Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Medical treatment of thyrotoxicosis.

Medical treatment is the primary therapeutic option for thyrotoxicosis/hyperthyroidism. Two groups of causes of thyrotoxicosis (i.e. thyrotoxicosis with hyperthyroidism and thyrotoxicosis without hyperthyroidism) need to be considered for therapeutic reasons. Herein we provide an updated review on the role of conventional medical therapies (i.e. ß-blockers, antithyroid drugs [ATDs], corticosteroids, inorganic iodide, perchlorate, cholecystographic agents, lithium, cholestyramine) in the main causes of thyrotoxicosis, starting from the rationale subtending their clinical application.

Interplay Between Thyroid Hormone Status and Pulmonary Hypertension in Graves' Disease: Relevance of the Assessment in Thyrotoxic and Euthyroid Patients.

Background: Graves' disease (GD) is the most common cause of hyperthyroidism and can cause cardiac changes, such as pulmonary hypertension. Methods: This is a prospective study in which we obtained demographic, clinical, laboratory data and characteristics of the GD, in addition to investigating cardiorespiratory function, focusing on the detection of pulmonary hypertension. Patients were separated into two groups: thyrotoxicosis and euthyroidism. Ninety patients with GD of both sexes, over 18 years of age, were included. The cardiorespiratory assessment included an echocardiographic evaluation, a questionnaire of specific symptoms, spirometry and a six-minute walk test. Results: The hyperthyroid group included 42 patients (47.73%) and the euthyroid group 46 patients (52.27%); 78 were women (86.67%). The prevalence of pulmonary hypertension between the hyperthyroidism (48.57%) and the euthyroidism (29.41%) groups was not different. Free thyroxine levels (FT4) (OR 1.266), higher left atrium volume (OR 1.113) and right ventricle diameter were associated with pulmonary hypertension. A direct correlation between FT4 with forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), as also an inverse correlation between initial oxygen saturation (SpO2) with diagnostic time and drop SpO2 with the ratio between the diastolic velocity E of the mitral flow and the diastolic velocity of the mitral ring (E/e') were observed in the euthyroid group. An inverse correlation between FT4 levels with walked distance as % of predicted value, and a direct correlation between E/e' ratio and walked distance as % of predicted value were observed in the hyperthyroid group. Conclusion: We emphasize the importance of a cardiorespiratory reassessment in GD, even after a long-term control of the thyrotoxic state, as we demonstrate that about 30% of these patients remain with PH and are subject to specific treatment.

Thyroid disorders and SARS-CoV-2 infection: From pathophysiological mechanism to patient management.

The World Health Organization (WHO) declared the COVID-19 epidemic to be a global pandemic in March 2020. COVID-19 is an infection caused by SARS-CoV-2, a coronavirus that utilizes the angiotensin-2 converting enzyme to penetrate thyroid and pituitary cells, and may result in a "cytokine storm". Based on the pathophysiological involvement of the pituitary-thyroid axis, the current review discusses the diagnosis of abnormal thyroid function test, and the management of patients presenting with thyrotoxicosis, thyroid-associated orbitopathy and hypothyroidism in the context of SARS-CoV-2 infection.

A pregnant woman with an autonomously functioning thyroid nodule: a case report.

BACKGROUND: The epidemiology and natural history of autonomously functioning thyroid nodules (AFTNs) have not been elucidated. Here we report the pregnant Japanese woman with an AFTN. CASE PRESENTATION: The patient was a 31-year-old woman who was hospitalized due to the placenta previa associated with threatened abortion at the 16 weeks of her third pregnancy. At her second pregnancy, she was euthyroid but had a single, 2.3 cm nodule on her right thyroid lobe. Her thyroid hormone level was trended increased with her pregnancy progression, and the thyrotoxic state was remained after delivery. Before her third pregnancy, her hyper-vascular nodule enlarged to 3.4 cm at regular monitoring. When she visited our hospital, she was at 16 weeks of pregnancy and had thyrotoxicosis with negative TSH-receptor antibody. She delivered a baby weighing 2615 g without hypothyroidism at 39 weeks of pregnancy by natural delivery. After delivery, a 99mTc scintigram showed a hot spot in her right thyroid lobe. She was diagnosed with AFTN and treated with methimazole while nursing. CONCLUSIONS: This case showed that hCG stimulation during pregnancy caused thyroid nodule enlargement and enhanced thyroid hormone production. The pregnancy could be the pathological stimulus and provides chance to diagnosis for AFTNs.

Pitfalls in the assessment of gestational transient thyrotoxicosis.

