Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2922-2929. doi: 10.1210/jc.2016-4025.


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.

MeSH terms

  • Aged
  • Amino Acid Transport Systems, Neutral / drug effects
  • Amino Acid Transport Systems, Neutral / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • COS Cells
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / pathology
  • Chlorocebus aethiops
  • Cohort Studies
  • Female
  • Humans
  • In Vitro Techniques
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Monocarboxylic Acid Transporters / drug effects
  • Monocarboxylic Acid Transporters / metabolism
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use*
  • Prospective Studies
  • Sorafenib
  • Symporters
  • Thyrotropin / metabolism*
  • Thyroxine / metabolism*
  • Triiodothyronine / drug effects
  • Triiodothyronine / metabolism*


  • Amino Acid Transport Systems, Neutral
  • Antineoplastic Agents
  • Monocarboxylic Acid Transporters
  • Phenylurea Compounds
  • SLC16A10 protein, human
  • SLC16A2 protein, human
  • Symporters
  • Triiodothyronine
  • Niacinamide
  • Thyrotropin
  • Sorafenib
  • Thyroxine