SARS-CoV-2 vaccine may trigger thyroid autoimmunity: real-life experience and review of the literature.

PURPOSE: SARS-CoV-2 infection can be associated with destructive thyroiditis and triggers thyroid autoimmunity. More recent evidence suggests that SARS-CoV-2 vaccines may also be associated with permanent or transient thyroid dysfunction in susceptible individuals. METHODS: We observed three patients who developed/exacerbated autoimmune thyroid diseases (AITDs) shortly after receiving mRNA-based vaccines against SARS-CoV2. Clinical histories are reported, and relevant literature in the field is summarized. RESULTS: Our case series gives a description of the full spectrum of autoimmune disorders that may occur after SARS-CoV-2 vaccines administration, ranging from a case of new-onset Graves' disease to autoimmune hypothyroidism in two patients with pre-existing AITDs. Our three patients had a personal and/or family history of autoimmune disorders, suggesting that genetic predisposition is an important risk factor for the development of AITDs following vaccination. Moreover, our real-life experience demonstrates that persistent hypothyroidism may occur in the long run and should be overlooked; subjects with a previous AITDs are at risk of developing it. Reviewing the pertinent literature up to date Graves' disease is the most common vaccine-related AITDs with up to 51 cases reported in the literature, occurring mainly in female patients with no personal history of AIDTs, while only a case of autoimmune hypothyroidism has been reported so far. CONCLUSIONS: SARS-CoV-2 vaccines can trigger autoimmune reactions and the present case series contributes to make clinicians aware of full spectrum of AITDs that may occur following vaccination. Thyroid function monitoring is recommended, mainly in subjects with a personal/family history of AITDs.

Serum levels of advanced glycation end products (AGEs) are increased and their soluble receptor (sRAGE) reduced in Hashimoto's thyroiditis.

PURPOSE: Advanced glycation end products (AGEs) are increased in conditions of oxidative stress and promote inflammation by interacting with their receptor RAGE on cell membrane. By contrast, the soluble receptor sRAGE exerts protective effects by competing with RAGE for ligand binding. AGEs/sRAGEs interaction is involved in the pathogenesis of several diseases related to oxidative stress. In the present study, we evaluated the AGEs/sRAGEs oxidative balance in Hashimoto' thyroiditis (HT). METHODS: We measured the levels of sRAGE, by ELISA, and AGEs, by spectrophotometric method, in the serum of 50 HT patients (5 M, 45 F; mean age 38.5 ± 12 years) and 50 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. RESULTS: Serum sRAGEs were significantly lower (median 424 vs 738 pg/ml; p = 0.001) and AGEs higher (205 vs 114 AU/g prot; p = 0.001) in HT patients compared to controls, and the two parameters were inversely correlated (p = 0.016). Accordingly, the AGEs/sRAGEs ratio was threefold higher in HT patients than controls (0.48 vs 0.15; p = 0.0001). In regression analysis models, serum TPO-Ab were the main predictors for AGEs and sRAGEs levels and AGEs/sRAGEs ratio (p < 0.0001), irrespective of TSH and/or FT4 values. CONCLUSION: sRAGEs were decreased and AGEs increased, suggesting a dysregulation of AGE/sRAGEs-related oxidative homeostasis in HT patients, even when in euthyroid status. Autoimmunity per se seems to play an important role in AGEs/sRAGE imbalance, irrespective of thyroid function alterations.

Non-specific rheumatic manifestations in patients with Hashimoto's thyroiditis: a pilot cross-sectional study.

