis–bladder pain syndrome. Stress can also weaken the overall immune system, making the urinary tract vulnerable to opportunistic infection, paving the way for cystitis.
Cystitis worsens at night due to urine retention and decreased production of urine. The urine is more concentrated at night, which increases the irritation to the bladder wall even in the absence of microbial proliferation. It is advisable to sleep in a position that relaxes the pelvic muscles, which may help ease the night discomfort.
Ciprofloxacin and Levofloxacin, which belong to the fluoroquinolones class of antibiotics, are usually reserved by doctors for more complicated cystitis. Other drugs like Amoxicillin-Clavulanate, Norfloxacin, Macrobid, and Macrodantin can be prescribed.
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Dr. Samer Sameer Juma Ali Altawil from iCliniq
Dr. Samer Sameer Juma Ali Altawil

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