Autoimmune thyroiditis (AIT) may impair radioiodine (¹³¹I) uptake in papillary thyroid cancer (PTC). Finding the mechanisms that govern immune cells during ¹³¹I therapy of PTC with concomitant AIT (PTC + AIT) could provide a rationale. Our study aimed to evaluate the effects of ¹³¹I on anti-thyroglobulin antibodies (TgAb), matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1 and tumor necrosis factor-α (TNF-α) and its receptors TNFR1 and TNFR2, in PTC and PTC + AIT patients. Peripheral blood was collected from 56 female patients with PTC and 32 with PTC + AIT before and 4 days after ¹³¹I (3.7 GBq). The serum levels of TgAb, MMP-9, TIMP-1, TNF-α, TNFR1 and TNFR2 were measured by ELISA. The mean radioactivity of blood samples collected after ¹³¹I intake was higher in the PTC + AIT group than in PTC (p < 0.001). In the PTC + AIT group, TNF-α/TNFR1 and TNF-α/TNFR2 ratios decreased by 0.38-fold and 0.32-fold after ¹³¹I and were positively correlated with the MMP-9/TIMP-1 ratio (r = 0.48, p = 0.005, and r = 0.46, p = 0.007). In the PTC group, TNF-α/TNFR1 and TNF-α/TNFR2 ratios increased by 3.17-fold and 3.33-fold and were negatively correlated with the MMP-9/TIMP-1 ratio (r = −0.62, p < 0.001 and r = −0.58, p < 0.001). Our results demonstrate that TNF-α may exert different antitumor effects in response to ¹³¹I therapy depending on the patient’s immune profile.

Publications investigating the effect of radioactive iodine (¹³¹I) therapy on the circulating peripheral blood cells in patients with differentiated thyroid cancer (DTC) are limited to blood samples collected more than 92 h after ¹³¹I. Studies conducted on blood samples collected up to 92 h are rare due to the radioactive contamination risk. This research aimed to assess the relationship between the prescribed ¹³¹I activity, human whole blood activity, and peripheral blood cells at many time points (6, 22, 46, 69, and 92 h after ¹³¹I). The study enrolled 50 female patients with DTC who received a ¹³¹I median activity of 90.54 mCi (3.35 GBq). The neutrophil-to-lymphocyte ratio (NLR) was measured as an inflammatory marker. ¹³¹I uptake in the residual thyroid tissue peaked after 46 h. Blood activity decreased in the first 46 h and increased 69 h after the ¹³¹I intake. Blood activity was associated with the absolute lymphocyte count and the NLR at 69 h (r = −0.49 and r = 0.52, p < 0.001). Our results demonstrate that the time interval between 46 and 69 h should be associated with the release of hematological inflammatory mediators, such as neutrophils and lymphocytes, to eradicate tumor cells in response to ¹³¹I therapy.

No clinical studies have investigated the effect of radioiodine (¹³¹I)-targeted therapy on the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as inflammatory response markers in patients with differentiated thyroid cancer (DTC) associated with type 2 diabetes mellitus (T2DM) and obesity. This study aimed to assess the relationship between blood radioactivity, body mass index (BMI), and peripheral blood cells three days after ¹³¹I intake in 56 female patients without T2DM (DTC/−T2DM) vs. 24 female patients with T2DM (DTC/+T2DM). Blood radioactivity, measured three days after ¹³¹I intake, was significantly lower in the DTC/+T2DM than in the DTC/−T2DM patients (0.7 mCi vs. 1.5 mCi, p < 0.001). The relationship between blood radioactivity and BMI (r = 0.83, p < 0.001), blood radioactivity and NLR (r = 0.53, p = 0.008), and BMI and NLR (r = 0.58, p = 0.003) indicates a possible connection between the bloodstream ¹³¹I uptake and T2DM-specific chronic inflammation. In patients without T2DM, ¹³¹I therapy has immunosuppressive effects, leading to increased NLR (19.6%, p = 0.009) and PLR (39.1%, p = 0.002). On the contrary, in the chronic inflammation context of T2DM, ¹³¹I therapy amplifies immune metabolism, leading to a drop in NLR (10%, p = 0.032) and PLR (13.4%, p = 0.021). Our results show that, in DTC/+T2DM, the bidirectional crosstalk between neutrophils and obesity may limit ¹³¹I uptake in the bloodstream. Considering the immune response to ¹³¹I therapy, the two groups of patients can be seen as a synchronous portrait of two sides. The explanation could lie in the different radiosensitivity of T and B lymphocytes, with T lymphocytes being predominant in patients with DTC/−T2DM and, most likely, B lymphocytes being predominant in T2DM.

Radioiodine (¹³¹I) therapy for differentiated thyroid cancer (DTC) involves exposure of the whole body, including the heart, to ionizing radiation. This exposure to the subsequent risk of heart disease is uncertain, especially in patients with DTC associated with type 2 diabetes mellitus (DTC/+T2DM). The current study aimed to assess the relationship between left ventricular ejection fraction (LVEF), high cumulative ¹³¹I dose, and peripheral blood parameters in patients with DTC/−T2DM and DTC/+T2DM. The study enrolled 72 female patients with DTC/−T2DM and 24 with DTC/+T2DM who received cumulative ¹³¹I doses above 150 mCi (5.55 GBq). LVEF was lower in patients with concomitant T2DM than those without (p < 0.001). The cumulative ¹³¹I dosage was inversely correlated with LVEF only in DTC/−T2DM patients (r = −0.57, p < 0.001). In the DTC/+T2DM group, LVEF was negatively associated with absolute platelet count (r = −0.67, p < 0.001) and platelet-to-lymphocyte ratio (r = −0.76, p < 0.001). Our results demonstrate that exposure to high cumulative ¹³¹I doses has different cardiovascular effects in DTC/−T2DM and DTC/+T2DM.

Starting from the metabolic profile of type 2 diabetes mellitus (T2DM), we hypothesized that the mechanisms of ¹³¹I-induced cardiotoxicity differ between patients diagnosed with differentiated thyroid cancer (DTC) with/without T2DM, with metformin potentially acting as a cardioprotective agent by mitigating inflammation in patients with T2DM. To address this hypothesis, we quantified, using ELISA, the serum concentration of several key biomarkers that reflect cardiac injury (NT-proBNP, NT-proANP, ST2/IL-33R, and cTn I) in 74 female patients with DTC/−T2DM and 25 with DTC/+T2DM treated with metformin. All patients received a cumulative oral dose of ¹³¹I exceeding 150 mCi (5.55 GBq) over approximately 53 months. Our results showed the following: (i) In DTC/−T2DM patients, high-cumulative ¹³¹I doses promote a pro-inflammatory state that accelerates the development of cardiotoxicity. Monitoring NT-proBNP, ST2/IL-33R, and cTn I in these patients may help identify those at risk of developing cardiac complications. (ii) In patients with DTC/+T2DM, high-cumulative ¹³¹I doses lead to the release of NT-proANP (r = 0.63), which signals that the atria are under significant stress. (iii) In patients with DTC/+T2DM, metformin suppresses inflammation, leading to a dose-dependent reduction in cTn I (r = −0.59). Monitoring cTn I and NT-proANP, and considering the use of metformin as part of the therapeutic strategy, could help manage cardiotoxicity in T2DM patients undergoing ¹³¹I therapy.