Endocrine Abstracts

Objectives: Drug-induced acute liver failure (ALF) is a rare but life-threatening clinical scenario which occurs in individuals without pre-existing liver disease. Intoxication of the pain-reliever acetaminophen (APAP) is a well-known trigger for ALF. The cytochrome P450 enzyme CYP2E1 converts APAP to the toxic metabolite N -acetyl- p -benzoquinone imine (NAPQI) which is inactivated by endogenous glutathione. If glutathione is depleted, NAPQI triggers hepatocellular necrosis leading to ALF. It is well known that triiodothyronine (T3) positively favors e.g. hepatocyte proliferation via thyroid hormone receptor β (TRβ) signaling. However, in how far hepatic TRβ action impacts disease progression of APAP-induced acute liver injury is not known so far. Using the APAP mouse model, we asked whether and if yes how abrogation of hepatic TRβ action influences the progression of acute liver injury.

Methods: Acute liver injury was induced via i.p. injection of 300 mg/kg body weight of APAP (or solvent control) in male C57BL/6J control (WT) mice and male mice with hepatocyte specific TRβ knockout (hepTRβKO). One hour to 24 hours post APAP intoxication, liver histology, liver function test, hepatic T3-responsive markers and APAP metabolism were evaluated.

Results: In WT mice, APAP resulted in pericentral hepatocellular necrosis and increased serum transaminase activities with a maximum peak 24 hours post intoxication. Abrogation of hepatic TH action in hepTRβKO mice attenuated APAP-induced acute liver injury. More in detail, 24 hours after APAP injection pericentral hepatocellular necrosis and elevated serum transaminases were absent, whereas 12 hours after APAP injection injured hepatocytes surrounding central veins were observed. T3-responsive markers revealed successful abrogation of hepatic TRβ signaling. APAP metabolism was evaluated by hepatic expression of Cyp2e1 and glutathione, both located in hepatocytes surrounding central veins.

Conclusions and outlook: Our data indicate that abrogation of hepatic TRβ action attenuates disease progression of APAP-induced acute liver injury in male C57BL/6J mice. The results provide novel insights how local hepatic thyroid hormone action impacts ALF and harbors great translational potential for new treatment strategies, e.g. to antagonize or agonize local thyroid hormone action depending on the disease status.