Drug-induced liver injury (DILI) is a significant concern in clinical practice, arising from medications, herbs, and dietary supplements. It can manifest in different forms, including hepatocellular, cholestatic, and mixed types, each associated with specific liver enzyme abnormalities and histological injury patterns. Hepatocellular DILI is characterized by inflammation, necrosis, and apoptosis, while cholestatic DILI involves bile plug formation and bile duct paucity. Ursodeoxycholic acid (UDCA), a widely used treatment for cholestatic liver diseases, has recently been investigated for its potential therapeutic effects in managing hepatocellular DILI as well.
Mechanistic Basis of the Beneficial Effects of UDCA in DILI
UDCA has a broad range of hepatoprotective mechanisms that may be beneficial across various types of DILI. It exhibits antioxidant, anti-inflammatory, anti-apoptotic, anti-necrotic, mitochondrial-protective, endoplasmic reticulum stress-relieving, and immunomodulatory properties. These mechanisms suggest that UDCA could address the diverse causes and pathomechanisms underlying DILI.
UDCA Beneficial Mechanisms in Hepatocellular DILI
In hepatocellular DILI, various insults such as oxidative stress, mitochondrial dysfunction, and immune-mediated attacks contribute to hepatocyte injury. UDCA plays a crucial role by acting as a ROS scavenger and inducing antioxidant enzymes, which help protect against mitochondrial damage. Furthermore, UDCA reduces inflammation by modulating immune responses and suppressing pro-inflammatory pathways, thus preventing apoptosis and necrosis. It also alleviates ER stress, which is a key driver of hepatocellular damage in DILI.
UDCA Beneficial Mechanisms in Cholestatic DILI
Cholestatic DILI is primarily driven by the accumulation of cytotoxic bile acids, which can lead to hepatocyte and cholangiocyte damage. UDCA mitigates these effects by replacing toxic bile acids with itself, reducing bile acid toxicity. It also improves bile acid clearance and modulates transporters in the liver and kidney, enhancing the elimination of both bile acids and toxic drugs. Furthermore, UDCA protects cholangiocytes by promoting bile acid excretion, maintaining the integrity of bile ducts, and preventing bile acid-induced cellular damage.
UDCA in DILI Treatment and Prevention
The experimental evidence supporting the use of UDCA in DILI treatment highlights its hepatoprotective effects in various preclinical models. In rodents, UDCA has been shown to protect against hepatotoxicity induced by different drugs, including methotrexate, amoxicillin-clavulanic acid, and cyclosporine. Clinical evidence, though limited, suggests that UDCA may improve liver function in patients with cholestatic DILI and could even have preventive effects when administered alongside hepatotoxic medications.
Experimental Evidence
In experimental models, UDCA has been shown to alleviate cholestasis and reduce hepatocyte death by modulating bile acid metabolism and oxidative stress. Studies on rodents have demonstrated its beneficial effects in models of cholestatic injury induced by bile duct ligation and other hepatotoxic agents, reaffirming its anticholestatic and hepatoprotective properties.
Clinical Evidence
Although the evidence from controlled studies is still insufficient, several case reports and clinical series suggest that UDCA may offer therapeutic benefits in both cholestatic and hepatocellular DILI. UDCA has been shown to improve biochemical parameters and alleviate symptoms like jaundice and pruritus in DILI patients, particularly in those with cholestatic patterns. Moreover, there is evidence to suggest that UDCA may serve as a preventive agent in patients at high risk of DILI, such as those undergoing treatment with hepatotoxic drugs.
New Horizons to Continue Exploring UDCA in DILI
Despite the promising data, there is a need for well-designed randomized controlled trials to firmly establish the role of UDCA in DILI management. Future research should focus on optimizing treatment protocols, determining the most effective dosages, and validating UDCA's prophylactic use in high-risk patients. Additionally, the use of biomarkers to monitor treatment efficacy could help refine the clinical application of UDCA.
Conclusions
UDCA is a multifaceted hepatoprotective agent with significant potential in the treatment and prevention of DILI. Its wide-ranging effects on oxidative stress, inflammation, apoptosis, and bile acid metabolism make it a promising therapeutic option for various forms of liver injury. However, more rigorous clinical trials are needed to confirm its effectiveness and establish clear guidelines for its use in DILI management. Given its safety profile, clinicians may consider using UDCA as a therapeutic tool for managing DILI, particularly in cases with cholestatic involvement.
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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00325
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
