Differential TAM receptor regulation of hepatic physiology and injury

AbstractThe TAM receptor tyrosine kinases (RTK) Mer and Axl have been implicated in liver disease, yet our understanding of their roles in liver homeostasis and injury is limited. We therefore examined the performance of Mer and Axl mutant mice during aging, and in four models of liver injury. We find that Mer and Axl are most prominently expressed in Kupffer and hepatic endothelial cells, and that as Axl-/-Mertk-/- mice normally age, they develop profound liver disease. We further find that Mer signaling is critical to the phagocytosis of apoptotic hepatocytes that are generated during acute hepatic injury, and that Mer and Axl act in concert to inhibit injury-triggered cytokine production. TAM expression in Kupffer cells is crucial for these effects. In contrast, we show that Axl is uniquely important in mitigating liver damage during acute acetaminophen intoxication. Finally, we demonstrate that Axl exacerbates the fibrosis that develops in a model of chronic hepatic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that target these RTKs in the liver.

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Development of a Spontaneous Liver Disease Resembling Autoimmune Hepatitis in Mice Lacking Tyro3, Axl and Mer Receptor Tyrosine Kinases

PLoS ONE ◽

10.1371/journal.pone.0066604 ◽

2013 ◽

Vol 8 (6) ◽

pp. e66604 ◽

Cited By ~ 19

Author(s):

Nan Qi ◽

Peipei Liu ◽

Yue Zhang ◽

Hui Wu ◽

Yongmei Chen ◽

...

Keyword(s):

Liver Disease ◽

Autoimmune Hepatitis ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases

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Acute Hepatic Injury Associated with Varenicline in a Patient with Underlying Liver Disease

Annals of Pharmacotherapy ◽

10.1345/aph.1m131 ◽

2009 ◽

Vol 43 (9) ◽

pp. 1539-1543 ◽

Cited By ~ 7

Author(s):

Andrew J Franck ◽

Lisa R Sliter

Keyword(s):

Alkaline Phosphatase ◽

Smoking Cessation ◽

Liver Disease ◽

Hepatitis C ◽

Alcoholic Liver Disease ◽

Hepatic Injury ◽

Liver Toxicity ◽

White Male ◽

Drug Induced ◽

Acute Hepatic Injury

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.

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Diagnosis and Monitoring of Hepatic Injury. II. Recommendations for Use of Laboratory Tests in Screening, Diagnosis, and Monitoring

Clinical Chemistry ◽

10.1093/clinchem/46.12.2050 ◽

2000 ◽

Vol 46 (12) ◽

pp. 2050-2068 ◽

Cited By ~ 190

Author(s):

D Robert Dufour ◽

John A Lott ◽

Frederick S Nolte ◽

David R Gretch ◽

Raymond S Koff ◽

...

Keyword(s):

Laboratory Tests ◽

Hepatic Injury ◽

Total Bilirubin ◽

Published Data ◽

Medline Search ◽

Hepatic Diseases ◽

Study Selection ◽

Acute Hepatic Injury ◽

Chronic Hepatic Injury ◽

Made In

Abstract Purpose: To review information on the use of laboratory tests in screening, diagnosis, and monitoring of acute and chronic hepatic injury. Data Sources and Study Selection: A MEDLINE search was performed for key words related to hepatic diseases, including acute hepatitis, chronic hepatitis, alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, and etiologic causes. Abstracts were reviewed, and articles discussing use of laboratory tests selected for review. Additional articles were selected from the references. Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact. Recommendations: Although many specific recommendations are made in the guidelines, only some summary recommendations are listed here. In acute hepatic injury, prothrombin time and, to a lesser extent, total bilirubin are the best indicators of severity of disease. Although ALT is useful for detecting acute and chronic hepatic injury, it is not related to severity of acute hepatic injury and only weakly related to severity of chronic hepatic injury. Specific tests of viral markers should be the initial differential tests in both acute and chronic hepatic injury; when positive, they are also useful for monitoring recovery from hepatitis B and C.

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