What is the association between Allopurinol (Zyloprim) and liver disease, specifically hepatotoxicity?

From the Guidelines

Allopurinol should be used with caution in patients with liver disease, and the dose should be adjusted based on both liver and kidney function, with careful monitoring for signs of hepatotoxicity 1. When considering the use of allopurinol in patients with liver disease, it is essential to weigh the potential benefits against the risks. The liver plays a crucial role in purine metabolism, and allopurinol works by inhibiting xanthine oxidase, which can potentially stress an already compromised liver.

• For patients with mild to moderate liver impairment, starting with a reduced dose of 100 mg daily and monitoring liver function tests regularly is recommended.
• In severe liver disease, allopurinol may be contraindicated or require significant dose reduction (50-100 mg every other day) with close monitoring.
• Dose adjustments should be based on both liver function and kidney function, as allopurinol is primarily eliminated by the kidneys.
• Patients with liver disease taking allopurinol should be monitored for signs of hepatotoxicity, including jaundice, right upper quadrant pain, fatigue, and elevated liver enzymes.
• If these occur, the medication should be discontinued immediately. Alternative medications like febuxostat might be considered in some cases of liver impairment, though it also requires careful monitoring and dose adjustment, as noted in the 2016 updated EULAR evidence-based recommendations for the management of gout 1.

From the FDA Drug Label

In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy. 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

• Liver Disease and Allopurinol: The FDA drug label recommends periodic liver function tests in patients with pre-existing liver disease during the early stages of allopurinol therapy.
• Hepatotoxicity: There have been cases of reversible clinical hepatotoxicity and asymptomatic rises in serum alkaline phosphatase or serum transaminase in patients taking allopurinol tablets.
• Monitoring: Patients on allopurinol should be monitored for signs of liver dysfunction, such as anorexia, weight loss, or pruritus, and liver function should be evaluated if these symptoms develop 2.

From the Research

Allopurinol and Liver Disease

• Allopurinol has been shown to have hepatoprotective effects in some studies, such as the one published in 2012 3, which found that allopurinol partially prevented liver injury induced by carbon tetrachloride.
• The study found that allopurinol reduced NF-κB nuclear translocation, cytokine production, and oxidative stress, and increased interleukin-10 levels.
• However, other studies have reported cases of allopurinol-induced hepatotoxicity, such as the case report published in 1977 4, which described a patient with allopurinol-induced granulomatous hepatitis.
• A systematic review of randomized controlled trials published in 2023 5 found that febuxostat and allopurinol had similar hepatic safety profiles, but liver function abnormalities were identified in all reviewed trials.
• Another study published in 2017 6 found that febuxostat had a higher incidence of abnormal liver function compared to allopurinol, especially at higher doses.

Liver Function and Allopurinol

• Allopurinol has been shown to alter liver function tests, such as alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (γ-GTP) levels, in some studies 3, 6.
• However, the clinical significance of these changes is not always clear, and some studies have found that allopurinol can actually improve liver function in certain patients, such as those with chronic kidney disease 7.
• The study published in 2014 7 found that switching from allopurinol to febuxostat slowed the progression of renal disease and reduced serum uric acid levels in patients with chronic kidney disease.

Hepatotoxicity and Allopurinol

• Allopurinol-induced hepatotoxicity is a rare but potentially serious side effect, with only a few cases reported in the literature 4.
• The clinical and histopathologic findings of allopurinol-induced liver injury can be variable, and the exact mechanisms of hepatotoxicity are not fully understood.
• Healthcare practitioners should be aware of the potential for hepatotoxicity when prescribing allopurinol, especially in patients with pre-existing liver disease or other risk factors.