Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

Objective: To report a case of acute hepatic injury associated with varenicline. Case Summary: A 53-year-old white male with underlying alcoholic liver disease and history of hepatitis C virus infection experienced elevated aminotransferase and alkaline phosphatase levels consistent with acute hepatic injury after initiation of varenicline for smoking cessation. The hepatic injury manifested 4 weeks after initiation of varenicline therapy at 0.5 mg once daily for 3 days, 0.5 mg twice daily for 4 days, and then 1 mg twice daily. Following discontinuation of varenicline, the patient's aminotransferase levels continued to rise for 2 days before steadily decreasing and returning to baseline levels in approximately 4 months. Alkaline phosphatase continued to rise for 8 days after discontinuation of varenicline before returning to baseline within 1 month. Rechallenge was not attempted. Discussion: Varenicline is a novel, first-line agent for smoking cessation. The presentation of this patient is most consistent with an acute hepatic injury related to drug toxicity. The pattern of the patient's elevated hepatic enzyme levels is not consistent with his underlying alcoholic liver disease or hepatitis C. Using the Naranjo probability scale, as well as the Counsel for International Organizations of Medical Science/Roussel Uclaf Causality Assessment Method algorithm for drug-induced liver toxicity, we determined that varenicline was the probable cause of the acute hepatic injury. Varenicline was a possible cause of the acute hepatic injury using the algorithm for drug-induced liver toxicity developed by Maria and Victorino. To our knowledge, this is the first report of acute hepatic injury associated with varenicline. Conclusions: While the benefits of smoking cessation are likely greater than the risk of hepatic injury, clinicians should be cognizant of this reaction associated with varenicline.

Download Full-text

Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease

Toxins ◽

10.3390/toxins11090486 ◽

2019 ◽

Vol 11 (9) ◽

pp. 486 ◽

Cited By ~ 7

Author(s):

Apurva Lad ◽

Robin Su ◽

Joshua Breidenbach ◽

Paul Stemmer ◽

Nicholas Carruthers ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Murine Model ◽

Fatty Liver Disease ◽

Hepatic Injury ◽

Health Concern ◽

Oral Exposure ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Microcystins are potent hepatotoxins that have become a global health concern in recent years. Their actions in at-risk populations with pre-existing liver disease is unknown. We tested the hypothesis that the No Observed Adverse Effect Level (NOAEL) of Microcystin-LR (MC-LR) established in healthy mice would cause exacerbation of hepatic injury in a murine model (Leprdb/J) of Non-alcoholic Fatty Liver Disease (NAFLD). Ten-week-old male Leprdb/J mice were gavaged with 50 μg/kg, 100 μg/kg MC-LR or vehicle every 48 h for 4 weeks (n = 15–17 mice/group). Early mortality was observed in both the 50 μg/kg (1/17, 6%), and 100 μg/kg (3/17, 18%) MC-LR exposed mice. MC-LR exposure resulted in significant increases in circulating alkaline phosphatase levels, and histopathological markers of hepatic injury as well as significant upregulation of genes associated with hepatotoxicity, necrosis, nongenotoxic hepatocarcinogenicity and oxidative stress response. In addition, we observed exposure dependent changes in protein phosphorylation sites in pathways involved in inflammation, immune function, and response to oxidative stress. These results demonstrate that exposure to MC-LR at levels that are below the NOAEL established in healthy animals results in significant exacerbation of hepatic injury that is accompanied by genetic and phosphoproteomic dysregulation in key signaling pathways in the livers of NAFLD mice.

Download Full-text