Correlation between remnant thyroid gland I-131 uptake and serum thyroglobulin levels: can we rely on I-131 whole body scans?

BACKGROUND: I-131 treatment (RAI) decision relies heavily on serum thyroglobulin (Tg) levels, as higher Tg levels are assumed to be correlated with higher I-131 uptake. Tg elevation, negative iodine scintigraphy (TENIS) definition is becoming more clinically relevant as alternative treatment methods are available. This study examined the correlation between Tg levels with I-131 uptake in remnant thyroid gland to evaluate the reliability of serum Tg levels in predicting I-131 uptake. METHODS: From March 2012 to July 2019, 281 papillary thyroid cancer patients treated with 150 mCi RAI were retrospectively enrolled. Early (2nd day) and Delayed (7th day) post-RAI whole-body scan (WBS) neck counts were correlated with clinical and pathologic findings. Patients with normal neck ultrasound and undetectable level of serum Tg (< 0.2 ng/mL) and thyroglobulin antibody (TgAb) (< 10 IU/mL) were defined as ablation success within 2 years after I-131 ablation. RESULTS: Thyroid gland weight, tumor size and thyroiditis were independent factors of preoperative serum Tg levels. Serum off-Tg levels correlated with Early and Delayed WBS neck counts, and thyroiditis pathology contributed to lower neck counts in both Early and Delayed WBSs. In multivariable analysis, Delayed WBS neck count, serum off-Tg and off-TgAb were significant factors for predicting ablation success. CONCLUSION: I-131 uptake and retention in remnant thyroid gland correlates with serum off-Tg levels, thyroiditis, and ablation success in thyroid cancer patients receiving high-dose I-131 therapy. Semi-quantitative I-131 analysis with Early and Delayed WBSs provides additional information in evaluating ablation success, with the potential application for metastasis treatment response evaluation.

Hyperthyroidism.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12-18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

Optimal levothyroxine dose to achieve euthyroidism in patients with primary hypothyroidism: analysis according to etiology.

INTRODUCTION: Levothyroxine (LT4) has been considered the standard of care for treatment of hypothyroidism. Current recommendations suggest a LT4 dose between 1.6-1.8 µg/kg/day. The aim of this study was to evaluate the LT4 dose for adult patients with primary hypothyroidism of different etiologies who reached euthyroidism. METHODS: A cross-sectional study was performed from the retrospective review of the charts of patients with primary hypothyroidism in treatment with LT4. Subjects were classified according to TSH level in overtreated (TSH < 0.4 µIU/ml), euthyroid (TSH 0.40-4.20), and undertreated (TSH >4.2) and according to the etiology of hypothyroidism. A stepwise logistic regression model was performed to evaluate the variables associated with TSH<0.4 µIU/ml. RESULTS: 955 patients were included. 75.13% of the patients had an adequate LT4 replacement. LT4 dose to achieve euthyroidism was higher in patients with a history of radioiodine therapy (1.92 µg/kg) and thyroid surgery (1.52 µg/kg), while the LT4 dose required to achieve euthyroidism in patients with Hashimoto's thyroiditis and atrophic thyroiditis was lower than that reported in previous studies (1.25 and 1.08 µg/kg, respectively). The variables that were associated with a higher probability of TSH<0.4 µIU/ml were male gender, Hashimoto's thyroiditis, radioiodine therapy, and thyroid surgery. MAJOR CONCLUSION: LT4 dose required to achieve euthyroidism in patients with hypothyroidism varies according to the etiology, being higher in patients with hypothyroidism due to radioiodine therapy and thyroid surgery. Patients with hypothyroidism due to Hashimoto's thyroiditis and atrophic thyroiditis require a lower dose than current recommendations.

