Lack of imatinib-induced thyroid dysfunction in a cohort of non-thyroidectomized patients

doi:10.1530/EJE-08-0006

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Lack of imatinib-induced thyroid dysfunction in a cohort of non-thyroidectomized patients

José Miguel Dora, Murilo Anderson Leie, Bruno Netto, Laura Maria Fogliatto¹, Lucia Silla¹, Felipe Torres² and Ana Luiza Maia

Endocrine Division, Thyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil^¹ , Hematology Division^² Radiology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

(Correspondence should be addressed to A L Maia who is now at Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos 2350, 90035-003 Porto Alegre, RS, Brazil; Email: almaia{at}ufrgs.br)

To the Editor

Understanding the role of tyrosine kinase (TK) proteins in thepathogenesis of various tumors triggered the development ofdrugs that specifically block TK actions (1). Imatinib, oneof the drugs in that class, has favorably altered the naturalhistory of chronic myeloid leukemia (CML) and gastrointestinalstromal tumors (1). However, given the short experience withthese drugs, the full spectrum of adverse effects remains unknown.Cardiotoxicity (2) and bone metabolism alterations (3) havebeen reported in association with TK inhibitor therapy. Recently,high rates of hypothyroidism have been described in patientsreceiving sunitinib (4, 5). In addition, adjustment of thyroidhormone replacement in thyroidectomized patients under sunitinibor imatinib therapy, with the need of up to 350% increase inlevothyroxine dose, has also been reported (6). Due to similarmechanisms, it is possible that imatinib is also associatedwith thyroid dysfunction in non-thyroidectomized patients. Becauseof the widespread use of this drug, we sought to evaluate theimpact of imatinib therapy on thyroid function.

Patients with CML under imatinib therapy, followed at the HematologicalDivision of Hospital de Clinicas de Porto Alegre (Porto Alegre,Brazil), between March and October 2007, were eligible for thestudy. Patients who used drugs with potential interference inthyroid function tests 6 months prior to the study entry orwith known previous thyroid dysfunction were excluded. All measurementswere performed using ECLIA (Roche). Interassay coefficientsof variation were as follows: thyrotrophin (TSH), 1.6%; thyroxine(T₄), 3.5%; (free T₄), 3.0%; tri-iodothyronine (T₃), 3.4%; Tg,1.9%; and anti-TPO, 7.1%. Fifty-four patients underwent thyroidultrasound (US) for thyroid volume estimation. Eleven patientsunderwent a 24-h radioiodine uptake (RAIU).

A total of 70 patients were eligible to enter in the study.Two patients were excluded because of a previous diagnosis ofhypothyroidism. Thus, 68 patients were included. Table 1 showsthe clinical and laboratory characteristics of study participants.All study subjects displayed levels of T₄, FT₄, and T₃ in thenormal range. Serum TSH was in the normal range of 63/68 (92.6%)and slightly elevated in 5 patients (range 5.08–12.55mU/l). The serum TSH levels before and after imatinib therapy,available for a subgroup of ten patients, were similar (2.39(1.82–3.05) vs 2.71 (1.71–3.25) mU/l, P=0.64). Furthermore,there was no correlation between serum TSH levels and dose (r=–0.043,P=0.73), duration of therapy (r=–0.084, P=0.50), or cumulativedose of imatinib (r=–0.105, P=0.39). Because of a previousstudy report supporting thyroiditis in patients under sunitinibtherapy (4, 7), Tg and anti-TPO were also measured. Serum Tgwas at normal levels and only one patient displayed positivityfor anti-TPO. Thyroid volume and RAIU were in the normal range.The power calculation of our study was the following: for correlations,considering an ${alpha}$ error of 0.05 and a β error of 0.20, estimationsof r values of 0.3, 0.4, and 0.5 resulted in calculated requiredsamples of 84, 46, and 29 patients respectively (NCSS Statistical& Power Analysis Software 2007, Kaysville, UT USA).

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Table 1 Clinical and laboratory characteristics of the 68 patients under imatinib therapy.

Despite previous positive reports, here we found no influenceof imatinib on thyroid function. The lack of correlation betweenTSH levels with dose, duration, or cumulative dose of imatinibtherapy suggests that this drug has no adverse effect on thyroidfunction. In addition, the prevalence of subclinical hypothyroidismin this sample was $~$ 10.0%, similar to that reported for our population(8).

Imatinib exerts its effects through inhibition of multiple TKs,including Bcr-Abl, platelet-derived growth factor receptors ${alpha}$ and β, c-Fms, and c-kit (1). The increased demand forlevothyroxine induced by imatinib in patients under levothyroxinereplacement (6) might indicate increased peripheral metabolismof thyroid hormones. As suggested by others (6), induction ofhepatic conjugation with glucoronates and sulfates would bea possible explanatory mechanism. Another potential explanationcould be increased hormonal deiodination to reverse T₃ throughenhanced deiodinase type 3 (D3) activity. Because both metabolicpathways would imply an increase in thyroid hormone output toovercome the increased peripheral clearance, it would be expectedto find borderline-low values of T₄ and T₃ and borderline-highvalues of TSH in non-thyroidectomized individuals. However,it does not seem to be the case, since all patients displayednormal T₄ and T₃ values. A reasonable explanation would be thatimatinib interferes with the gastrointestinal absorption ofLT₄, but this remains to be clarified.

It is interesting that previous studies with sunitinib haveshown induction of hypothyroidism in nearly one-third of chronicusers (4, 5). TSH suppression was demonstrated prior to thedevelopment of overt hypothyroidism in 6 out of 15 patients,suggesting that sunitinib induces hypothyroidism through a mechanismof destructive thyroiditis (4). Reduction in RAIU concomitantwith elevation in TSH levels has also been reported, suggestingthat reduction in thyroid iodine incorporation may be involvedin sunitinib-induced hypothyroidism (9). The distinct patternsof TK inhibition presented by sunitinib or imatinib might explaintheir divergent effects on thyroid function. Of note, imatinibhas inhibitory activity neither against vascular endothelialgrowth factor (VEGF) nor against EGF (1). Our study has somelimitations such as sample size and lack of TSH values beforeimatinib therapy for all patients. However, the sample sizewas calculated to detect correlations of moderate significanceand previous TSH measurements would be critical if an associationbetween imatinib and TSH had emerged from this study.

In conclusion, imatinib does not seem to be associated withhypothyroidism induction in non-thyroidectomized individuals.This information implies that routine screening of thyroid functionin patients receiving imatinib should be precluded.

Acknowledgements

Grant Support: Conselho Nacional de Desenvolvimento Científicoe Tecnológico (CNPq), Fundacão de Amparo Pesquisado Estado do Rio Grande do Sul (FAPERGS), and Fundo de Incentivoa Pesquisa (FIPE), Brazil.