Endocrine Abstracts

Objectives: Acute liver failure (ALF) is a rare but life-threatening condition with severe liver dysfunction. In ALF liver regeneration capacity is exceeded due to loss of hepatocyte function. A well-known trigger of ALF is paracetamol (acetaminophen, APAP) intoxication. Unfortunately, based on the poor prognosis and rapidly increasing mortality rate liver transplantation offers the so far only effective therapeutic strategy. Even if the underlying mechanisms of ALF are not yet fully understood, it is well known that triiodothyronine (T3) positively favors hepatocyte proliferation via thyroid hormone receptor β (TRβ) signaling and could therefore improve liver regeneration. Using the APAP mouse model, we asked whether hepatic T3 signaling influences ALF progression and regeneration.

Methods: ALF was induced via i.p. injection of 300 mg/kg body weight of APAP (or solvent control) in male C57BL/6J mice. T3 (100 µg/kg body weight or solvent control) was administered 6 h (progression) and 24 h (regeneration) post APAP intoxication via oral gavage. Twelve hours to 72 h post APAP intoxication, liver function test, liver histology, proliferation and hepatic T3- and APAP-responsive markers were evaluated.

Results: APAP increased serum transaminase activities. Liver histology revealed centrilobular hepatocyte necrosis and inflammation by APAP intoxication. Serum T3 concentration and hepatic T3-responsive markers showed successful T3 administration 12-24 h post oral gavage. T3 impacts hepatocyte proliferation and APAP-responsive markers evaluated by Pcna and Cyp2e1 staining suggesting improved hepatocyte regeneration and metabolism.

Conclusions and outlook: Our data indicate that T3 positively favors liver regeneration and metabolism after APAP-induced ALF in male C57BL/6J mice, which will be further studied in comparison to hepatocyte-specific TRβ knockout mice. We expect that results of this study provide new insight how hepatic thyroid hormone signaling improves the course of APAP-induced ALF, with the aim of optimizing the treatment and prognosis of patients.