Fighting thyrotoxicosis with therapeutic plasma exchange: A case report.

Thyrotoxicosis is the clinical condition resulting from an excess of thyroid hormones for any reason. The main causes are Graves-Basedow disease, toxic multinodular goitre and toxic adenoma. The medical treatment to control thyroid function includes antithyroid drugs, beta blockers, iodine solutions, corticosteroids and cholestyramine. Although therapeutic plasma exchange is not generally part of the therapy, it is an alternative as a preliminary stage before the definitive treatment. This procedure makes it possible to eliminate T4, T3, TSI, cytokines and amiodarone. In most cases, more than one cycle is necessary, either daily or every three days, until clinical improvement is observed. The effect on thyrotoxicosis is temporary, with an approximate duration of 24-48h. This approach has been proposed as a safe and effective alternative when the medical treatment is contraindicated or not effective, and when there is multiple organ failure or emergency surgery is required.

Plasmapheresis in thyrotoxicosis: a single-center case series.

BACKGROUND: Plasmapheresis represent an alternative therapeutic option for hyperthyroidism with thyroid storm or refractory cases. It provides a rapid decrease in plasma thyroid hormones and anti-thyroid antibodies. The aim of this paper was to report our single center's experience in managing particular situations of hyperthyroidism using apheresis. CASES PRESENTATION: The following case series describes three young African patients (two females, one male) aged 29, 37, and 25 years old, respectively, with Graves' disease who presented with drug ineffectiveness, drug-induced agranulocytosis, and thyroid storm with multi-organ failure. The three patients underwent plasmapheresis sessions leading to effective decline of thyroid hormone levels and offering a window for processing total thyroidectomy. DISCUSSION/CONCLUSION: The standard management of thyrotoxicosis and thyroid storm was usually codified by the concomitant use of antithyroid medication, iodine, beta-blockers, and corticosteroids. This medical preparation can be effective in most cases. However, drug toxicity or ineffectiveness can limit the use of such therapeutics. Our paper supports the efficiency and safety of therapeutic plasma exchange in the preoperative management of thyrotoxicosis.

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.

In Vivo Evaluation of the Pharmacokinetic Interaction between Levothyroxine and Amiodarone in Rat Plasma: Evaluation of Importance of Therapeutic Drug Monitoring during Co-Therapy.

Amiodarone-induced thyrotoxicosis (AIT) is a common condition in patients who are receiving amiodarone for cardiac arrhythmia. This risk is elevated in iodine-deficient regions. Levothyroxine is the standard treatment for patients with hypothyroidism. This investigation is concerned with the evaluation of the possible pharmacokinetic interaction between amiodarone and levothyroxine upon co-therapy in rats and to investigate the cause of thyrotoxicosis. A selective, sensitive and precise RP-HPLC method was developed for the simultaneous determination of levothyroxine and amiodarone in rat plasma. A stationary phase of C18 Xterra RP column and a mobile phase consisting of acetonitrile: acidified water with 0.1% trifluoracetic acid (pH = 4.8) with gradient elution were used. The experiment was conducted at ambient temperature with flow rate of 1.5 mL/min for the chromatographic separation and quantitation of the investigated drugs. Protein precipitation with methanol was applied for the analysis of the two drugs in rat plasma. The method was linear over concentration range of 5-200 µg/mL for both levothyroxine and amiodarone. The European Medicines Agency guideline was applied for the validation of the developed bioanalytical method. The method was successfully applied to in vivo pharmacokinetic study in which levothyroxine and amiodarone were quantified in plasma of rats after receiving an oral dose of levothyroxine and amiodarone. After the calculation of the pharmacokinetic parameters, a statistical analysis was performed to elucidate the existence of significant difference between test and control groups in rats. The combination of levothyroxine and amiodarone significantly decreased levothyroxine bioavailability in rats, making the therapeutic drug monitoring mandatory in patients receiving levothyroxine and amiodarone. In addition, the increased clearance of levothyroxine upon the co-administration with amiodarone may explain the reported hypothyroidism.

Hyperthyroidism: A Review.

Importance: Overt hyperthyroidism, defined as suppressed thyrotropin (previously thyroid-stimulating hormone) and high concentration of triiodothyronine (T3) and/or free thyroxine (FT4), affects approximately 0.2% to 1.4% of people worldwide. Subclinical hyperthyroidism, defined as low concentrations of thyrotropin and normal concentrations of T3 and FT4, affects approximately 0.7% to 1.4% of people worldwide. Untreated hyperthyroidism can cause cardiac arrhythmias, heart failure, osteoporosis, and adverse pregnancy outcomes. It may lead to unintentional weight loss and is associated with increased mortality. Observations: The most common cause of hyperthyroidism is Graves disease, with a global prevalence of 2% in women and 0.5% in men. Other causes of hyperthyroidism and thyrotoxicosis include toxic nodules and the thyrotoxic phase of thyroiditis. Common symptoms of thyrotoxicosis include anxiety, insomnia, palpitations, unintentional weight loss, diarrhea, and heat intolerance. Patients with Graves disease may have a diffusely enlarged thyroid gland, stare, or exophthalmos on examination. Patients with toxic nodules (ie, in which thyroid nodules develop autonomous function) may have symptoms from local compression of structures in the neck by the thyroid gland, such as dysphagia, orthopnea, or voice changes. Etiology can typically be established based on clinical presentation, thyroid function tests, and thyrotropin-receptor antibody status. Thyroid scintigraphy is recommended if thyroid nodules are present or the etiology is unclear. Thyrotoxicosis from thyroiditis may be observed if symptomatic or treated with supportive care. Treatment options for overt hyperthyroidism from autonomous thyroid nodules or Graves disease include antithyroid drugs, radioactive iodine ablation, and surgery. Treatment for subclinical hyperthyroidism is recommended for patients at highest risk of osteoporosis and cardiovascular disease, such as those older than 65 years or with persistent serum thyrotropin level less than 0.1 mIU/L. Conclusions and Relevance: Hyperthyroidism affects 2.5% of adults worldwide and is associated with osteoporosis, heart disease, and increased mortality. First-line treatments are antithyroid drugs, thyroid surgery, and radioactive iodine treatment. Treatment choices should be individualized and patient centered.