Introducción: La levotiroxina (LT4) se considera el estándar de tratamiento del hipotiroidismo. Las recomendaciones actuales sugieren una dosis de LT4 entre 1,6-1,8 µg/kg/día. El objetivo de este estudio fue evaluar la dosis de LT4 en pacientes adultos con hipotiroidismo primario de diferentes etiologías que alcanzaron el eutiroidismo. Métodos: Estudio transversal a partir de la revisión retrospectiva de historias clínicas de pacientes con hipotiroidismo primario en tratamiento con LT4. Los sujetos se clasificaron según el nivel de TSH en sobretratados (TSH<0,4 µUI/ml), eutiroideos (TSH 0,40-4,20) y subtratados (TSH>4,2) y según la etiología del hipotiroidismo. Se realizó un modelo de regresión logística escalonada para evaluar las variables asociadas con TSH <0,4 µUI/ml. Resultados: Se incluyeron 955 pacientes. El 75,13% tuvo un reemplazo adecuado de LT4. La dosis de LT4 para lograr el eutiroidismo fue mayor en pacientes con antecedentes de terapia con yodo radiactivo (1,92 µg/kg) y cirugía de tiroides (1,52 µg/kg), mientras que la dosis de LT4 para lograr el eutiroidismo en pacientes con tiroiditis de Hashimoto y tiroiditis atrófica fue menor que el reportado en estudios previos (1,25 y 1,08 µg/kg, respectivamente). Las variables que se asociaron con una mayor probabilidad de TSH<0,4 µUI/ml fueron el sexo masculino, tiroiditis de Hashimoto, terapia con yodo radiactivo y cirugía de tiroides. Conclusión principal: La dosis de LT4 necesaria para alcanzar el eutiroidismo en pacientes con hipotiroidismo varía según la etiología, siendo mayor en pacientes con hipotiroidismo por tratamiento con yodo radiactivo y cirugía tiroidea. Los pacientes con hipotiroidismo debido a tiroiditis de Hashimoto y tiroiditis atrófica requieren una dosis más baja que las recomendaciones actuales.

Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinopathies. We report a unique case of hypophysitis, thyroiditis, severe hypercalcaemia and pancreatitis following combined ICI therapy. CASE PRESENTATION: A 46-year old Caucasian female with a background history of malignant melanoma and lung metastases presented to the emergency department with lethargy, nausea, palpitations and tremors. She had been started on a combination of nivolumab and ipilimumab 24 weeks earlier. Initial investigations revealed thyrotoxicosis with a thyroid stimulating hormone (TSH) of < 0.01 (0.38-5.33) mIU/L, free T4 of 66.9 (7-16) pmol/.L. TSH receptor and thyroperoxidase antibodies were negative. She was diagnosed with thyroiditis and treated with a beta blocker. Six weeks later she represented with polyuria and polydipsia. A corrected calcium of 3.54 (2.2-2.5) mmol/l and parathyroid hormone (PTH) of 9 (10-65) pg/ml confirmed a diagnosis of non-PTH mediated hypercalcaemia. PTH-related peptide and 1, 25-dihydroxycholecalciferol levels were within the normal range. Cross-sectional imaging and a bone scan out ruled bone metastases but did reveal an incidental finding of acute pancreatitis - both glucose and amylase levels were normal. The patient was treated with intravenous hydration and zoledronic acid. Assessment of the hypothalamic-pituitary-adrenal (HPA) axis uncovered adrenocorticotrophic hormone (ACTH) deficiency with a morning cortisol of 17 nmol/L. A pituitary Magnetic Resonance Image (MRI) was unremarkable. Given her excellent response to ICI therapy she remained on ipilimumab and nivolumab. On follow-up this patient's thyrotoxicosis had resolved without anti-thyroid mediations - consistent with a diagnosis of thyroiditis secondary to nivolumab use. Calcium levels normalised rapidly and remained normal. ACTH deficiency persisted, and she is maintained on oral prednisolone. CONCLUSION: This is a remarkable case in which ACTH deficiency due to hypophysitis; thyroiditis; hypercalcaemia and pancreatitis developed in the same patient on ipilimumab and nivolumab combination therapy. We postulate that hypercalcaemia in this case was secondary to a combination of hyperthyroidism and secondary adrenal insufficiency.

Safety of current immune checkpoint inhibitors in non-small cell lung cancer.

Introduction: Immune checkpoint inhibitors (ICIs) achieved response rates around 20% in advanced non-small cell lung cancer (NSCLC) with 8% of patients becoming long-term survivors. Outcomes have improved with the addition of chemotherapy to immunotherapy or the combination of anti-PD(L)1 with anti-CTLA-4 agents.Areas covered: The incidence of immune-related adverse events (irAEs) in patients with NSCLC treated with ICIs varied across clinical trials and real-life studies. The onset of irAEs was 10 weeks. Toxic deaths from irAEs following anti-PD(L)1 administration resulted mainly from pneumonitis. Some irAEs such as rash and thyroiditis were probably associated with better clinical outcomes, though confounding biases exist. Investigations are on-going to determine ideal biomarkers to predict the occurrence, to screen for and to diagnose irAEs.Expert opinion: Prevention, anticipation, detection, treatment and careful monitoring are the five principles that characterize our management of irAEs. Distinguishing immune-induced pneumonitis from progression, pseudo progression, hyper progression, or other etiologies (COVID-19) can be particularly challenging in lung cancer due to the baseline vulnerable pulmonary function and thus requires caution and teamwork. We treat patients according to institutional and international guidelines and we only rechallenge them with ICIs after resolution of the AE and corticosteroid tapering.

