Azathioprine Toxicity - Causes, Symptoms, Diagnosis, and Treatment

Introduction

The class of drugs known as immunosuppressants includes Azathioprine. It suppresses the body's immune system, which prevents it from attacking the transplanted organ or joints. By doing so, Azathioprine can help to prevent the immune system from attacking healthy tissues and organs, which can occur in certain medical conditions. Azathioprine is typically taken orally, either in tablet or capsule form.

Azathioprine is usually taken in combination with other medications, such as corticosteroids or other immunosuppressants, to maximize its effectiveness. Metabolism of this substance takes place in the liver, and it is eliminated from the body through the kidneys, which may heighten its toxicity in cases of renal failure. The dosage and length of treatment will depend on the patient's condition and response to the medication.

What Are the Indications of Azathioprine?

Azathioprine is approved by the FDA for treating active rheumatoid arthritis and as an adjunctive therapy for preventing kidney transplant rejection.

Off-Label Uses-

• Autoimmune Diseases: Azathioprine is often used to treat autoimmune diseases like lupus, rheumatoid arthritis, and psoriasis. These conditions occur when healthy tissues and organs are damaged and inflamed as a result of the immune system attacking them. Azathioprine can help to suppress the immune system and reduce inflammation, which can alleviate symptoms and slow the progression of the disease.

• Inflammatory Bowel Disease: Azathioprine is also used to treat inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. These conditions cause inflammation and damage to the digestive tract resulting in symptoms such as diarrhea, abdominal pain, and weight loss. Azathioprine can help to reduce inflammation in the digestive tract and improve symptoms. Azathioprine can be used as a maintenance treatment option for Crohn's disease in children.

• Skin Conditions: Azathioprine can also be used to treat certain dermatological conditions, such as atopic dermatitis, pemphigus vulgaris, and bullous pemphigoid. These conditions cause blistering and skin damage, and Azathioprine can help to suppress the immune system and reduce inflammation, which can alleviate symptoms.

• It also serves as a second-line agent for chronic ITP.

What Is Azathioprine Toxicity?

Azathioprine toxicity refers to the harmful effects that may result from the use of Azathioprine. Azathioprine is converted in the body to a compound called 6-mercaptopurine (6-MP), which helps to suppress the immune system and reduce inflammation. However, if the levels of 6-MP become too high, it can cause damage to various organs and tissues which could result in a range of symptoms and complications. Azathioprine toxicity can occur due to various factors, such as genetics, drug interactions, and impaired kidney function, and may require immediate medical attention to prevent serious harm.

What Factors Can Contribute to Azathioprine Toxicity?

Several factors that can contribute to toxicity, including:

1. Improper Dosage: Azathioprine dosage needs to be carefully monitored and adjusted based on individual patient response and the presence of side effects. Incorrect dosing, whether too high or too low, can increase the risk of toxicity.

2. Genetic Problems: The metabolism of Azathioprine depends on a specific enzyme called thiopurine methyltransferase (TPMT), which is responsible for breaking down the medication in the liver. Patients with a genetic deficiency in TPMT are at increased risk of developing toxicity, as metabolism is impaired in such cases.

3. Drug Interactions: Azathioprine can interact with other medications, including Allopurinol and ACE (angiotensin-converting enzyme) inhibitors, which increase the level of the medication in the blood.

4. Kidney or Liver Disease: Patients with impaired kidney or liver function may be at increased risk of developing toxicity, as their bodies may not be able to properly clear the medication from the bloodstream.

5. Extended Treatment: Long-term use of azathioprine can increase the risk of toxicity, as the medication may accumulate in the body over time.

6. Preexisting Medical Conditions: Patients with concurrent medical conditions, such as infections or malignancies, may be at increased risk of developing toxicity, as their bodies may not be able to properly clear the medication from the bloodstream.

What Are the Signs and Symptoms of Azathioprine Toxicity?