PURPOSE: Hashimoto's thyroiditis (HT) is often associated with rheumatic disorders (arthritis, etc.), but many HT patients report non-specific rheumatic signs and symptoms in the absence of clinically evident rheumatic diseases. Aim of this study was to evaluate the prevalence of non-specific rheumatic manifestations (RMs) in HT subjects without classified autoimmune comorbidities. METHODS: 500 HT patients (467 F, 33 M; median age 41 years, range 14-69) and 310 age- and sex-matched controls, consecutively referred to the Endocrine Unit of Messina University Hospital, were evaluated for non-specific RMs. None took L-thyroxine. EXCLUSION CRITERIA: autoimmune comorbidities, infectious, and/or inflammatory diseases, history of neoplasia, BMI > 30 kg/m2. RESULTS: In our HT cohort, 100 patients (20%) complained of one or more RMs, vs 21 controls (6.8%; P < 0.001). There were minimal differences between the manifestations recorded in the two groups, the most common being polyarthralgias and myalgias/fibromyalgia, but non-specific RMs occurred threefold more in HT patients. Comparing HT patients with RMs (96 F and 4 M) with those affected by HT alone, female sex was prevalent (F:M ratio 24:1 vs 5:1) with higher age at diagnosis (median 43 vs 37 years; P < 0.001). HT patients with RMs (62%) were mostly euthyroid (median TSH 2.0 µIU/L) and only 7% overtly hypothyroid, discouraging a possible causal relationship between thyroid dysfunction per se and RMs. CONCLUSIONS: A significant percentage of HT patients complains of non-specific rheumatic signs and symptoms, in the absence of other diagnosed systemic comorbidities and regardless of thyroid functional status, deserving careful evaluation and prolonged follow-up.

Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis.

PURPOSE: Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust evidence on prevalence and outcome of the spectrum of alemtuzumab-induced autoimmune thyroid events in patients with multiple sclerosis. METHODS: PubMed and Scopus were systematically searched through July 2019. Studies dealing with patients without personal history of thyroid dysfunctions and affected by MS treated with ALZ and reporting ATEs were selected. Data on prevalence and outcome of ATEs were extracted. A proportion of meta-analysis with random-effects model was performed. RESULTS: Considering the overall pooled number of 1362 MS patients treated with ALZ (seven included studies), a 33% prevalence of newly diagnosed ATEs was recorded. Among all ATEs, Graves' disease (GD) was the most represented [63% of cases, 95% confidence interval (CI) 52-74%], followed by Hashimoto thyroiditis (15%, 95% CI 10-22%). Interestingly, GD showed a fluctuating course in 15% of cases (95% CI 8-25%). Of all GD, 12% (95% CI 2-42%) likely had spontaneous remission, 56% (95% CI 34-76%) required only antithyroid drugs, 22% (95% CI 13-32%) needed additional RAI, and 11% (95% CI 0.9-29%) underwent definitive surgery. CONCLUSION: Among different categories of ATEs, Graves' hyperthyroidism was the most common thyroid dysfunction, occurring in more than half of cases. Antithyroid drugs should represent the first-line treatment for ALZ-induced GD patients. However, alemtuzumab-induced GD could not be considered as having a more favourable outcome than conventional GD, given the substantial chance to encounter a fluctuating and unpredictable course.

Increased serum interleukin-37 (IL-37) levels correlate with oxidative stress parameters in Hashimoto's thyroiditis.

PURPOSE: Interleukin-37 (IL-37), member of the IL-1 family, is a natural suppressor of immune and inflammatory responses. Increased serum IL-37 levels were observed in several autoimmune diseases, including Graves' disease. To our knowledge, no data on Hashimoto's thyroiditis (HT) are available in the literature. METHODS: Aim of our study was to measure serum IL-37 levels and evaluate their relationship, if any, with oxidative stress markers in HT patients. We enrolled 45 euthyroid HT patients (5 M e 40 F, median age 40 years) and 50 age- and sex-matched healthy controls. None was under L-thyroxine therapy. Serum IL-37 levels were measured by ELISA. Specific serum tests, such as derived reactive oxygen metabolites (d-ROMs), and biological anti-oxidant potential (BAP) test were performed in all subjects to investigate the changes in oxidative balance, and advanced glycation end products (AGEs) were determined as a specific marker of oxidative stress. RESULTS: IL-37 levels were significantly higher in HT than in controls (median 475 vs. 268 pg/ml, P = 0.018). In the same patients, serum oxidants (d-ROMs) were increased and anti-oxidants (BAP) decreased compared with controls (P = 0.011 and < 0.0001, respectively), clearly indicating an enhanced oxidative stress. In addition, AGEs levels were higher in HT patients than in controls (210 vs. 140 AU/g prot, P < 0.0001) and directly correlated with IL-37 levels (P = 0.048). At multivariate analysis, the main independent predictors that influenced IL-37 levels were both anti-thyroid antibodies (P = 0.026) and AGEs levels (P = 0.001). CONCLUSIONS: IL-37 is up-regulated in HT and may exert a protective role by counteracting oxidative stress and inflammation.

Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know).

Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.

Combined BRAFV600E analysis and 99mTc-MIBI scintigraphy can be a useful diagnostic tool in differentiated thyroid cancer patients with incomplete bio-chemical response to first radioiodine therapy (RAIT): a pilot investigation.

PURPOSE: The aim of the present study was to evaluate the possible diagnostic role of the combined performance of BRAF mutation analysis and MIBI scintigraphy in papillary thyroid cancer (PTC) patients with incomplete bio-chemical response to first radioiodine therapy (RAIT) performed for thyroid remnant ablation. METHODS: The records of 15 PTC patients with bio-chemical incomplete response to first RAIT were retrospectively analyzed. BRAFV600E analysis on primary tumor samples was obtained in all cases along with neck ultrasonography and 99mTc-MIBI scintigraphy of the neck-thorax regions at first follow-up. All patients then underwent RAIT with high radioiodine activities. A post-therapy whole-body scan (pT-WBS) was acquired 5-7 days after RAIT. RESULTS: Abnormal radioiodine uptake was found in 10 out of the 15 patients (67%, 131I+ve), while in the remaining 33%, no abnormal radioiodine uptake was detected (5/15, 131I-ve). Abnormal tracer uptake was found in 6 out of 10 131I+ve patients at 99mTc-MIBI scintigraphy (MIBI+ve). BRAFV600E mutation was not found in the majority of 131I+ve patients (9 out of 10 BRAFV600E-ve). On the contrary, in the 5 131I-ve patients, 99mTc-MIBI scintigraphy did not show any abnormal tracer uptake (MIBI-ve), while BRAFV600E mutation was present (BRAFV600E+ve). Thus, in our series, the association between MIBI-ve scintigraphy and BRAF+ve mutation was a useful diagnostic tool in predicting negative pT-WBS outcome. CONCLUSION: Albeit obtained in a small retrospective series, our results suggest that the combination of BRAFV600E+ve mutation and MIBI-ve scintigraphy may be considered a negative prognostic clue, which predicts the absence of radioiodine uptake at pT-WBS in DTC patients with incomplete bio-chemical response to first RAIT.

Multicentre clinical evaluation of the new highly sensitive Elecsys® thyroglobulin II assay in patients with differentiated thyroid carcinoma.

OBJECTIVE: A highly sensitive thyroglobulin assay (Elecsys® Tg II, Roche Diagnostics, Penzberg, Germany) has become available for monitoring patients with differentiated thyroid cancer (DTC). Here, we evaluated the clinical performance of Elecsys® Tg II assay in a multicentre patients series and compare it with the established Access® Tg assay (Beckman Coulter, Brea, CA, USA). DESIGN: Retrospective analysis on prospectively selected patients in four thyroid cancer referral centres with uniform DTC management. PARTICIPANTS: All DTC cases diagnosed, treated and followed up in four tertiary referral centres for thyroid cancer since January 2005 (n = 1456) were retrieved, and predefined selection criteria were applied to prevent relevant enrolment biases. A series of 204 patients was finally selected for this study. MEASUREMENTS: Samples had been stored at -80°C. Tg was measured by fully automated immunometric Elecsys® Tg II and Access® Tg assays in a centralized laboratory. RESULTS: Two hundred and four DTC were finally included. Of these, 10.8% had structural recurrence (sREC), and 81.4% showed no evidence of disease (NED) at the end of follow-up. There was a significant analytical bias between methods that cannot be used interchangeably. Using ROC curve analysis, the best basal and rhTSH-stimulated Tg cut-offs to detect sREC were 0.41 µg/L and 1.82 µg/L for Elecsys® and 0.36 µg/L and 1.62 µg/L for Access® assay, respectively. Using Cox proportional hazard regression, Tg was the only independent predictor of cancer relapse. CONCLUSIONS: Using appropriate assay-specific cut-offs, the clinical performance of the Elecsys® Tg II assay was comparable to that provided by the well-established Access® Tg assay.

Differentiating malignant from benign thyroid nodules with indeterminate cytology by 99mTc-MIBI scan: a new quantitative method for improving diagnostic accuracy.

