Endocrine Abstracts

Background: Tyrosine kinase inhibitors (TKI) are a chemotherapeutic group which include drugs known to cause thyroid dysfunction such as axitinib, imatinib, pazopanib, sorafenib, and sunitinib. However, reports of TKI-Ibrutinib causing thyroid dysfunction are scarce. Although several hypotheses have been proposed to explain TKI-associated thyroid dysfunction there is no clear guidance on how to manage this situation.

Case: 86-year-old lady was referred to the endocrinology clinic for evaluation of abnormal thyroid function tests. Her relevant medical histories included stage IV mantle cell lymphoma, hypothyroidism, stage III chronic kidney disease, hypertension, and diverticular disease. She was diagnosed with hypothyroidism in 2003 and has been on Levothyroxine dose of 100 mg and 75 mg on alternate days for many years. She was diagnosed with stage IV mantle cell lymphoma and was commenced on Ibrutinib in June 2020. Her first recorded thyroid function test in 2012 showed hypothyroidism, following that remained relatively stable with the same dose of Levothyroxine. Following introduction of Ibrutinib in June 2020, there was a concurrent rise in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) with mildly decreased free triiodothyronine (FT3). She was fully compliant with Levothyroxine and confirmed taking the tablet well apart from her meals and other tablets. Other relevant blood tests showed stable chronic kidney disease, normal liver function test. Assay interference results were unremarkable. Serial thyroid functions showed rise in TSH (9.4;11.4;8.34;4.39;5.91;11.1) with concurrent rise in FT4 (19.5;23;26;26.9;23;23.1) and low FT3 levels (2.4;2.2;2.5) following Ibrutinib. Thyroxine dose was increased to 100 mg daily as TSH had risen to 11.1 and she complained of excessive tiredness.

Discussion: Suggested mechanism for this pattern is the induction of type 3 deiodinase (D3) pathway which converts FT4 to rT3 and inhibition of type 2 deiodinase (D2) which converts FT4 to FT3, with the balance towards D2 inhibition. Thyroid-binding globulin was not elevated hence it could not account for the raised TT4. Non thyroidal illness causing this picture is unlikely given raised TSH. Induction of uridine diphosphate-glucuronosyltransferases is a plausible cause, which enhances clearance of T4 and T3 (as suggested for another TKI-Imatinib) resulting in hypothyroidism in patients receiving Levothyroxine replacement, however T4 levels were not reduced.

Conclsion: This case highlights the importance of thyroid function testing prior to starting Ibrutinib and the value of close monitoring of thyroid status throughout. Clinicians who prescribe Ibrutinib should be aware of this potential thyroid function dysfunction, and to seek endocrinology advice as appropriate.