Gestational transient thyrotoxicosis (GTT) is associated with direct stimulation of the maternal thyroid gland by human chorionic gonadotropin (hCG). It is characterized by slightly higher thyroid hormone and lower thyroid-stimulating hormone (TSH) levels in early pregnancy and mild or no symptoms. While GTT must be distinguished from Graves' disease (GD), which is associated with maternal and fetal complications, treated GD and new-onset GD in pregnancy are occasionally challenging to distinguish. Evaluating serum hCG levels and TSH receptor antibody (TRAb) titers can help, but the results are not irrefutable due to pregnancy-related immunosuppression. Moreover, GTT can follow unusual clinical courses in relation to some pregnancy complications. Excessive hCG production can cause severe GTT symptoms in patients with hyperemesis gravidarum, trophoblastic disease, or multiple pregnancies. Thyrotoxicosis can emerge beyond the second trimester in patients with gestational diabetes mellitus and mirror syndrome, because of delayed elevations in the hCG levels. Detailed knowledge about GTT is necessary for correct diagnoses and its appropriate management. This review focuses on the diagnosis of GTT, and, particularly, its differentiation from GD, and unusual clinical conditions associated with GTT that require comprehensive management.

Hyperthyroxinemia with a non-suppressed TSH: how to confidently reach a diagnosis in this clinical conundrum.

Disorders of thyroid function are among the commonest referrals to endocrinology. While interpretation of thyroid function testing is usually straightforward, accurate interpretation becomes significantly more challenging when the parameters do not behave as would be expected in normal negative feedback. In such cases, uncertainty regarding further investigation and management arises. An important abnormal pattern encountered in clinical practice is that of high normal or raised free thyroxine (fT4) with inappropriately non-suppressed or elevated thyroid-stimulating hormone (TSH). In this short review using two clinical vignettes, we examine the diagnostic approach in such cases. A diagnostic algorithm is proposed to ensure that a definitive diagnosis is reached in these challenging cases.

Thyrotoxic periodic paralysis: A retrospective, observational study from India.

Background & objectives: Thyrotoxic periodic paralysis (TPP) is an endocrine emergency presenting with acute-onset flaccid paralysis in a patient having thyrotoxicosis accompanied by hypokalaemia. This study was conducted to evaluate the clinical profile of patients with TPP presenting to three centres in India. Methods: This retrospective, observational study was conducted at three tertiary care Armed Forces medical centres, located at Lucknow, Kolkata and Delhi. The history, clinical features, treatment details and outcomes were evaluated. Results: Of the 244 patients with thyrotoxicosis, 15 were diagnosed with TPP and included in the study. These 15 patients (14 male and 1 female) had 32 episodes of TPP which were analyzed. The mean age was 30.2±6.2 yr (range: 21-39), and overt thyrotoxicosis was seen in all patients except one who had subclinical hyperthyroidism. Graves' disease was the most common cause of thyrotoxicosis (13/15) and the remaining two patients had subacute thyroiditis and gestational thyrotoxicosis. Hypokalaemia (serum potassium <3.5 mmol/l) was seen in 12 patients, and the mean serum potassium was 3.2±0.9 mmol/l (range: 2.1-4.9). All patients had flaccid weakness, predominantly involving the lower limb with no bulbar, respiratory or cranial nerve involvement. The average duration of paralysis was 10.6±5.7 h (range: 3-28 h). Interpretation & conclusions: Our study demonstrated an early age of presentation and presence of clinical and biochemical thyrotoxicosis in majority of patients with TPP. Hypokalaemia may not always be evident in patients with TPP.

The Influence of Thyroid Hormones on Brain Structure and Function in Humans.

The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action.

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.

Thyroid detectives: on the trail of Munchausen's syndrome.

Thyrotoxicosis factitia, a disorder frequently seen in young or middle-aged women with psychological disorders, most commonly results from surreptitious ingestion of excess thyroid hormones. In most patients, diagnosis is relatively straightforward and depends on the demonstration of biochemical thyrotoxicosis, suppressed endogenous thyroid function and absence of clinical features of underlying thyroid disease. However, at times, confounding factors can make the diagnosis particularly challenging and necessitate the investigating physician to don the detective's cap to get to the root of the problem. We discuss a patient whose diagnosis was reached with ingenuity after considerable effort from four endocrinologists having a total experience of 37 years in their field.

The Delayed Diagnosis of Thyroid Storm in Patients with Psychosis.

We herein report two cases of patients with thyroid storm with a delayed diagnosis due to psychosis. The patients were a 63-year-old woman with bipolar II disorder and a 37-year-old man with major depressive disorder. The psychoses in both patients were well controlled with medication. Although they both showed symptoms of thyrotoxicosis, the symptoms were ignored, presumably because the psychological manifestations of worsening of psychosis and thyroid storm are similar. When the mental or physical state of patients with psychosis changes, thyroid hormone levels should be measured for early treatment.

Aberrant intra and inter network resting state functional connectivity in thyrotoxicosis.

