TY - JOUR
T1 - Sorafenib-induced changes in thyroid hormone levels in patients treated for hepatocellular carcinoma
AU - Beukhof, CM (Carolien)
AU - van Doorn, L
AU - Visser, Theo
AU - Bins, Sander
AU - Visser, Edward
AU - van Heerebeek, Ramona
AU - van Kemenade, Folkert
AU - de Rijke, Yolanda
AU - de Herder, W.W.
AU - Chaker, Layal
AU - Mathijssen, Ron
AU - Peeters, Robin
N1 - Publisher Copyright:
© Copyright 2017 Endocrine Society.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P<0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P<0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10.
AB - Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P<0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P<0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10.
UR - http://www.scopus.com/inward/record.url?scp=85026901602&partnerID=8YFLogxK
U2 - 10.1210/jc.2016-4025
DO - 10.1210/jc.2016-4025
M3 - Article
C2 - 28575418
SN - 0021-972X
VL - 102
SP - 2922
EP - 2929
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 8
ER -
