Long-term treatment-related morbidity in differentiated thyroid cancer: a systematic review of the literature

Abstract

BackgroundDifferentiated thyroid cancer (DTC) occurs in relatively young patients and is associated with a good prognosis and long survival. The management of this disease involves thyroidectomy, radioiodine therapy, and long-term thyroid-stimulating hormone suppression therapy (THST). The long-term effects of the treatment and the interaction between subclinical hyperthyroidism and long-term hypoparathyroidism are poorly understood. This review sought to examine the available evidence.MethodsA PubMed search was carried out using the search terms “Thyroid Neoplasms” AND (“Thyroxine” OR “Hypocalcemia” OR “Thyrotropin”). Original English language articles published in the last 30 years studying the morbidity from thyroid-stimulating hormone (TSH) suppression and hypoparathyroidism following a surgery for DTC were retrieved and reviewed by 2 authors.ResultsOf the 3,000 results, 66 papers including 4,517 patients were selected for the present study. Studies reported on a range of skeletal (included in 34 studies, 1,647 patients), cardiovascular (17 studies, 957 patients), psychological (10 studies, 663 patients), and other outcomes (10 studies, 1,348 patients). Nine of 26 studies on patients who underwent THST showed a reduction in bone density, and 13 of 23 studies showed an increase in bone turnover markers. Skeletal effects were more marked in postmenopausal women. There was no evidence of increased fracture risk, and only little data were available on hypoparathyroidism. Four of five studies showed an increased left ventricular mass index on echocardiography, and one study showed a higher prevalence of atrial fibrillation (AF). There was little difference in basic physiological parameters and limited literature regarding symptoms or significant events. Six studies showed associations between long-term TSH suppression and impaired quality of life. Impaired glucose metabolism and prothrombotic states were also found in DTC patients.ConclusionThere is limited literature regarding long-term DTC treatment-related morbidity, particularly regarding the effects of long-term hypocalcemia. Most studies have focused on surrogate markers and not on clinical outcomes. A large prospective study on defined clinical outcomes would help characterize the morbidity of treatment and stimulate research on tailoring treatment strategies.

Postoperative Thyroid-Stimulating Hormone Levels Did Not Affect Recurrence after Thyroid Lobectomy in Patients with Papillary Thyroid Cancer

“…However, effects of TSH suppression were more significant in patients with advanced stage thyroid cancer (stage 3 or 4), and not as significant in patients with early stage thyroid cancer (stage 1 or 2) [56]. In addition, TSH suppression is associated with several morbidities, including cardiovascular and skeletal disease [9] and cardiovascular mortality [10]. TSH suppression therapy is associated with an increased risk of arrhythmias including atrial fibrillation [11] and osteoporosis/bone strength [1121314].…”

The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer

“…TSH suppression therapy may be associated with some adverse events such as bone and cardiovascular sequelae as well as psychological manifestations, but their causal relationships have been controversial [275]. Sugitani and Fujimoto demonstrated that bone mineral density significantly decreased in females aged 50 years or older who were allocated to TSH suppression therapy in a randomized controlled study [271,276].…”

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

“…The need for accurate risk stratification and long-term outcome data to support the treatment decisions is highly relevant for those with early-stage, very low-risk tumors, as well as for those with advanced and metastatic disease [134]. There is also limited information regarding the DTCA treatment-related morbidity associated with a long-term hypocalcemia [158] that may provoke rhythm disturbances.…”

“…The need for accurate risk stratification and long-term outcome data to support the treatment decisions is highly relevant for those with early-stage, very low-risk tumors, as well as for those with advanced and metastatic disease [134]. There is also limited information regarding the DTCA treatment-related morbidity associated with a long-term hypocalcemia [158] that may provoke rhythm disturbances. In the context of arrhythmias, an interesting question arises as to whether TCA patients during follow-up exhibit some specific risk factors for cardiac arrhythmias, such as the pro-arrhythmic β1adrenergic and M2 muscarinic receptor autoantibodies or changes in the myocardial connexins.…”

“…Impairment of the connexin channels deteriorates the electrical coupling required for an AP propagation, thereby affecting the myocardial conduction and promoting re-entry mechanisms [8]. Hyperthyroid rats exhibited a down-regulation of Cx43 in both the atrial and ventricular tissues and were prone to an electrically inducible AF and VF [21,101,158]. In this context, it should be noted that functional phosphorylated forms of Cx43 were markedly suppressed in both the atria and ventricles of hyperthyroid rats.…”