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.

Short review: novel concepts in the approach to patients with amiodarone-induced thyrotoxicosis.

INTRODUCTION: Amiodarone-induced thyrotoxicosis is associated with high morbidity and mortality rates. The approach to this condition is widely variable across different medical specialists and even among expert endocrinologists. As a matter of fact, the approach to amiodarone-induced thyrotoxicosis has always been considered difficult, due to diagnostic uncertainties easily resulting in missteps, and therapeutic challenges easily resulting in unresponsiveness or slow-responsiveness to the administered drugs. PURPOSE: Our purpose is to review novelties emerged during the last years about this condition, with the aim to provide novel insights on the diagnostic and therapeutic management of this challenging condition.

Enhanced Differentiation of Amiodarone-Induced Thyrotoxicosis Types Using Semi-Quantitative 99mTc-MIBI Uptake Analysis: A Pilot Study.

BACKGROUND Technetium (99mTc)-labelled Methoxy-2-Isobutylisonitrile (MIBI) is a diagnostic lipophilic cationic radiotracer used to evaluate the cardiac, breast, thyroid, and parathyroid pathology. This study aimed to evaluate the role of MIBI combined with Tc-99m pertechnetate thyroid scintigraphy, thyroid ultrasonography, and measurement of thyrotropin, thyroid hormones, and autoantibodies to subtype amiodarone-induced thyrotoxicosis (AIT) and the contribution of semi-quantitative analysis of MIBI uptake. MATERIAL AND METHODS This cross-sectional study included 36 patients with AIT who underwent thyrotropin, thyroid hormone, and autoantibody analysis using chemiluminescent method, ultrasonography, pertechnetate, and MIBI thyroid scintigraphy with semi-quantitative uptake, including calculation of the target-to-background ratio (TBR) with 2 different background regions. The MIBI washout rate (WR) was analyzed in all groups. Statistical analysis was performed using descriptive statistics, correlations, and the receiver operating characteristic curve - area under the curve (ROC-AUC). The results were compared with the control group. RESULTS Based on visual and semi-quantitative analyses, patients were successfully categorized into AIT groups (AIT-1, AIT-2 and AIT-3) but the latter method enabled better differentiation of MIBI uptake between all groups. Additionally, ROC-AUC analysis determined cutoff values which enabled discerning between AIT-1 and AIT-2 groups, and AIT-1 and AIT-3 groups. WR showed no significant difference between all AIT groups and controls (P>0.05). CONCLUSIONS Visual MIBI analysis enabled differentiation between AIT-1 and 2 groups, but the method was substantially improved with semi-quantitative analysis, especially in defining AIT-3 group. However, multicenter collaboration with larger studies is needed to standardize the method and obtain more accurate and consistent results.

Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade.

Anti-thyroglobulin antibodies (TgAb) and/or anti-thyroid peroxidase antibodies (TPOAb) positivity at baseline is a risk marker for thyroid immune-related adverse events (thyroid-irAEs) in anti-programmed cell death-1 antibody (PD-1-Ab) treatment; however, it is unknown if TgAb and TPOAb titers are associated with clinical characteristics of thyroid-irAEs. Among 586 patients treated with PD-1-Ab at Nagoya University Hospital between 2 November 2015 and 30 September 2021, 57 patients developed thyroid-irAEs (thyrotoxicosis [n = 38]; hypothyroidism without prior thyrotoxicosis {isolated hypothyroidism} [n = 19]) in whom thyroid function, and TgAb and TPOAb titers were determined at baseline and at the onset. The changes in TgAb (median, 54.8 vs. 0.2 IU/mL; p = 0.002) and TPOAb titers (31.6 vs. 0 IU/mL; p = 0.032) from baseline to onset of developing thyroid-irAEs were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism. Higher TgAb and TPOAb titers, and the TgAb titer at baseline were associated with an earlier onset of thyrotoxicosis and higher peak free thyroxine levels, respectively. Twenty-eight patients who developed hypothyroidism after thyrotoxicosis had higher TgAb (54.5 vs. 10.7 IU/mL; p = 0.011) and TPOAb titers at baseline (46.1 vs. 9.0 IU/mL; p < 0.001) and greater changes in TgAb (61.7 vs. 7.8 IU/mL; p = 0.025) and TPOAb titers (52.8 vs. -0.8 IU/mL; p < 0.001) than patients who did not develop hypothyroidism. The TgAb titer at baseline and changes in the TgAb and TPOAb titers were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism, suggesting that the magnitude of the thyroid autoimmune response reflects the clinical types of thyroid-irAEs.