Quantitative 99mTc-MIBI thyroid scintigraphy is a useful tool in differentiating malignant from benign thyroid nodules with indeterminate cytology. The aim of our report is to compare the diagnostic performance of different quantitative methods. We prospectively evaluated 20 patients affected by a thyroid nodule with a cytological diagnosis of class III or IV according to the Bethesda system. Planar images of the thyroid were acquired 10 and 60 minutes after 99mTc-MIBI administration and two different quantitative methods applied (i.e. wash-out index, WOind; retention index, R.I.). All patients underwent lobectomy or thyroidectomy and final histological findings were matched with MIBI results obtained with both quantitative methods. Four out of 20 patients had a final histological result of differentiated thyroid cancer, while benign findings were found in the remaining cases. Overall sensitivity, specificity, accuracy, PPV and NPV were 100% in all for the WOind and 100%, 57.1%, 62.5%, 25% for the R.I., respectively. In conclusion 99mTc-semiquantitative MIBI thyroid scintigraphy with WOind calculation is highly accurate in differential diagnosis of nodules with indeterminate cytology reading.

Correlation of cardio-metabolic parameters with vitamin D status in healthy premenopausal women.

PURPOSE: Vitamin D has been associated with metabolic disorders and increasing risk of cardiovascular diseases, with conflicting results. Aim of our study was to evaluate the relationship, if any, between cardio-metabolic risk factors and serum 25(OH)D concentrations in healthy women in premenopausal age. METHODS: We enrolled 200 healthy women, aged 19-50 years (mean age ± SD, 38 ± 11 years). In each subject, we measured serum 25(OH)D in relation to metabolic biomarkers and cardiovascular parameters. RESULTS: A status of vitamin D deficiency was found in 48% of the study population, while 38% showed levels higher than 30 ng/ml. Fasting glucose and insulin levels were significantly higher in subjects with vitamin D deficiency/insufficiency (P = 0.034 and P = 0.049, respectively) as well as HOMA-IR (P = 0.05). HDL cholesterol was significantly lower (P = 0.024) and intima-media thickness (IMT) higher (P = 0.014) in the vitamin D deficient/insufficient subjects. Moreover, serum 25(OH)D levels inversely correlated with insulin levels (P = 0.0001) and intima-media thickness (P = 0.015), and directly with serum HDL cholesterol (P = 0.010). At univariate regression analysis, the parameters that were significantly associated with vitamin D levels were insulin (P = 0.050), HDL cholesterol (P = 0.016), and intima-media thickness (P = 0.015). At multivariate analysis adjusted for age and BMI, vitamin D was still significantly associated with HDL cholesterol and intima-media thickness. CONCLUSIONS: A positive association between vitamin D and HDL cholesterol was found in healthy women without any evidence of metabolic disorders, with a significant inverse correlation between vitamin D and IMT. These results suggest a possible protective role of 25(OH)D in cardiovascular disorders.

Autoimmune comorbidities in Hashimoto's thyroiditis: different patterns of association in adulthood and childhood/adolescence.

OBJECTIVE: Hashimoto's thyroiditis (HT), the most common autoimmune thyroid disease at any age, is often associated with other autoimmune diseases. The present study was aimed to describe the type and frequency of non-thyroidal autoimmune diseases (NTADs) in HT patients and to delineate the clinical pattern of diseases clustering in pediatric/adolescent and adult age. DESIGN: Cross-sectional study. METHODS: 1053 newly diagnosed HT patients (500 adults (467 F, mean age 40.2 ± 13.7 years) and 553 children/adolescents (449 F, mean age 11.1 ± 3.0 years)) were evaluated for common NTADs by means of careful recording of medical history, physical examination and assessment of selected autoantibody profiles. RESULTS: The prevalence of associated NTADs was significantly higher in adults than that in pediatric/adolescent HT patients (P < .0001). In addition, the number of adult patients suffering from two or more associated NTADs was significantly higher than that of children/adolescent (P < 0.0001). A female prevalence was evident in both cohorts, but was significant in the adults (P < 0.0001). The epidemiological distribution of NTADs was strongly different in the two cohorts, the most frequent associated diseases being arthropathies and connective tissue diseases in adults and type 1 diabetes and coeliac disease in children/adolescents. Skin diseases were represented with similar prevalence in both cohorts, vitiligo being the most common. CONCLUSIONS: Age at HT presentation may influence autoimmune diseases clustering, favoring the association of specific NTADs in different ages of life. Moreover, the association between HT and NTADs increases with age and occurs most frequently in adults.

