Steroid treatment in the management of destructive thyrotoxicosis induced by PD1 blockade.

Objective: Destructive thyroiditis is the most common endocrine immune-related adverse event (iRAEs) in patients treated with anti-PD1/PD-L1 agents. Given its self-limited course, current guidelines recommend no treatment for this iRAE. Nevertheless, in patients with enlarged thyroid volume and a poor performance status, thyrotoxicosis may be particularly severe and harmful. The aim of the study is to evaluate if steroid treatment might be useful in improving thyrotoxicosis in subjects with a poor performance status. Methods: We conducted a retrospective study, comparing the course of thyrotoxicosis of four patients treated with oral prednisone at the dosage of 25 mg/day (tapered to discontinuation in 3 weeks) and an enlarged thyroid volume to that of eight patients with similar thyroid volume who were left untreated. Results: The levels of thyroid hormones were lower in subjects treated compared to those untreated at time of 7, 14, 21, 28, 35, 42, 60 and 90 days (P < 0.05 at each time). The time to remission of thyrotoxicosis was 24 days in patients treated with steroids and 120 days in untreated patients (P < 0.001). At 6 months, the rate of evolution to hypothyroidism was similar in the two groups (4/4 in the steroid group vs 7/8 in the untreated group, P = 0.74) and no difference was found in tumor progression (P = 0.89). Conclusions: Our preliminary data suggest that in patients with a poor performance status experiencing a severe destructive thyrotoxicosis induced by PD-1 blockade, a short period of administration of oral prednisone is effective in obtaining a quick reduction of the levels of thyroid hormones.

Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade.

CONTEXT: Thyrotoxicosis is a common immune-related adverse event in patients treated with programmed cell death protein-1 (PD1) or programmed cell death protein ligand-1 (PD-L1) blockade. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy, is lacking, as are data on response to treatment and follow-up. OBJECTIVE: The aim of this study was to better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and treatment. METHODS: We conducted a retrospective study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis on PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, 99mtechnecium scintiscan, and longitudinal thyroid function tests. RESULTS: Five patients had normal or increased scintigraphic uptake (Sci+), no serum antibodies against the thyrotropin receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci-) and experienced destructive thyrotoxicosis followed by hypothyroidism (N = 9) or euthyroidism (N = 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P = .04). Among Sci- individuals, a larger thyroid volume was associated with a longer time to remission (P < .05). Methimazole (MMI) was effective only in Sci+ individuals (P < .05). CONCLUSION: Administration of PD1- or PD-L1-blocking antibodies may induce 2 different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2, characterized by destructive and transient thyrotoxicosis that evolves to hypothyroidism or euthyroidism. Thyroid scintigraphy and ultrasound help in differentiating and managing these 2 forms of iatrogenic thyrotoxicosis.

Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study.

BACKGROUND: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS: At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS: When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.

Iodine contributes to thyroid autoimmunity in humans by unmasking a cryptic epitope on thyroglobulin.

CONTEXT: The mechanisms linking thyroid autoimmunity and iodine use in humans are unknown. OBJECTIVE: Our aim was to correlate iodine intake, thyroid autoimmunity, and recognition of thyroglobulin (Tg) epitopes after implementation of iodine prophylaxis. SETTING: The general community living in an Italian village was evaluated. MAIN OUTCOME MEASURES: Thyroglobulin autoantibodies (TgAb), thyroperoxidase autoantibodies (TPOAb), and urinary iodine excretion were assessed in 906 iodized salt users (IS-users) and 389 nonusers (IS-nonusers). Ultrasound (US) was performed to identify thyroid hypoechogenicity, suggestive of Hashimoto thyroiditis (HT). TgAb epitope pattern in 16 IS-users and 17 IS-nonusers was evaluated by an inhibition binding assay to Tg, using human monoclonal TgAb-Fab directed to A, B, C, and D epitopes on Tg. RESULTS: Median urinary iodine excretion was slightly higher in IS-users than in IS-nonusers (112.0 µg/L vs 86.5 µg/L; P < .01). TgAb, and not TPOAb, was more frequent in IS-users (18.9% vs 13.6%, P = .02). HT-US was found in 87 subjects, among whom both positive TgAb (58.4% vs 31.8%, P = .03) and TPOAb (61.5% vs 45.4%. P = .04) were more frequent in IS-users. In this group significantly higher serum levels of TgAb (median 108 U/mL vs 30 U/mL; P = .02), but not of TPOAb, were present. Iodized salt use had no effect on the 1208 non HT-US subjects. TgAb directed to the epitope B of Tg were more frequent in IS-users than in IS-nonusers (27.5% vs 3.0%, P = .047). CONCLUSIONS: Iodine-induced thyroid autoimmunity is related to TgAb and the unmasking of a cryptic epitope on Tg contributes to this relationship in humans.