Effects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism.

The increasing knowledge of the molecular mechanisms in the cell signaling pathways of malignant cells, has recently led to the discovery of several tyrosine kinases (TKs), mainly TK receptors (TKR), which play a major role in the pathogenesis of many types of cancer. These receptors, physiologically involved in cell growth and angiogenesis, may harbor mutations or be overexpressed in malignant cells, and represent a target for anticancer therapy. Indeed, several therapeutic agents targeting specific altered pathways such as RET, BRAF, RAS, EGFR and VEGFR, have been identified. Tyrosine kinase inhibitors (TKIs) affect TK dependent oncogenic pathways by competing with ATP binding sites of the TK domain, thus blocking the activity of the enzyme, and thereby inhibiting the growth and spread of several cancers. Although the therapeutic action may be very effective, these molecules, due to their mechanism of multitargeted inhibition, may produce adverse events involving several biological systems. Both hypothyroidism and thyrotoxicosis have been reported during treatment with TKI, as well as an effect on the activity of enzymes involved in thyroid hormone metabolism. The pathogenic mechanisms leading to thyroid dysfunction and changes in serum thyroid function tests occurring in patients on TKI are reviewed and discussed in this manuscript.

Graves' disease after exposure to the SARS-CoV-2 vaccine: a case report and review of the literature.

BACKGROUND: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is characterized by immune system dysregulation after exposure to adjuvants, such as aluminum. Although cases of autoimmune thyroid diseases caused by ASIA have been reported, Graves' disease is one of the rarer diseases. There are some reports that vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause ASIA. Here, we describe a case of Graves' disease following SARS-CoV-2 vaccination and a review of the literature. CASE PRESENTATION: A 41-year-old woman was admitted to our hospital because of palpitations and fatigue. Two weeks after receiving the second SARS-CoV-2 vaccine (BNT162b2, Coronavirus Modified Uridine messenger RNA (mRNA) Vaccine, Pfizer), she developed fatigue and gradually worsened. On admission, she exhibited thyrotoxicosis (thyroid-stimulating hormone (TSH) < 0.01 mIU/L (0.08-0.54), free triiodothyronine (FT3) 33.2 pmol/L (3.8-6.3), and free thyroxine (FT4) 72.1 pmol/L (11.6-19.3)) and palpitations associated with atrial fibrillation. TSH receptor antibody (TRAb) was positive (TRAb 5.0 IU/L (< 2.0)), and 99mTc scintigraphy showed diffuse uptake in the thyroid gland, suggesting that the thyrotoxicosis in this case was caused by Graves' disease. Thiamazole was prescribed to correct her condition, and soon after this treatment was initiated, her symptoms and thyroid hormone levels were significantly reduced. CONCLUSIONS: This case report reinforces the potential correlation between ASIA affecting the thyroid and SARS-CoV-2 mRNA vaccines. The clinical course suggests that it is essential to consider the possibility of developing ASIA, such as Graves' disease, after exposure to the SARS-CoV-2 vaccine.

Therapeutic plasma exchange in hyperthyroidism prior to surgery.