Compared with classic Hashimoto's thyroiditis, chronic autoimmune serum-negative thyroiditis requires a lower substitution dose of L-thyroxine to correct hypothyroidism.

PURPOSE: Serum-negative-chronic-autoimmune-thyroiditis (SN-CAT) is considered a milder variant of classic Hashimoto's thyroiditis (CHT). However, its prevalence remains unknown and it is still unclear whether SN-CAT behaves differently in terms of L-thyroxine (LT4) substitution treatment of hypothyroidism. Aims of this study were to estimate the prevalence of SN-CAT in a large series of hypothyroid patients and to compare LT4 requirements in hypothyroid patients with SN-CAT and CHT. METHODS: Five-hundred-eighty-one consecutive patients with primary-autoimmune-hypothyroidism were enrolled in a cross-sectional study. LT4 requirements and thyroid-volume changes were longitudinally evaluated in 49 hypothyroid patients with SN-CAT and in 98 sex and age-matched hypothyroid patients with CHT. RESULTS: In our series the prevalence of SN-CAT was 20.8%. At diagnosis, patients in the CHT and SN-CAT groups had similar male/female ratio, age and BMI, while serum TSH and thyroid-volume were significantly greater in the CHT group. In the longitudinal study, during a follow-up of 8.9 ± 4.6 years, 8 out of 49 (16.3%) SN-CAT patients developed positive tests for of circulating TPO-Ab and/or Tg-Ab. Thyroid-volume significantly decreased in CHT patients, but not in those with SN-CAT. The maximum daily substitution dose of LT4 was smaller in SN-CAT patients as compared with the CHT ones. Multivariate analysis showed that age, BMI, basal TSH and thyroid antibody status independently and significantly predicted the maximum daily substitution dose of LT4. CONCLUSIONS: SN-CAT accounts for a significant proportion of patients with autoimmune hypothyroidism. Compared with hypothyroid patients diagnosed with CHT, the SN-CAT ones require smaller doses of LT4 to correct their hypothyroidism.

Continued administration of pembrolizumab for adenocarcinoma of the lung after the onset of fulminant type 1 diabetes mellitus as an immune-related adverse effect: A case report.

A 61-year-old woman with stage IVA lung adenocarcinoma exhibited high PD-L1 expression. Pembrolizumab was administered as second-line therapy. She developed destructive thyroiditis and her thyroid function started to decline during the administration of three to five courses. She was subsequently diagnosed with fulminant type 1 diabetes mellitus and ketoacidosis during the eighth course and insulin treatment was initiated. Pembrolizumab remained effective and was continued for 21 courses, even after the onset of diabetes mellitus. Immune-checkpoint inhibitor treatment can be continued with hormone replacement even after the development of type 1 diabetes mellitus as an immune-related adverse event.

Management of toxicities of immune checkpoint inhibitors.

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Association of tuberculous thyroiditis and papillary carcinoma of the thyroid: a rare coincidence.

We report the case of a 25 year-old patient with no medical history, admitted to our unit for nodular goiter of the right lobe without clinical or laboratory signs of hyperthyroidism. We carried out a right lobo-isthmectomy revealing the association of tuberculosis and thyroid papillary carcinoma. A left lobectomy has, therefore, been performed in a second stage. The patient underwent a six-month antituberculosis treatment with a good clinical outcome. We discuss this rare association and its best diagnostic and therapeutic support, with a review of the literature.

Tyrosine kinase inhibitors induced thyroid dysfunction: a review of its incidence, pathophysiology, clinical relevance, and treatment.

Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST), a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.

[Adult male with tubulointerstitial nephritis and uveitis syndrome complicated with thyroiditis].

