Can Valsartan (Angiotensin II Receptor Blocker) cause acute liver injury?

From the Guidelines

Valsartan can cause acute liver injury, although this is a rare side effect, and patients should be monitored for signs of liver problems, especially during the initial months of treatment. Valsartan is an angiotensin II receptor blocker (ARB) commonly used to treat high blood pressure, heart failure, and diabetic kidney disease. While most patients tolerate valsartan well, a small percentage may experience liver problems, typically within the first few weeks to months of starting treatment. Signs of liver injury include fatigue, nausea, abdominal pain, dark urine, yellowing of the skin or eyes (jaundice), and abnormal liver function tests.

The mechanism behind valsartan-induced liver injury is not fully understood but is thought to be an idiosyncratic reaction rather than a direct toxic effect. According to a recent review by the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy 1, patients with moderate hepatic impairment should be started on a lower dose of sacubitril-valsartan, suggesting that valsartan can affect liver function. However, the review does not provide direct evidence of valsartan-induced liver injury.

In contrast, an older study on the treatment of tuberculosis 1 discusses the potential for liver injury with certain medications, but it does not specifically address valsartan. Given the lack of direct evidence in the provided studies, the recommendation to monitor patients for signs of liver injury is based on the general principles of pharmacotherapy and the potential for idiosyncratic reactions with any medication.

Some key points to consider when prescribing valsartan include:

• Baseline liver function tests before starting treatment
• Periodic monitoring of liver function, especially during the initial months
• Discontinuation of the medication if signs of liver injury develop
• Medical attention should be sought promptly if liver injury is suspected

Overall, while the evidence for valsartan-induced liver injury is limited, it is essential to monitor patients for signs of liver problems and adjust treatment accordingly to minimize the risk of morbidity and mortality.

From the FDA Drug Label

On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight) The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2.

Valsartan and Liver Injury: The FDA drug label does not directly address whether valsartan can cause acute liver injury. However, it does provide information on the pharmacokinetics of valsartan in patients with liver disease, indicating that patients with mild-to-moderate chronic liver disease have increased exposure to valsartan.

• Key Points:
  • Increased exposure to valsartan in patients with liver disease
  • Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2 However, this information does not directly answer the question of whether valsartan can cause acute liver injury. 2

From the Research

Valsartan and Acute Liver Injury

• Valsartan is a medication used to treat high blood pressure and heart failure, and it has been reported to cause liver injury in some cases 3, 4.
• A case report published in 2023 described a 90-year-old female patient who developed severe liver injury after taking sacubitril/valsartan, which is a combination of valsartan and another medication 3.
• Another case report published in 2022 described a 76-year-old woman who developed acute liver failure after taking sacubitril/valsartan for one month and acarbose for one day 4.
• However, a study published in 2020 found that sacubitril/valsartan improved measures of liver function in patients with heart failure with reduced ejection fraction compared to enalapril 5.
• A review of the safety and tolerability of valsartan published in 2011 found that the medication is generally safe and well-tolerated, but it did not mention liver injury as a common adverse event 6.
• A study published in 1997 found that valsartan is eliminated mainly by hepatic clearance, and that patients with mild and moderate liver impairment had increased exposure to the medication 7.

Mechanism of Liver Injury

• The exact mechanism of liver injury caused by valsartan is not fully understood, but it is thought to be related to the medication's effect on the liver's ability to clear toxins 3, 7.
• Valsartan is metabolized by the liver, and patients with liver impairment may have increased levels of the medication in their system, which could contribute to liver injury 7.

Clinical Implications

• Clinicians should be aware of the potential for liver injury in patients taking valsartan, especially those with pre-existing liver disease 3, 4.
• Patients taking valsartan should be monitored for signs of liver injury, such as elevated liver enzymes and bilirubin levels 5.
• The benefits and risks of using valsartan in patients with liver disease should be carefully weighed, and alternative medications may be considered in some cases 6.