PURPOSE: Therapeutic plasma exchange (TPE) is a treatment option to reduce thyroid hormones in the event of contraindication or unresponsiveness to antithyroid drugs (ATDs). METHODS: We analyzed 11 patients with hyperthyroidism who received TPE prior to surgery between January 2008 and December 2016 at our center. RESULTS: In total, 41 processes were applied to 11 patients with hyperthyroidism. The median age was 40 years, and 90.9% of the patients were female. Seven patients had Graves' disease, while four had a toxic multinodular goiter. The distribution of TPE indications comprised contraindication to ATDs (64%) and insufficient response to ATDs (36%). An adequate response was not obtained with TPE in two patients, and cholestyramine plus methimazole and Lugol solution were applied. The median number of TPE sessions was 3. During the TPE period, a ß-blocker was applied concurrently except in one patient who was contraindicated for the drug. The reduction in FT3 and FT4 hormones and the increase in TSH levels were statistically significant after TPE application (p values of 0.003, 0.033 and 0.008, respectively). Regarding adverse events of TPE application, an allergic reaction was seen in one patient, while prolongation of prothrombin time without any clinical findings was seen in another patient. Ten patients underwent total thyroidectomy, and one patient underwent a gynecological surgery procedure without any major complications. CONCLUSION: The American Society for Apheresis guideline, which is the most referenced guideline, mentions the utilization of TPE before thyroid surgery, only in patients with thyrotoxicosis despite the wider necessity of this treatment choice under the condition of uncontrolled hyperthyroidism prior to any kind of surgery. We concluded that TPE is a reliable and effective application in patients with hyperthyroidism before any surgical procedure, according to our study results.

Prediction-based prompt levothyroxine replacement to prevent a hypothyroid state after immune-related adverse events involving the thyroid gland.

Immune checkpoint inhibitors (ICIs) are used for various malignancies, although they frequently cause immune-related adverse events involving the thyroid gland (thyroid irAEs). We conducted a retrospective cohort study to elucidate thyroid function outcomes. Fifty of 639 patients who received PD-1 blockade therapy met criteria and were divided into the following groups: thyrotoxicosis with subsequent hypothyroidism (Toxic-Hypo, n = 21); thyrotoxicosis without subsequent hypothyroidism (Toxic, n = 9); and hypothyroidism without prior thyrotoxicosis (Hypo, n = 20). The Toxic-Hypo group developed thyroid irAEs earlier than the Toxic group (26 vs. 91 days; p < 0.001), and had higher serum free T4 levels (3.210 vs. 1.880 ng/dL; p = 0.011). In addition, positive anti-thyroglobulin antibodies (TgAbs) at thyroid irAE onset were more common in the Toxic-Hypo group (93.3%) than in the Toxic group (0.0%; p = 0.005) and Hypo group (44.4%; p = 0.007). The Toxic-Hypo group developed severe hypothyroidism and required larger levothyroxine (LT4) doses than the Hypo group (75 vs. 25 µg/day; p = 0.007). We predicted that patients with positive TgAbs who developed severe thyrotoxicosis within 4 weeks after the first ICI administration would develop subsequent hypothyroidism. We treated 4 such patients with prompt LT4 replacement, characterized by LT4 initiation after thyrotoxicosis improvement and quick dose titration. Their euthyroid state was successfully maintained, in contrast with patients receiving conventional replacement. In conclusion, rapid-onset severe thyrotoxicosis in patients with TgAbs correlated with a high likelihood of subsequent hypothyroidism. Accordingly, prompt LT4 replacement is suggested to prevent a severely hypothyroid state.

Delayed-onset immune-related adverse events involving the thyroid gland by immune checkpoint inhibitors in combination with chemotherapy: a case report and retrospective cohort study.

Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs) that often involve endocrine organs. Pembrolizumab and atezolizumab are currently administered in combination with chemotherapy for several malignancies. Although transient thyrotoxicosis within 6 weeks after the first ICI dose is the typical course of thyroid irAEs with ICI monotherapy, we encountered a unique course of a thyroid irAE in a patient who received combination therapy consisting of pembrolizumab plus pemetrexed and carboplatin. Delayed onset of thyrotoxicosis occurred at 22 weeks after the first dose of pembrolizumab. To understand more about this curious event, we conducted a retrospective cohort study of the following groups: pembrolizumab monotherapy (Pem-mono), pembrolizumab plus chemotherapy (Pem-combi), atezolizumab monotherapy (Atezo-mono), and atezolizumab plus chemotherapy (Atezo-combi). There were no differences in the incidence of overt thyroid irAEs: Pem-mono, 12 of 151 patients (7.9%) versus Pem-combi, 4 of 56 patients (7.1%) (p = 0.85) and Atezo-mono, 5 of 27 patients (18.5%) versus Atezo-combi, 5 of 57 patients (8.8%) (p = 0.20). Through detailed analyses of patients with thyrotoxicosis, we found some patients with delayed-onset thyroid irAE, defined as development at 16 weeks or more after the first ICI dose. Delayed-onset thyroid irAEs were only observed in the combination therapy groups: Pem-combi or Atezo-combi, 3 of 8 patients versus Pem-mono or Atezo-mono, 0 of 10 patients. Our observation that thyroid irAE development can be delayed with ICIs when used in combination with chemotherapy suggests longer monitoring of thyroid function is needed to avoid missing irAEs.

DUOX1 Gene Missense Mutation Confers Susceptibility on Type 2 Amiodarone-Induced Thyrotoxicosis.

Possible triggers and genetic markers involved in pathogenesis of amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) are currently unknown. This study aimed to analyze the association between polymorphisms in the genes involved in thyroid hormones biosynthesis and metabolism. Thirty-nine consecutive patients with confirmed type 2 amiodarone-induced thyrotoxicosis were enrolled; 39 patients on the same therapy for at least 6 months without thyroid pathology were included as a control group. A comparative study was carried out to determine the distribution and genotypes of polymorphic markers of the (Na)-iodide symporter (NIS) genes (rs7250346, C/G substitution), thyroid stimulating hormone receptor (TSHR) (rs1991517, C/G substitution), thyroid peroxidase (TPO) (rs 732609, A/C substitution), DUOX 1-1 (C/T substitution), DUOX 1-2 (G/T substitution), DUOX 1-3 (C/T substitution), glutathione peroxidase 3 (GPX3) (C/T substitution), glutathione peroxidase 4 (GPX4) (C/T substitution). Statistical analysis was performed using Prism (Version 9.0.0 (86)). This study showed that the risk of AIT2 is 3.18 times higher in the G/T of the DUOX1 gene carriers. This study is the first report of genetic markers associated with amiodarone-related adverse events conducted in humans. The obtained results indicate the necessity for a personalized approach to amiodarone administration.

Covid-induced thyroiditis.

Thyroiditis is one of the manifestations of novel Covid-19 virus. Thyroid function test (TFTs) shows typical features of hyperthyroidism. Inflammatory markers and thyroid scan give clue to the diagnosis. This report is about a 39-year-old female who presented with signs and symptoms of thyrotoxicosis along with pain in the neck, odynophagia, and intermittent fever after recovering from Covid-19 a few weeks back. She had no significant history of past medical or endocrine disease. TFTs revealed high T3 and T4 and low TSH. Thyroid scan revealed decrease uptake and ESR was 115. She was started on NSAID, steroids, and beta blocker. Four weeks later, she reverted with the resolution of symptoms and normal TFTs.

AMIODARONE AND THYROID DYSFUNCTION.