Molecular imaging with (99m)Tc-MIBI and molecular testing for mutations in differentiating benign from malignant follicular neoplasm: a prospective comparison.

PURPOSE: To compare mutation analysis of cytology specimens and (99m)Tc-MIBI thyroid scintigraphy for differentiating benign from malignant thyroid nodules in patients with a cytological reading of follicular neoplasm. METHODS: Patients ≥18 years of age with a solitary hypofunctioning thyroid nodule (≥10 mm), normal thyrotropin and calcitonin levels, and a cytological diagnosis of follicular neoplasm were prospectively enrolled. Mutation analysis and (99m)Tc-MIBI scintigraphy were performed and patients were subsequently operated on to confirm or exclude a malignant lesion. Mutations for KRAS, HRAS and NRAS and for BRAF and translocations of PAX8/PPARγ, RET/PTC1 and RET/PTC3 were investigated. Static thyroid scintigraphic images were acquired 10 and 60 min after intravenous injection of 200 MBq of (99m)Tc-MIBI and visually assessed. Additionally, the MIBI washout index was calculated using a semiquantitative method. RESULTS: In our series, 26 % of nodules with a follicular pattern on cytology were malignant with a prevalence of follicular carcinomas. (99m)Tc-MIBI scintigraphy was found to be significantly more accurate (positive likelihood ratio 4.56 for visual assessment and 12.35 for semiquantitative assessment) than mutation analysis (positive likelihood ratio 1.74). A negative (99m)Tc-MIBI scan reliably excluded malignancy. CONCLUSION: In patients with a thyroid nodule cytologically diagnosed as a follicular proliferation, semiquantitative analysis of (99m)Tc-MIBI scintigraphy should be the preferred method for differentiating benign from malignant nodules. It is superior to molecular testing for the presence of differentiated thyroid cancer-associated mutations in fine-needle aspiration cytology sample material.

Chronic idiopathic urticaria and Graves' disease.

Chronic urticaria is a common condition characterized by recurrent episodes of mast cell-driven wheal and flare-type skin reactions lasting for more than 6 weeks. In about 75% of cases, the underlying causes remain unknown, and the term chronic idiopathic urticaria (CIU) is used to emphasize that wheals develop independently of identified external stimuli. Although CIU affects about 1.0% of the general population, its etiopathogenesis is not yet well understood. It is now widely accepted that in many cases CIU should be regarded as an autoimmune disorder caused by circulating and functionally active IgG autoantibodies specific for the IgE receptor (FceRI) present on mast cells and basophils or for IgE itself. The well-known association of CIU with other autoimmune processes/diseases represents further indirect evidence of its autoimmune origin. Autoimmune thyroid diseases, especially autoimmune thyroiditis, represent the most frequently investigated diseases in association with CIU. Here we review this topic with particular regard to the association between Graves' disease and CIU. The possible pathogenetic mechanisms and the clinical implications of such an association are discussed.

Cell proliferation parameters and apoptosis indices in pituitary macroadenomas.

BACKGROUND: Pituitary adenomas are usually well-differentiated tumors but may show locally aggressive behavior. AIM: To investigate the relationship between proliferation and apoptosis parameters and tumor recurrence in a series of 20 radically resected pituitary macroadenomas (11 functioning, 9 non-functioning). MATERIALS AND METHODS: Proliferative activity and DNA ploidy were analyzed by flow cytometry (FCM) on fresh surgical specimens. Immunohistochemistry for Ki-67/MIB-1 and for the anti-apoptotic protein Bcl-2 was performed on paraffin-embedded specimens from the same tumors. Tumor regrowth was evaluated by magnetic resonance imaging (MRI). RESULTS: Six adenomas recurred after surgery, regardless of hormonal hypersecretion. Pre-surgical tumor size was significantly higher in recurrent than in non-recurrent adenomas (p=0.003). Pre-surgical MRI demonstrated cavernous sinus (CS) invasiveness in all recurrent tumors, while none of the non-invasive adenomas recurred (p=0.042, by Fisher's exact test). The DNA content was aneuploid in 5/20 adenomas, one of which recurred. Cell percentages in the S (%SPF) and G2+M (%G2-M) phases and proliferative index (PI) (PI=%SPF+%G2-M) were significantly higher in aneuploid than in diploid adenomas (p<0.05), but no significant differences concerning all FCM parameters were observed between recurrent and non-recurrent adenomas. Similarly, MIB-1 did not show a significant difference of expression between recurrent and non-recurrent adenomas (p=0.33). Bcl-2 immunoreactivity was detected in 12/15 pituitary adenomas, involving 63±35% of tumor cells, regardless of tumor recurrence. CONCLUSIONS: In this group of radically resected pituitary macroadenomas, neuroradiological finding of CS invasiveness--but not FCM parameters nor MIB-1 and Bcl-2 expression--is useful for predicting tumor recurrence.