Incidental versus clinically evident thyroid cancer: a 5-year follow-up study.

BACKGROUND: The incidence of differentiated thyroid cancer in patients undergoing surgery for presumed benign thyroid disease (incidental thyroid cancer) is not negligible. The purpose of this study was to verify if incidental thyroid cancers have a different clinical course than the clinically evident thyroid cancer. METHODS: A group of patients with incidental thyroid cancer (n = 95) has been compared to a control group with clinically evident thyroid cancer (n = 93). Both the histology and the outcome after a 5-year follow-up have been compared. RESULTS: At the univariate analysis, the groups demonstrated significant differences in many pathologic features, remnant ablation (p < .001), and persistent disease (p = .006). Nevertheless, the multivariate analysis revealed that the outcome was not influenced by the preoperative or the incidental diagnosis. CONCLUSION: Incidental thyroid cancers show a different pathological pattern when compared to clinically evident thyroid cancers. Nonetheless, the final outcome is not influenced by preoperative or postoperative diagnosis. Hence, patients with incidental thyroid cancer should follow the same postoperative protocols of patients with clinically evident thyroid cancer.

Radioiodine 131I treatment for large nodular goiter: recombinant human thyrotropin allows the reduction of radioiodine 131I activity to be administered in patients with low uptake.

BACKGROUND: (131)I therapy is effective in reducing the volume of large nodular goiters (thyroid volume [TV]), mainly after stimulation with recombinant human thyrotropin (rhTSH). The amount of (131)I to be administered inversely depends on thyroid radioactive iodine uptake (RAIU). In patients with low RAIU, we evaluated the efficacy of (131)I treatment at lower doses with respect to those calculated on the basal RAIU, after rhTSH stimulation. METHODS: Eighteen consecutive patients (17 women and 1 man, 49-83 years) with large nodular goiter were included in the study. At enrollment, 24th h RAIU, TSH, free thyroxine, free triiodothyronine, thyroglobulin antibodies, thyroid peroxidase antibodies, TSH receptors antibodies, urinary iodine, and TV were measured. RAIU was <40% in 11 patients (lower uptake group [LUG]) and >40% in 7 (higher uptake group [HUG]). RAIU difference in the two groups was significant (p < 0.0001). LUG patients were treated with rhTSH (0.03 mg i.m.) and RAIU was measured again after 24 hours. The administered amount of (131)I was aimed to give the thyroid a dose of 100 Gy, by the formula: (131)I activity = 370 MBq × TV (mL)/RAIU(%), taking into account RAIU value after rhTSH for LUG patients. Patients were re-evaluated 3 and 12 months after therapy. RESULTS: At enrollment, LUG and HUG patients did not differ for TV, free thyroxine, free triiodothyronine, TSH, and urinary iodine. LUG patients were older than HUG patients (p = 0.027). In LUG, the uptake increased after rhTSH (42.8% [36%-47.5%] vs. 30% [23.4%-31.6%], p = 0.0044). The (131)I activity was 1073 MBq (740-1103 MBq) in LUG and 851 MBq (677-918 MBq) in HUG (p = 0.22, NS), vs. 1300 MBq (1077-2150 MBq) in LUG, based on RAIU before rhTSH. At 3 and 12 months after radioiodine, TV was reduced to 74% [59%-84%] and 53% [42%-72%] in LUG and 75% [70%-77%] and 65% [54%-74%] in HUG, respectively. The reduction was significant with respect to the basal, both at 3 and 12 months, but not different between the two groups. CONCLUSIONS: One single dose of 0.03 mg of rhTSH increased the thyroid RAIU by 40% in patients with nodular goiter and low basal uptake. This allowed a mean reduction of 36% (26%-42%) in the administered (131)I activity without loss of effectiveness. In patients with low RAIU, rhTSH pre-treatment may optimize (131)I therapy.

Early textural and functional alterations of left ventricular myocardium in mild hypothyroidism.

