A Case for Lithium Pretreatment Prior to Radioactive Iodine Ablation in Grave’s Disease

Radioactive iodine ablation (RAIA) therapy with Iodine-131 (I-131) is an established treatment for grave’s thyrotoxicosis. However, there is 10 to 20% chance of treatment failure. Lithium, a drug used to treat bipolar disorder, has significant effects on thyroid function. The most clinically relevant is the inhibition of thyroid hormone release. It is also known to inhibit colloid formation, and is involved in blocking organic iodine as well as thyroid hormone release from the thyroid gland without an effect on radioiodine uptake. This leads to increased radioiodine retention in the thyroid gland. Here, we present a case which exemplifies this action of lithium. A 46 year old male with a history of atrial fibrillation and grave’s disease presented to the endocrine clinic. TSH was <0.01 and FT4 was 36. RAI uptake (RAIU) scan showed diffusely increased uptakes with 4 and 24 hour values of 61.2 and 54.6 %. He subsequently underwent RAI ablation with 18 mCi of I 131. He then presented three years later with persistent hyperthyroid symptoms. TSH <0.01 and FT4 4.3. RAIU showed 24-h thyroid uptake of 41%. Patient opted for a second treatment with RAIA and was treated with 30 millicuries of I 131. He however continued to have clinical and biochemical evidence of thyrotoxicosis and was started on methimazole (MMI). Although he was biochemically euthyroid on MMI, he continued to complain of hyperthyroid symptoms such as palpitations, tremors and weight loss. When methimazole was briefly held six months after initiation, TSH was undetectable and FT4 had increased from 0.83 to 1.42. He subsequently underwent a third RAIU off MMI which showed normal 4 and 24 hour uptake, measuring 15.7% and 28% respectively. Patient subsequently opted for third trial of RAI ablation with lithium pretreatment. He declined surgery. He was started on lithium 900mg/day for 6 days, starting on the day of RAI ablation. He underwent RAI ablation with 45 mCi I-131. Patient tolerated the procedure well with subsequent tests indicating hypothyroidism requiring levothyroxine supplementation. Patient’s hyperthyroid symptoms resolved. Several factors affect the efficacy of radioiodide therapy for hyperthyroidism including the short persistence of radioiodide in the thyroid gland. In hyperthyroid Graves’ patients, radioactive iodide uptake is enhanced due to presence of TSH receptor antibody, however, radioiodide is also rapidly discharged because of its increased turnover. Lithium can significantly reduce the release of iodine from the thyroid gland and thus increase iodine retention. There is evidence to suggest that adjuvant lithium can increase thyroidal radioiodine uptake in patients with a low baseline RAIU (< 30%). This case demonstrate that lithium can be used safely prior to RAI therapy in cases of RAI ablation failure even with low baseline RAIU.

A Carboxy-Terminal Monoleucine-Based Motif Participates in the Basolateral Targeting of the Na+/I− Symporter

The Na+/iodide (I−) symporter (NIS), a glycoprotein expressed at the basolateral plasma membrane of thyroid follicular cells, mediates I− accumulation for thyroid hormonogenesis and radioiodide therapy for differentiated thyroid carcinoma. However, differentiated thyroid tumors often exhibit lower I− transport than normal thyroid tissue (or even undetectable I− transport). Paradoxically, the majority of differentiated thyroid cancers show intracellular NIS expression, suggesting abnormal targeting to the plasma membrane. Therefore, a thorough understanding of the mechanisms that regulate NIS plasma membrane transport would have multiple implications for radioiodide therapy. In this study, we show that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. Moreover, the carboxy-terminus contains dominant basolateral information. Using internal deletions and site-directed mutagenesis at the carboxy-terminus, we identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Furthermore, in clathrin adaptor protein (AP)-1B–deficient cells, NIS sorting to the basolateral plasma membrane is compromised, causing the protein to also be expressed at the apical plasma membrane. Computer simulations suggest that the AP-1B subunit σ1 recognizes the monoleucine-based sorting motif in NIS carboxy-terminus. Although the mechanisms by which NIS is intracellularly retained in thyroid cancer remain elusive, our findings may open up avenues for identifying molecular targets that can be used to treat radioiodide-refractory thyroid tumors that express NIS intracellularly.

Iodide transport and breast cancer

Breast cancer is the second most common cancer worldwide and the leading cause of cancer death in women, with incidence rates that continue to rise. The heterogeneity of the disease makes breast cancer exceptionally difficult to treat, particularly for those patients with triple-negative disease. To address the therapeutic complexity of these tumours, new strategies for diagnosis and treatment are urgently required. The ability of lactating and malignant breast cells to uptake and transport iodide has led to the hypothesis that radioiodide therapy could be a potentially viable treatment for many breast cancer patients. Understanding how iodide is transported, and the factors regulating the expression and function of the proteins responsible for iodide transport, is critical for translating this hypothesis into reality. This review covers the three known iodide transporters – the sodium iodide symporter, pendrin and the sodium-coupled monocarboxylate transporter – and their role in iodide transport in breast cells, along with efforts to manipulate them to increase the potential for radioiodide therapy as a treatment for breast cancer.