Thyroid hormones epigenetically play an important role in the regularisation of neural networks and in neural differentiation during brain development. The present study aimed to explore the intra and inter network resting state functional connectivity changes underlying the neurobehavioural symptoms in thyrotoxicosis. To understand the pathophysiological changes, we investigated the correlation between functional connectivity and clinical and behavioural measures. Twenty-eight freshly diagnosed thyrotoxicosis patients suffering with symptoms such as palpitation, loss of weight, trembling and heat intolerance from days to weeks and 28 healthy controls were recruited for the study. Thyrotoxicosis patients showed significantly decreased functional connectivity in sensorimotor network, fronto-temporal network, default mode network, right fronto-parietal network, left fronto-parietal network and salience network. Inter network functional connectivity was significantly reduced between the basal ganglia network and sensorimotor network and increased between the salience network and fronto-temporal network in thyrotoxicosis. Cognitive functions such as visual retention, recognition of objects, mental balance and performance on neuropsychological tests (ie, the Bender Gestalt test, Nahar-Benson test and Mini Mental State Examination) also showed significant decline in thyrotoxicosis patients. The altered intrinsic resting state functional connectivity might underlie these cognitive deficits. The increased functional connectivity between the salience network and fronto-temporal network suggests the recruitment of additional neuronal circuitry needed to compensate for the neuropathology in the primary neural network in thyrotoxicosis.

Thyrotoxic hypokalemic periodic paralysis: a life-threatening disorder in Asian men.

Thyrotoxicosis can present as a sporadic form of hypokalaemic periodic paralysis. The condition is associated with massive intracellular shift of potassium, mainly in skeletal muscles. As the total body stores of potassium remain normal, overzealous potassium supplementation targeting serum potassium level results in a poor outcome. We present a fatal case of thyrotoxic hypokalaemic periodic paralysis.

Investigational drugs in early stage clinical trials for thyrotoxicosis with hyperthyroidism.

INTRODUCTION: Thyrotoxicosis with hyperthyroidism is treated with these classical approaches (i) antithyroid drugs to blockade thyroid hormone release and normalize thyroid hormone production and (ii) destruction of the thyroid using radioiodine or surgical removal of the thyroid. The optimal medical therapy, especially for Graves´ disease, remains a subject of debate and there has been little progress in Graves' disease therapeutics over the last decade. AREAS COVERED: Novel treatments of thyrotoxicosis with hyperthyroidism. This includes (i) small molecules such as synthetic thyroid hormone receptor antagonists and environmental molecules and (ii) molecules with interaction between thyroid stimulating hormone (TSH) receptor and TSH receptor antibodies such as M22, ANTAG3, org274179-0, 5C9, and K1-70. Other approaches to Graves´ disease treatment includes immunosuppressive treatment, glucocorticosteroids, rituximab, and intrathyroid injection of dexamethasone. Optimal iodine and selenium supplementation can also be considered. EXPERT OPINION: Clinical trials results suggest that novel thyroid treatments involving small molecule therapy, may predict a good future in Graves' disease treatment; however, a greater understanding of these antagonists is needed. Other treatments comprising immunosuppressives have demonstrated a significant reduction of relapse of the disease, but are not recommended by international guidelines.

Acute Right Ventricular Heart Failure: An Uncommon Case of Thyrotoxicosis.

Right ventricular failure can be secondary to right ventricular ischemia, pulmonary or tricuspid valvular disease, myocardial shunts, cardiomyopathy, acute and chronic pulmonary hypertension, myocarditis and pericardial disease and it generally carries a poor prognosis. Thyrotoxicosis is a clinical state resulting from high thyroid hormone action in tissues generally due to high thyroid hormone levels. The association between severe hyperthyroidism and high-output heart failure is well-known. Less widespread is the concept that hyperthyroid patients, irrespective of coexisting diseases and through mechanisms not fully elucidated, are at higher risk for pulmonary hypertension and right heart failure, both reversible with the achievement of euthyroidism and associated with a good prognosis. We describe the case of a 44-year-old woman with right ventricular failure and moderate pulmonary hypertension in the setting of thyrotoxicosis, which resolved rapidly after antithyroid treatment. The potential mechanisms underlying this condition will also be discussed.

Changing Management Guidelines in Thyrotoxic Hypokalemic Periodic Paralysis.

BACKGROUND: Periodic paralysis is a rare complication of hyperthyroidism. Patients of East Asian descent are most commonly affected. Presentation is characterized by recurrent episodes of painless, abrupt-onset weakness, with laboratory evaluation characterized by profound hypokalemia. Underlying hyperthyroidism may not be clinically evident, but differentiation from the familial variant is critical due to differing treatment pathways. CASE REPORT: We describe the presentation of a 22-year-old man with recurrent relapsing-remitting weakness with undiagnosed hyperthyroidism. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In patients with acute-onset paralysis with significant hypokalemia, or relapsing-remitting symptoms, hyperthyroidism should be suspected. Obese patients are at an especially increased risk due to underlying insulin resistance, which enhances basal sodium-potassium ATPase function. Hypokalemia is functional in nature. Nonselective ß-blockers (such as propranolol) should be considered first line, as they simultaneously decrease ATPase activity, limit insulin secretion, and address the underlying disorder. Administration of > 50 mEq of exogenous potassium places patients at risk of dysrhythmias from rebound hyperkalemia.