The symptoms of azathioprine toxicity can vary and may include:

Typically, acute toxicity occurs when a patient ingests a dose that exceeds 1.5 times the prescribed daily amount.

• Bradycardia (reduced heart rate), hepatotoxicity, and bone marrow suppression develop as a result of toxicity.

• Hepatotoxicity associated with azathioprine is correlated with a 6-MMP (mercaptopurine) level greater than 5700 pmol/8 x 10^8 RBC (picomoles per 8 x 10^8 red blood cells). This type of toxicity can be divided into two categories:

  • Acute idiosyncratic liver injury typically occurs early in treatment and usually resolves once the medication is discontinued.

  • Nodular regenerative hyperplasia, on the other hand, tends to occur several years after therapy and is commonly observed in patients with IBD and those who have undergone organ transplants.

• Reports suggest that dose-dependent, life-threatening cases of bone marrow suppression, causing pancytopenia, thrombocytopenia, and leukopenia, have been associated with Azathioprine toxicity. The severity of this complication correlates with the 6-thioguanine nucleotide (6-TGN) level.

• Persistent nausea and vomiting may be present, which can be severe in some cases.

• Diarrhea, which may be severe and accompanied by cramping and abdominal pain.

• Patients may experience extreme fatigue or weakness, which can impact their ability to carry out daily activities. A low-grade fever might exist in some patients with this toxicity.

• Patients may experience severe abdominal pain, particularly in the upper right quadrant, which can be a sign of liver toxicity. Patients with liver toxicity may develop jaundice, which manifests as yellowing of the skin and eyes.

• Itching and skin rash may be present in some patients with toxicity.

• Hypersensitivity reactions manifest as a range of symptoms such as fever, chills, joint or muscle pain, liver dysfunction, and erythema nodosum (a skin condition characterized by tender, red bumps on the legs).

How to Diagnose Azathioprine Toxicity?

• Blood Tests: Regular blood tests can be used to monitor the level of Azathioprine in the blood and assess for potential toxicity. Patients may also undergo liver function tests to evaluate for liver toxicity.

  • Monitor complete blood count (CBC) and liver function tests (LFT) more frequently in patients with renal disease, elderly patients on high doses of AZA, or with low TPMT activity.

  • Discontinuation of the medication should be considered if the labs show leukopenia (white blood cells less than 3 x 10^9/L), thrombocytopenia (platelet less than 120 x 10^9/L), or elevated liver enzymes (liver biochemistry greater than half of the normal upper limit).

• Thiopurine Methyltransferase (TPMT) Testing: TPMT is the enzyme responsible for breaking down azathioprine in the liver. Patients with a genetic deficiency in TPMT may be at increased risk of developing toxicity. TPMT testing can identify patients who may be at increased risk of toxicity and help guide dosing adjustments.

What Is the Treatment for Azathioprine Toxicity?

The following are the treatment options to manage toxicity:

• Dose Reduction: One of the first steps in treating azathioprine toxicity is to reduce the dose of the medication or temporarily discontinue it. This can help to lower the level of medication in the blood and reduce the severity of symptoms.

• Supportive Care: Patients with azathioprine toxicity may require supportive care might involve intravenous fluids to prevent dehydration, anti-nausea medication to control vomiting, or pain medication to manage abdominal pain.

• Switch to an Alternative Medication: In some circumstances, it may be mandatory to switch to an alternative medication to treat the underlying condition if Azathioprine toxicity cannot be effectively managed.

• Close Monitoring: Patients with azathioprine toxicity may require close monitoring and regular blood tests to evaluate the level of medication in the blood and monitor for potential complications.

Conclusion

Azathioprine can be a versatile medication for various medical conditions. Patients who are taking Azathioprine should be closely monitored for potential toxicity, and any symptoms should be reported to a healthcare provider immediately. With proper monitoring and care, the benefits of this medication can be enhanced while minimizing the risk of toxicity.