What is the relationship between Allopurinol (Zyloprim) and elevated Liver Function Tests (LFTs)?

From the Guidelines

Allopurinol should be discontinued if significant liver function test (LFT) elevations occur, as it can rarely cause hepatotoxicity. The relationship between Allopurinol (Zyloprim) and elevated Liver Function Tests (LFTs) is a critical consideration in the management of gout, as highlighted in the 2016 updated EULAR evidence-based recommendations for the management of gout 1. For mild LFT elevations (less than 3 times the upper limit of normal), close monitoring may be appropriate while continuing the medication. However, for moderate to severe elevations, especially if accompanied by symptoms like jaundice, fatigue, or abdominal pain, immediate discontinuation is recommended.

Alternative medications for gout management include febuxostat, probenecid, or pegloticase, though febuxostat may also cause liver injury. Allopurinol-induced liver injury typically occurs within the first few months of treatment and presents as a hepatocellular or mixed pattern of injury. The mechanism is thought to be an idiosyncratic hypersensitivity reaction rather than direct toxicity. If allopurinol is suspected as the cause of elevated LFTs, rechallenge is generally not recommended due to the risk of more severe reactions.

Regular LFT monitoring is advisable during the first few months of allopurinol therapy, particularly in patients with pre-existing liver disease or those taking other potentially hepatotoxic medications. The guidelines on the management of abnormal liver blood tests, as outlined in the Gut journal 1, emphasize the importance of careful evaluation and monitoring of liver function in patients on medications like allopurinol. Key considerations include:

• The clinical significance of abnormal LFT results
• The potential for liver injury with certain medications
• The importance of regular monitoring and prompt discontinuation of offending agents in cases of significant LFT elevations
• The role of alternative medications in the management of gout in patients with liver disease or elevated LFTs.

In clinical practice, a "start low, go slow" approach is recommended when initiating allopurinol, with careful monitoring of LFTs and adjustment of the dose as needed to minimize the risk of hepatotoxicity 1. This approach, combined with regular monitoring and prompt discontinuation of allopurinol in cases of significant LFT elevations, can help to minimize the risk of liver injury and optimize outcomes in patients with gout.

From the FDA Drug Label

A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol tablets, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol tablets, evaluation of liver function should be part of their diagnostic workup In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.

Allopurinol (Zyloprim) may be associated with elevated Liver Function Tests (LFTs), as evidenced by asymptomatic rises in serum alkaline phosphatase or serum transaminase in some patients. Additionally, reversible clinical hepatotoxicity has been noted in a few cases. It is recommended to monitor liver function in patients with pre-existing liver disease during the early stages of therapy, and to evaluate liver function if symptoms such as anorexia, weight loss, or pruritus develop 2.

From the Research

Relationship Between Allopurinol and Elevated Liver Function Tests (LFTs)

• Allopurinol, a medication used to treat gout, has been associated with elevated Liver Function Tests (LFTs) in some patients 3, 4, 5, 6.
• A systematic review of randomized controlled trials found that allopurinol and febuxostat, another medication used to treat gout, had similar hepatic safety profiles, with liver function abnormalities observed in all studies 3.
• However, a study comparing the hepatotoxicity of febuxostat and allopurinol in patients with gout and fatty liver disease found that the incidence of hepatotoxicity was significantly lower in the febuxostat group than in the allopurinol group 4.
• Another study found that febuxostat was well tolerated in patients with gout and severe allopurinol adverse reactions, but cautioned that careful dose escalation and close monitoring were necessary due to the risk of hypersensitivity reactions 6.
• The evidence suggests that allopurinol can cause elevated LFTs in some patients, but the risk is generally considered to be low to moderate 3, 4, 5.

Factors Associated with Hepatotoxicity

• Diabetes and colchicine use have been identified as factors associated with a higher risk of hepatotoxicity in patients taking allopurinol 4.
• Febuxostat use, on the other hand, has been associated with a lower risk of hepatotoxicity compared to allopurinol 4.
• The presence of fatty liver disease may also increase the risk of hepatotoxicity in patients taking allopurinol 4.

Clinical Implications

• Healthcare practitioners should be aware of the potential risk of elevated LFTs in patients taking allopurinol and monitor liver function tests regularly 3, 4, 5.
• Patients with a history of severe allopurinol adverse reactions may be considered for treatment with febuxostat, but careful dose escalation and close monitoring are necessary due to the risk of hypersensitivity reactions 6.