Thyroid gland has a key role in maintaining the body homeostasis. Thyroxine is the main hormone secreted from the thyroid gland, its effect being predominantly achieved after the intracellular conversion of thyroxine to triiodothyronine, which exhibits a higher affinity for the receptor complex, thus modifying gene expression of the target cells. Amiodarone is one of the most commonly used antiarrhythmics in the treatment of a broad spectrum of arrhythmias, usually tachyarrhythmias. Amiodarone contains a large proportion of iodine, which is, in addition to the intrinsic effect of the medication, the basis of the impact on thyroid function. It is believed that 15%-20% of patients treated with amiodarone develop some form of thyroid dysfunction. Amiodarone may cause amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). AIT is usually developed in the areas with too low uptake of iodine, while AIH is developed in the areas where there is a sufficient iodine uptake. Type 1 AIT is more common among patients with an underlying thyroid pathology, such as nodular goiter or Graves' (Basedow's) disease, while type 2 mostly develops in a previously healthy thyroid. AIH is more common in patients with previously diagnosed Hashimoto's thyroiditis. Combined types of the diseases have also been described. Patients treated with amiodarone should be monitored regularly, including laboratory testing and clinical examinations, to early detect any deviations in the functioning of the thyroid gland. Supplementary levothyroxine therapy is the basis of AIH treatment. In such cases, amiodarone therapy quite often need not be discontinued. Type 1 AIT is treated with thyrostatic agents, like any other type of thyrotoxicosis. If possible, the underlying amiodarone therapy should be discontinued. In contrast to type 1 AIT, the basic pathophysiological substrate of which is the increased synthesis and release of thyroid hormones, the basis of type 2 AIT is destructive thyroiditis caused by amiodarone, desethylamiodarone as its main metabolite, and an increased iodine uptake. Glucocorticoid therapy is the basis of treatment for this type of disease.

Two Cases of Thyrotoxicosis due to Redotex Ingestion, a Mexican Weight Loss Drug.

BACKGROUND: Redotex™ is a Mexican weight-loss supplement that is not U.S. Food and Drug Administration-approved. It consists of the following five ingredients: tri-iodothyronine 75 µg, atropine 0.36 mg, diazepam 8 mg, aloin 16 mg, and d-norpseudoephedrine 50 mg per tablet. There are few case reports with clinically severe ingestions. We report two cases of clinical thyrotoxicosis due to use of Redotex. CASE REPORTS: A 29-year-old woman presented to the emergency department (ED) with anxiety and palpitations. She reported taking Redotex daily for 1 week. Her temperature was 37.1°C, blood pressure (BP) was 166/104 mm Hg, and heart rate (HR) was 140 beats/min. Laboratory analysis was significant for a bicarbonate level of 20 mmol/L (reference 22-29 mmol/L), free T4 0.75 ng/dL (reference 0.93-1.70 ng/dL), and thyroid-stimulating hormone (TSH) 0.05 uIU/mL (reference 0.27-4.20 uIU/mL). She was treated with 2 mg i.v. lorazepam and 20 mg oral propranolol. A 37-year-old woman presented with chest pain, palpitations, and nausea after taking Redotex 1 to 2 tablets daily for 6 weeks. Her HR was 134 beats/min and BP was 130/66 mm Hg. Thyroid function tests on initial presentation showed a TSH of 0.013 uU/mL, free T4 of 0.24 ng/dL, and free T3 of >30 pg/mL. She was treated with propranolol 1 mg i.v. twice per day and 2 doses of lorazepam 1 mg. Both patients had resolution of their symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: When taken chronically and at recommended doses, Redotex can present with clinically significant T3 thyrotoxicosis. This has not been seen in prior reports.

Amiodarone-induced thyrotoxicosis. / Amiodaronindusert tyreotoksikose.

We see an increasing number of patients with amiodarone-induced thyrotoxicosis. This condition can be treated pharmacologically, but treatment over several months may give rise to adverse reactions. In most cases we recommend that amiodarone therapy be continued despite newly detected thyrotoxicosis. Particularly in cases of heart failure, one should not wait too long before considering thyroidectomy. Treatment of amiodarone-induced thyrotoxicosis must be delivered with close collaboration between endocrinologist and cardiologist.

[AMIODARONE-INDUCED THYROTOXICOSIS - RISK FACTORS AND PREDICTORS OF OUTCOME: A RETROSPECTIVE STUDY].