Association of autonomously functioning thyroid nodules with Hashimoto's thyroiditis: study on a large series of patients.

OBJECTIVE: Autonomously functioning thyroid nodules (AFTNs) associated with Hashimoto's thyroiditis (HT) are rarely reported. This study evaluates the magnitude of such association, elaborating the clinical and biochemical characteristics of HT and AFTN. MATERIALS AND METHODS: We reviewed the records of our patients with thyroid nodules, including serum TSH, free T4 and T3, Tg-Ab, TPO-Ab, ultrasonography, Tc-99m Sodium Pertechnetate scintigraphy (performed in overt or subclinical hyperthyroid patients). HT patients with coexisting AFTN(s) (group A) were compared with patients with AFTNs alone (group B, n=267). RESULTS: 80 patients (65 women and 15 men; F:M ratio 4.3:1; age 57±15 years) had AFTN(s) and coexisting HT. Except 9 patients who were under methimazole, all had suppressed (<0.01 mU/L) or low (<0.4 mU/L) TSH; 17/71 (24%) had increased FT4 and/or FT3. Subclinical hyperthyroidism prevailed over frank hyperthyroidism in group A (76 vs. 24%), but not in group B (56 vs. 44%) ( P=0.005). Group A patients had lower serum FT3 (∼0.6 pmol/L or 9%) and FT4 (∼0.9 pmol/L or 4%) as compared to group B. The maximum diameter of the AFTN(s) was 8% smaller in group A as compared with group B, thus matching the said difference in FT3. A positive correlation between nodule size and age was found only in group B ( P=0.015). CONCLUSION: Even if difference in the size of nodules between groups A and B does not reach statistical significance, the chronic intrathyroid lymphocytic infiltration of HT may decrease the tendency of the AFTNs to grow and diminish their degree of functioning.

An analytical model for improving absorbed dose calculation accuracy in non spherical autonomous functioning thyroid nodule.

AIM: Patients candidate to radioiodine treatment of autonomous functioning thyroid nodule (AFTN) are characterized by a wide range of nodule volumes with different shapes. To optimize the treatment, pretherapeutic dosimetry should account also for the dependence of deposited energy on the nodule geometry. METHODS: We developed a Monte Carlo code in Geant4 to simulate the interaction of beta and gamma radiations emitted by Na-131I into ellipsoidal volumes of soft tissue homogeneously uptaking the radionuclide, surrounded by a simplified antropomorphic phantom. We simulated 9 volumes between 0.1 and 50 cm3, each one with 8 different ellipsoidal shapes. We considered the data of 10 patients affected by AFTN, whose nodule volumes were in the range 1-40 cm3, who underwent radioiodine therapy following the traditional dosimetric approach. The patients underwent ultrasonographic (US) study, in order to determine the nodule volume, and radioiodine thyroid uptake measurements between 3 and 168 hours after radioiodine tracer dose administration. RESULTS: We found an analytical relationship between the average deposited energy and the ellipsoid's semiaxes and we included it in the formula for the calculation of activity to be administered, A0. For the 10 patients studied, A0 calculated with our approach ranges from +9% to -2% with respect to the one calculated with the traditional formula. CONCLUSION: The proposed model, accounting for the dependence of beta and gamma absorbed fractions from nodule volume and shape, can lead to a more accurate estimation of A0 during AFTN therapy. Since the measurement of nodule axes is routinely obtained from pretherapeutic US, our approach can be introduced in the clinical practice without changing the diagnostic pre-therapeutic protocol.