TSH-receptor antibodies may prevent bone loss in pre- and postmenopausal women with Graves' disease and Graves' orbitopathy.

OBJECTIVE: Thyrotoxicosis is established risk factor for osteoporosis due to increased bone turnover. Glucocorticoids often administered for Graves' orbitopathy (GO) have additional negative effect on bone mineral density (BMD). Our aim was to examine the influence of thyroid hormones, TSH, TSH-receptor antibodies (TRAb) and glucocorticoid treatment on bone in women with Graves' thyrotoxicosis and Graves' orbitopathy (GO). SUBJECTS AND METHODS: Forty seven women with Graves' disease, mean age 55.6 ± 12.8 (23 women with thyrotoxicosis and 24 hyperthyroid with concomitant GO and glucocorticoid therapy) and 40 age-matched healthy female controls were enrolled in the study. We analyzed clinical features, TSH, FT4, FT3, TRAb, TPO antibodies. BMD of lumbar spine and hip was measured by DEXA and 10-year fracture risk was calculated with FRAX tool. RESULTS: The study showed significantly lower spine and femoral BMD (g/cm2) in patients with and without GO compared to controls, as well as significantly higher fracture risk. Comparison between hyperthyroid patients without and with orbitopathy found out significantly lower spine BMD in the first group (p = 0.0049). Negative correlations between FT3 and femoral neck BMD (p = 0.0001), between FT4 and BMD (p = 0.049) and positive between TSH and BMD (p = 0.0001), TRAb and BMD (p = 0.026) were observed. Fracture risk for major fractures and TRAb were negatively associated (p = 0.05). We found negative correlation of BMD to duration of thyrotoxicosis and cumulative steroid dose. CONCLUSIONS: Our results confirm the negative effect of hyperthyroid status on BMD. TRAb, often in high titers in patients with GO, may have protective role for the bone, but further research is needed.

Amiodarone-Induced Thyroid Dysfunction: A Clinical Update.

Amiodarone is one of the most commonly prescribed antiarrhythmic agents in clinical practice owing to its efficacy, even with high toxicity profile. The high iodine content and the prolonged biological half-life of the drug can result in thyroid dysfunction in a high proportion of patients treated with amiodarone even after cessation of amiodarone. Both hypothyroidism and hyperthyroidism are common side effects that mandate regular monitoring of patients with thyroid function tests. Amiodarone-induced hypothyroidism (AIH) is diagnosed and managed in the same way as a usual case of hypothyroidism. However, differential diagnosis and clinical management of amiodarone-induced thyrotoxicosis (AIT) subtypes can be challenging. With the aid of a case snippet, we update the current evidence for the diagnostic work up and management of patients with amiodarone-induced thyroid dysfunction in this article.

Management of thyrotoxicosis in children and adolescents: 35 years' experience in 304 patients.

BACKGROUND: Diffuse toxic goiter accounts for about 15% of all childhood thyroid diseases. There is great controversy over the management of Graves' disease in children and adolescents. This article reports our experience in 304 children and juvenile patients with Graves' disease. METHODS: Between 1981 and 2015, 304 patients aged 5-19 years with diffuse toxic goiter were studied, of whom 296 patients were treated with antithyroid drugs (ATD) for 18 months. Patients with persistent or relapsed hyperthyroidism who refused ablative therapy with surgery or radioiodine were managed with continuous methimazole (MMI) treatment. RESULTS: In 304 patients (245 females and 59 males), the mean age was 15.6±2.6 years. After 18 months of ATD therapy, 37 remained in remission and of the 128 who relapsed, two, 29 and 97 patients chose surgery, continuous ATD and radioiodine therapy, respectively. Of the 136 patients who received radioiodine, 66.2% became hypothyroid. Twenty-nine patients received continuous ATD therapy for 5.7±2.4 years. The mean MMI dose was 4.6±12 mg daily, no serious complications occurred and all of them remained euthyroid during the follow-up. Less abnormal thyroid-stimulating hormone (TSH) values were observed in these patients, as compared to patients who were on a maintenance dose of levothyroxine after radioiodine induced hypothyroidism. CONCLUSIONS: Original treatment with ATD and subsequent radioiodine therapy remain the mainstay of treatment for juvenile hyperthyroidism. Continuous ATD administration may be considered as another treatment modality for hyperthyroidism.