Endocrine Abstracts

Background: Recent reports have suggested a link between the thyroid hormone (TH) signalling pathway and liver disease, including hepatocellular carcinoma (HCC). Deiodinases are enzymes responsible for the peripheral metabolism of TH. Although the expression of deiodinases type 1 (D1) and 3 (D3) has been shown to change during induced liver injury, their role in hepatocarcinogenesis is still poorly understood.

Aims: To evaluate the role of deiodinases and their regulation in liver carcinogenesis and to investigate whether and how TH homeostasis affects HCC phenotype and patient outcome.

Methods: This is an ongoing monocentric prospective case-control study. We enrolled 49 patients who underwent liver surgery for HCC (31 cases) or for other non-neoplastic liver diseases in a non-cirrhotic context (18 controls). We evaluated genes and protein expression of the TH signaling pathway (D1, monocarboxylate transporter 8 -MCT-8-, thyroid receptors alpha and beta -TRα, TRβ- and Kruppel-like factor 9 - KLF9-) by RT-PCR and Western blot analysis in HCC, and for D3 also by immunohistochemistry of cirrhotic and healthy liver samples.

Results: RT-PCR analysis showed a progressive statistically significant decrease in DIO1 (P 0.004), MCT-8 (P 0.001) and TR β (P 0.02) mRNA expression from healthy liver to HCC. There was a corresponding decrease (P 0.03) in the expression of KLF9, which is involved in cell differentiation and proliferation. Western blot analysis showed a decrease in the expression of D1 protein in all cirrhotic samples and HCC samples (P 0.01), whereas D3 protein was increased in 55% of the HCC samples (P 0.02). In patients with HCC, D3 expression was associated with a higher degree of liver stiffness (32 kPa, IQR 23.47-35.5, P 0.002) and a higher BMI (P 0.004). A statistically significant difference in overall survival (OS) was observed between D3-positive and D3-negative HCC patients (log rank P 0.003), with a median OS of 17.9 (IQR 15.5-18.7) months for D3-positive vs 41.3 (35.1-43.8) months for D3-negative patients. In addition, a shorter progression-free survival and an increased recurrence rate were observed in D3-positive patients, although not statistically significant. Interestingly, D3 expression was associated with higher tumour grade.

Conclusions: These preliminary data showed that D3 expression may define a more severe phenotype of HCC and could be used in clinical practice as a negative prognostic biomarker for patient outcome. Our exploratory findings need to be applied to a larger sample size to be confirmed.