Renal dysfunction was detected by routine medical examination in a 46-year-old man (blood urea nitrogen : 26 mg/dL, creatinine : 2.4 mg/dL and moderate proteinuria). A few weeks later, he visited a local ophthalmologist complaining of left eye pain and red eye. He was diagnosed as left uveitis, prescribed eye-drops and referred to our hospital for further examination. At the first visit, test results pointed to renal dysfunction and a high level of thyroid hormones (creatinine : 1.8 mg/dL, free T3 : 7.41 microg/mL, free T4 : 3.18 ng/dL, thyroid stimulating hormone : 0.010micro IU/mL). Gallium scintigraphy showed an increased uptake of the tracer in bilateral thyroid glands, parotid glands and kidneys. No autoantibodies to thyroid gland were detected. Ultrasonography of the thyroid gland revealed no abnormal findings. Renal biopsy showed interstitial nephritis with minor glomerular abnormalities except for a few sclerotic changes. As no improvement was observed after stopping all drugs, and no disease causing uveitis was detected, he was diagnosed as tubulointerstitial nephritis and uveitis syndrome (TINU syndrome). After oral glucocorticoid was prescribed (prednisolone 15 mg/day), both renal function and thyroid abnormalities were normalized gradually. TINU syndrome with hyperthyroidism is rare. Although the precise etiology is not known, the same mechanism might occur in the thyroid gland as in TINU syndrome where abnormal cellular immunity, especially in helper T cell is said to play a role. In conclusion, in cases of TINU syndrome, systemic investigation, including the thyroid gland should be mandatory.

Parathyroidectomy-induced thyroiditis.

OBJECTIVE: To highlight the possibility of development of thyroiditis after parathyroidectomy. METHODS: Clinical and laboratory findings in 2 cases are presented, and the relevant literature is reviewed. RESULTS: In 2 women (84 years old and 55 years old) with no history of thyroid disease in one of them and a remote history of excision of a follicular adenoma in the other, thyrotoxicosis developed a few days to a week after parathyroidectomy for primary hyperparathyroidism. The first patient underwent bilateral cervical exploration with removal of a right inferior parathyroid adenoma, whereas the second patient had excision of 3 1/2 parathyroid glands for 4-gland hyperplasia and 2 benign nodules from the left thyroid lobe. Both surgical procedures were uncomplicated. Neither patient had received any iodinated contrast agents or medications such as lithium or amiodarone before presentation. Laboratory results showed elevated levels of free thyroxine, suppressed thyroid-stimulating hormone levels, very low radioiodine uptake (in the second patient), and an elevated thyroglobulin level (in the first patient). Both patients were treated symptomatically with beta-adrenergic antagonists. Thyroid function normalized and symptoms diminished after 1 to 2 months. CONCLUSION: Parathyroidectomy-induced thyroiditis is underrecognized. The majority of patients are asymptomatic, although clinically significant thyrotoxicosis can also occur. Candidates for parathyroidectomy should be informed of this potential complication, and thyroid function should be assessed if clinically indicated.

Combined mycophenolate mofetil and prednisone therapy in tamoxifen- and prednisone-resistant Reidel's thyroiditis.

BACKGROUND: Mycophenolate mofetil is a recently identified therapy for disorders associated with systemic fibrosis, but has never been reported in the treatment of Reidel's thyroiditis. We report the first case of Reidel's thyroiditis that became resectable after treatment with mycophenolate and prednisone. SUMMARY: A 27-year-old woman presented to an outside hospital with thyromegaly associated with compressive symptoms. The patient underwent a neck exploration with thyroid biopsy that revealed evidence of fibrosing variant Hashimoto's thyroiditis. The patient was then treated with tamoxifen and prednisone at an outside hospital without resolution. After initial evaluation she underwent an open thyroid wedge biopsy that revealed Reidel's thyroiditis. She was subsequently treated with both 1 g mycophenolate twice daily and 100 mg prednisone daily. The patient experienced immediate subjective improvement of compressive symptoms and objective decrease in mass size at 30 days, as seen by serial computed tomography examination. By 90 days of therapy the mass had decreased to a size small enough to allow subtotal thyroidectomy, which was completed over two staged procedures. CONCLUSIONS: Reidel's thyroiditis remains a primarily surgical disease. Patients who are not surgical candidates have been treated with tamoxifen and prednisone with equivocal results. Our report is the first to suggest the combination of mycophenolate and prednisone as a viable treatment option for patients with Reidel's thyroiditis.