BACKGROUND: Amiodarone induced thyrotoxicosis (AIT) occurs with considerable incidence and is associated with significant morbidity and mortality. Factors that predict poor prognosis in this disease have not yet been sufficiently investigated. OBJECTIVES: We examined the characteristics and short-term clinical outcomes of patients with AIT (up to six months from diagnosis). We evaluated the relationship between T3 and T4 levels at time of presentation and complications associated with AIT. METHODS: A retrospective epidemiological study was conducted reviewing all cases diagnosed with thyrotoxicosis and amiodarone consumption of patients treated in the Carmel Medical Center between the years 2004-2008. We examined the characteristics of patients who tend to develop AIT. In addition, we examined whether T3 and T4 levels at the time of presentation were a predictor of a poor prognosis. Three major complications associated with AIT were defined as primary outcomes within six months of diagnosis: 1. mortality; 2. development of AIT-related complications that required hospitalization; 3. the need for thyroidectomy. RESULTS: A total of 400 patients were diagnosed with thyrotoxicosis and consumed amiodarone. However, only 39 patients met the definition of AIT. The composite outcome of mortality, AIT-related complications and thyroidectomy were found in the vast majority of patients (94.8%, 37 out of 39 participants); 3 (7.6%) died and 35 (89.7%) were hospitalized with AIT-related complications and 8 (20.5%) required thyroidectomy. We found a statistically significant relationship between high T4 levels (above 64.3 mcg/dL or above 3 times the upper limit of the norm) and the composite of two main endpoints: mortality and the need for thyroidectomy in the first half year of diagnosis (P=0.009). CONCLUSIONS: AIT is associated with significant morbidity and mortality. An elevated level of free T4 reflects the severity of AIT. In patients with significantly increased T4 values, an early surgical intervention should be considered.

Effect of high-dose intravenous glucocorticoid therapy on serum thyroid hormone concentrations in type 2 amiodarone-induced thyrotoxicosis: an exploratory study.

PURPOSE: Type 2 amiodarone-induced thyrotoxicosis (AIT2) is a form of drug-induced destructive thyroiditis, usually treated with oral glucocorticoids (oGCs). Our objective was to investigate the short-term effects of intravenous glucocorticoids (ivGCs) on serum thyroid hormone concentrations in patients with AIT2. METHODS: Exploratory study of three naive AIT2 patients treated with iv methylprednisolone (two pulses of 400 mg with no interpulse oGCs), followed by oGCs, matched 1:3 with AIT2 patients treated with oGCs alone. Changes in serum thyroid hormone concentrations were evaluated in the short-term period (24 h and 7 days) and after a cumulative dosage of 400 and 800 mg equivalents of methylprednisolone; in addition, healing time and duration of exposure to GCs were calculated. RESULTS: During the first 24 h of treatment, serum FT4 concentrations increased in ivGCs patients, and decreased in oGCs patients (+ 3.3% vs - 10.7%, respectively, p = 0.025). After 7 days, serum FT4 and FT3 concentrations decreased significantly in both groups, with no statistical difference between them (p = 0.439 for FT4 and p = 0.071 for FT3), even though the cumulative GCs dose was higher in ivGCs than in oGCs patients (800 mg vs 280 mg, p = 0.008). Furthermore, the iv administration of single 400 mg pulses of methylprednisolone resulted in a less significant decrease in serum thyroid hormone concentrations when compared to equivalent GCs doses fractionated in several consecutive days (p = 0.021 for FT4 and p = 0.052 for FT3). There were no significant differences in the healing time (p = 0.239) and duration of exposure to GCs (p = 0.099). CONCLUSIONS: High-dose ivGCs therapy does not offer advantages over standard oGCs therapy in the rapid, short-term control of AIT2.

Thyroid Dysfunction in Patients with Pulmonary Artery Hypertension (PAH): The Effect of Therapies Affecting the Prostanoid Pathway.