The aim of the present study was to evaluate cardiac function and texture in patients with subclinical hypothyroidism (sHT) both by conventional and new ultrasonic intramyocardial tissue techniques. sHT was characterized by normal serum free tetraiodotironine and free triiodotironine levels and slightly increased serum TSH level. Twenty-four patients affected by sHT and 24 sex- and age-matched healthy volunteers were studied. All subjects were submitted to conventional two-dimensional (2D)-color Doppler echocardiography, pulsed wave tissue Doppler imaging (PWTDI) for the analysis of the diastolic function, color Doppler myocardial imaging (CDMI) for the analysis of regional strain and strain-rate and integrated backscatter (IBS) for the evaluation of intrinsic contractility and tissue characterization. The results of the present study were: (a) the detection in sHT subjects of a lower cyclic variation index (CVI) indicating an altered myocardial intrinsic contractility; (b) a higher ultrasonic myocardial reflectivity indicating an altered myocardial texture; (c) the detection of lower systolic strain and strain-rate indicating an alteration of myocardial regional deformability; (d) an initial impairment of left ventricular diastolic function indicated by a decrease of peak E mitral flow velocity and an increase of peak A mitral flow velocity. All parameters studied with conventional 2D-echo in sHT patients were comparable with controls, except for a mild alteration in diastolic function. A significant correlation among systo-diastolic modifications detected by CDMI and IBS and serum TSH levels were found. The CVI at septum, the PWDTI S-peak wave and the systolic strain at septum were inversely related to the serum TSH levels. In conclusion, the new intramyocardial ultrasonic techniques confirm and extend the previous knowledge on the effect of the sHT on the heart, allowing the detection of early ultrastructural and regional functional systolic and diastolic abnormalities.

Incidental thyroid carcinoma in a large series of consecutive patients operated on for benign thyroid disease.

BACKGROUND: The diagnosis of incidental thyroid carcinoma (ITC) in patients operated on for a benign disease is frequent. This study aims to determine both its clinical effect and the possibility of identifying this class of patients preoperatively. METHODS: A total of 998 consecutive patients (697 women and 301 men; mean age, 49.5 years) undergoing surgery for benign thyroid pathology in a single institution were studied. The mean time between first diagnosis of thyroid disease and operation was 9.0 years (range, 0-50 years). All patients underwent at least one ultrasonography before surgery, and 678 patients underwent fine-needle aspiration cytology. Patients with undetermined cytology or follicular nodules were excluded from the study. RESULTS: Histology revealed an ITC in 104 patients (10.4%): 99 had a papillary carcinoma. Mean and median diameters of ITC were 1.4 and 0.7 cm, respectively (range, 0.1-7.5 cm). In 43 patients, the tumour size was greater than 1 cm, whereas it exceeded 2 cm in 25 patients. Tumours were multicentric in 19.8% of the patients and occurred in 8.2% of patients with nodular toxic goiter, 8.7% of patients with toxic diffuse goiter and 13.8% of patients with multinodular goiter. DISCUSSION: The results confirm the high frequency of ITC. ITC was more frequent in euthyroid patients than in thyrotoxic patients (P < 0.03). Sex, age, thyroid volume and interval between diagnosis and surgery did not significantly influence its incidence. The majority of ITC was represented by microcarcinomas, but in approximately 25% of patients, the tumour size was greater than 2 cm. The role played by FNAC in excluding malignancies proved to be fairly inconclusive.

Comparison of two different doses of iodide in the prevention of gestational goiter in marginal iodine deficiency: a longitudinal study.

OBJECTIVE: A prospective randomized trial was performed to assess the usefulness of iodine supplementation in the prevention of goiter in pregnant women living in marginally iodine-deficient areas. DESIGN: Eighty-six pregnant women were recruited and randomized in two groups and treated daily for up to six months after delivery with 200 microg iodide (group A) or 50 microg iodide (group B). Sixty-seven women (32 in group A and 35 in group B) completed the study. METHODS: Thyroid volume (TV), thyroid functional parameters and urinary iodine concentration were determined in all subjects at booking, at the 18th-26th, and the 29th-33rd week of gestation, and at the 3rd and 6th month after delivery. RESULTS: A slight but not significant increase in TV during gestation was observed only in group B. After delivery a progressive decrease in TV was documented in both groups, the final TV being significantly reduced with respect to the initial volume in group A. No significant changes in serum free thyroid hormones and TSH concentrations were found during gestation in either group. Postpartum thyroiditis was observed in 5 women (2 in group A, 3 in group B). No side effects were seen. CONCLUSION: The present data indicate that in marginally iodine-deficient areas, the administration of iodide is recommended in pregnancy and lactation. In the conditions of the present trial a dose of 50 microg iodide/day is a safe and effective measure in preventing an increase in TV during pregnancy but a dose of 200 microg iodide/day appeared to be more effective without inducing side effects and without enhancing the frequency of post-partum thyroiditis.