Does unilateral lobectomy suffice to manage unilateral nontoxic goiter?

OBJECTIVE: To evaluate the effectiveness of ipsilateral lobectomy to treat unilateral, nontoxic, benign nodular goiter and to define predictive factors for recurrence. METHODS: Patients undergoing thyroid lobectomy for unilateral, nontoxic, benign nodular goiter between 2002 and 2007 were included. Patients were excluded if coincidental thyroid cancer was detected at histopathologic examination and completion thyroidectomy was performed. Potential predictors of recurrence including age; sex; family history; preoperative volume of the thyroid gland; preoperative number, size, and ultrasonography characteristics of the nodules; duration of postoperative follow-up; postoperative use of thyroxine; and histopathologic diagnoses were recorded at baseline. Follow-up visits were scheduled every 3 months during the first year and every 6 months thereafter. Recurrent disease was defined as a hypoechogenic or hyperechogenic nodule larger than or equal to 3 mm detected in the remaining contralateral lobe during ultrasonography. Patients with a thyrotropin value greater than 5 mIU/L received thyroxine. Fine-needle aspiration biopsy was performed for nodules greater than 10 mm or for nodules with characteristics suggestive of malignancy. Reoperation was indicated if a nodule was greater than 3 cm in diameter, posed a risk of malignancy, or caused compression signs or symptoms. RESULTS: A total of 104 patients were included. Histopathologic diagnoses at initial operation were adenoma in 45 patients, colloidal nodular goiter in 45 patients, and chronic lymphocytic thyroiditis in 14 patients. Average duration of follow-up was 39.75 +/- 21.75 months (range, 5-87 months). Recurrence was seen in 63 patients (60.6%). Histopathologic characteristics of the lobectomy material (P<.001), preoperative volume of the thyroid gland (P<.006), and multinodularity (P<.011) were significant predictors of recurrence. CONCLUSIONS: Higher preoperative thyroid volume, histopathologic characteristics of nodules, and multinodular disease are associated with an increased risk of recurrence in patients with unilateral nodular goiter. Unilateral lobectomy is an effective therapeutic option with low reoperation rates in unilateral benign thyroid disease.

Interferon induced thyroiditis.

Interferon-alpha (IFNalpha) is used for the treatment of various disorders, most notable chronic hepatitis C virus (HCV) infection. One of the commonest side effects of IFNalpha therapy is thyroiditis, with up to 40% of HCV patients on IFNalpha developing clinical or subclinical disease. In some cases interferon induced thyroiditis (IIT) may result in severe symptomatology necessitating discontinuation of therapy. IIT can manifest as clinical autoimmune thyroiditis, presenting with symptoms of classical Hashimoto's thyroiditis or Graves' disease, or as non-autoimmune thyroiditis. Non-autoimmune thyroiditis can manifest as destructive thyroiditis, with early thyrotoxicosis and later hypothyroidism, or as non-autoimmune hypothyroidism. While the epidemiology and clinical presentation of IIT have been well characterized the mechanisms causing IIT are still poorly understood. It is likely that the hepatitis C virus (HCV) itself plays a role in the disease, as the association between HCV infection and thyroiditis is well established. It is believed that IFNalpha induces thyroiditis by both immune stimulatory effects and by direct effects on the thyroid. Early detection and therapy of this condition are important in order to avoid complications of thyroid disease such as cardiac arrhythmias.

An uncommon endocrine cause of pyrexia of unknown origin.

We report a previously healthy 43 yr old male who presented with prolonged fever, weight loss and neck pain for 3 weeks. Even after extensive work up for the possible causes of pyrexia, the cause remained elusive. In view of persistent tachycardia and neck pain, possibility of subacute thyroiditis was suspected. Thyroid function test (TFT) revealed thyrotoxicosis, which on further evaluation was found to be secondary to DeQuervains thyroiditis. He was treated with NSAIDs, beta-blockers and steroids. He improved rapidly but went on to develop hypothyroidism on follow-up and required levothyroxine replacement.

Tireoidite / Thyroiditis

As tireoidites são doenças inflamatórias da tireóide. Consistem um grupo variado de patologias correlacionadas que apresentam, ao mesmo tempo,características comuns e diferenças importantes.Este artigo tem como proposta fazer uma breve revisão sobre as principais tireoidites, apresentando sua classificação, suas manifestações clínicas e laboratoriais e o tratamento de cada subgrupo.