INTRODUCTION: Epoprostenol, a synthetic prostaglandin I2 (PGI2) analog, has been the mainstay of treatment for severe pulmonary arterial hypertension (PAH) for the last two decades. Treprostinil, another synthetic prostaglandin analog, and selexipag, an oral selective Inositol Phosphate (IP) prostacyclin receptor agonist, have also been approved for treatment of PAH. Prostacyclin and its analogs cause a variety of side effects in patients with PAH; however, thyroid dysfunction is rarely reported. METHODS: After treating an index case of thyroid dysfunction occurring after initiation of epoprostenol, we reviewed our databases of PAH patients treated with epoprostenol, treprostinil or selexipag to identify the occurrence of this association. RESULTS: We identified six cases of thyroid dysfunction in our cohort: five after initiation of an intravenous prostacyclin (epoprostenol) and one after initiation of an oral prostacyclin receptor agonist (selexipag). Four of the patients presented with hyperthyroidism and two with a large autoimmune goiter. Graves' disease was seen in three patients, Hashimoto's disease in two patients and thyrotoxicosis in one patient. CONCLUSION: Therapy with medications targeting the prostacyclin pathway is a potential risk factor for the development of symptomatic thyroid disease.

Lenvatinib-induced thyroid abnormalities in unresectable hepatocellular carcinoma.

Lenvatinib has anti-tumor activity against advanced hepatocellular carcinoma (HCC). Hypothyroidism is also a frequent complication in patients treated with lenvatinib. However, studies on lenvatinib-induced thyroid toxicity and destructive thyroiditis are limited. Therefore, this study aimed to clarify the frequency and timing of thyroid abnormalities in lenvatinib for unresectable HCC. This retrospective study enrolled 50 patients with advanced HCC treated with lenvatinib. Patients were classified to have euthyroid, subclinical hypothyroidism, overt hypothyroidism, and thyrotoxicosis. The timing of thyroid dysfunction was assessed, and risk factors for incident hypothyroidism or thyrotoxicosis were evaluated using multivariate models. Subclinical hypothyroidism, overt hypothyroidism, and thyrotoxicosis occurred in 7 (14.0%), 26 (52.0%), and 5 (10.0%) patients, respectively. In the 33 patients with hypothyroidism, 27 (84.4%) developed the condition within 2 weeks of starting lenvatinib treatment. Of the 5 patients with thyrotoxicosis, 3 developed the condition within 8 weeks of starting lenvatinib administration. One patient developed thyrotoxicosis in only 1 week of the initiation of treatment. No correlation between the presence of antibodies and the incidence and severity of thyroid dysfunction due to the autoimmune mechanism was observed. The progression-free survival was significantly better in the hypothyroidism group. Lenvatinib treatment for unresectable HCC not only causes hypothyroidism, but also thyrotoxicosis. Moreover, these thyroid conditions develop within the early period of treatment at a higher prevalence. Patients with thyroid dysfunction had better prognosis. Based on these results, in patients administered with lenvatinib, there is need for careful assessment for the possibility of thyroid dysfunction from the onset of treatment.

Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients.

Previous reports by us and other investigators showed that among athyreotic patients on levothyroxine (LT4) following total thyroidectomy patients with normal serum thyroid-stimulating hormone (TSH) levels had mildly low serum free triiodothyronine (FT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum FT3 levels and patients with strongly suppressed serum TSH had elevated serum FT3 levels. The objective of this study was to clarify which of these three patient groups are closer to their preoperative euthyroid condition based on reported subjective symptoms. We prospectively studied 148 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy. Symptoms reflecting thyroid function documented preoperatively and following 12 months of LT4 after thyroidectomy were compared. In 65 patients with strongly suppressed TSH levels significant changes in symptoms with tendencies towards thyrotoxicosis were seen with regards to heat and cold tolerance (p < 0.01), bowel movements (p < 0.05), and hand tremors (p < 0.05). In 33 patients with normal TSH levels, significant changes in symptoms with tendencies towards hypothyroidism were seen with regards to heat and cold tolerance (p < 0.05) and activity (p < 0.05). Lastly, in 50 patients with mildly suppressed TSH levels and FT3 levels equivalent to preoperative levels, all symptom items remained equivalent to their preoperative levels. Symptoms reflecting thyroid function in patients on LT4 following total thyroidectomy suggested that patients with mildly suppressed TSH levels were closest to a euthyroid status. These data provide useful findings regarding the management of patients following total thyroidectomy.