Thyrotoxicosis.

Hyperthyroidism is a diagnosis existing along a spectrum of severity. Patients present with a variety of signs and symptoms: tachycardia, elevated heart rate, anxiety, changes in mental status, gastrointestinal disturbances, and hyperthermia. Management of subclinical hyperthyroidism and thyrotoxicosis without thyroid storm is heavily dependent on outpatient evaluation. Thyroid storm is the most severe form of hyperthyroidism with the highest mortality. Management of thyroid storm follows a stepwise approach, with resuscitation and detection of the precipitating cause being paramount. Special attention should be paid to cardiac function in patients with thyroid storm before treatment, as these patients may develop cardiac collapse.

Real-life Data on the Effect of Medical Therapy for Amiodarone-induced Thyrotoxicosis on CV Events and Hospitalizations.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) often receive initial therapy for thyrotoxicosis in several different medical settings before admission to a referral center. OBJECTIVE: This work aimed to determine whether first-line medical therapy (ie, therapies for thyrotoxicosis at first diagnosis of AIT) affects the outcome of AIT patients. METHODS: A single-center historical-prospective cohort study was conducted on 313 AIT patients. Clinical and biochemical data were collected at first diagnosis, at a referral center, and during the course of AIT. Primary outcomes were cardiovascular (CV) events and hospitalizations. First-line therapies were considered appropriate when they included glucocorticoids for type 2 AIT and methimazole for type 1 AIT at the approved dose, either alone (optimal medical therapy, OMT) or in combination (right-dose combination therapy, RCT). Other therapies were considered not appropriate, including no therapy. Duration of exposure to thyrotoxicosis was the time from first diagnosis of AIT to its remission. RESULTS: A total of 34.5% patients received appropriate therapies (28.1% OMT, 6.4% RCT), whereas the remaining (65.5%) received inappropriate therapies. CV events and hospitalizations were more frequent in patients who received inappropriate therapies (33.2% vs 4.5%, and 24.9% vs 6.5%, respectively; P < .0001 for both). Appropriate therapies reduced serum thyroid hormone concentrations (P = .018) from first diagnosis to referral, unlike the inappropriate therapies. The duration of exposure to thyrotoxicosis was longer in patients receiving inappropriate therapies and was a risk factor for arrhythmias (hazard ratio [HR] 1.004; P = .0008), major acute CV events (HR 1.004; P = .020), and hospitalizations (HR 1.006; P < .0001). CONCLUSION: The first medical therapy of AIT influences the exposure time to thyrotoxicosis and the occurrence of CV events and hospitalizations.

[Radioactive iodine in the treatment of Graves' disease: history and modern concept of radionuclide therapy].

Radioactive iodine 131I is a theranostic isotope used both for diagnosis and therapy of benign thyroid diseases and thyroid cancer for 85 years. The formation of nuclear medicine is closely linked with the use of 131I. The history of radioiodine therapy began in 1941, when endocrinologist Saul Hertz for the first time used 131I to treat patients with Graves' disease. Since 1946 radioactive iodine 131I became widely available, and its effectiveness became public knowledge after reports on thyrotoxicosis treatment published in the Journal of the American Medical Association by multidisciplinary groups of scientists - physicists and endocrinologists. In 1951, isotope 131I became the first Food and Drug Administration approved RP for the treatment of thyroid disorders. Around the same time on the basis of the First Moscow Medical Institute studies on the use of radioiodine isotopes in patients with thyrotoxicosis began. The head of the Soviet group on the studying of radioactive iodine was the physician-scientist Vera Georgievna Spesivtseva. The research works of medical physicists Edith Quimby and Leonidas Marinelli in optimizing therapeutic strategies using radioactive substances in the late 1940s and the wording of the ALARA (As Low As Reasonably Achievable) principle of minimizing exposure of ionizing radiation by the International Commission on Radiological Protection in 1954 contributed to the greater introduction of radionuclides into the medicine.

A systematic review and meta-analysis of the etiology and treatment patterns of thyrotoxicosis in Africa.

INTRODUCTION: Thyrotoxicosis is one of the most common endocrine disorders seen in clinical practice. This study aims to determine the etiologies and treatment modalities of thyrotoxicosis in Africa. AREAS COVERED: The study design is a systematic review with a meta-analysis. Medical databases and the gray literature were systematically searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies done in Africa on the etiology and treatment of thyrotoxicosis were selected. EXPERT OPINION: In Africa, it is still believed that autoimmune diseases, generally, are not as common as what is seen in the western world. The frequency of Graves' disease is reportedly lower in Africa. The treatment of thyrotoxicosis depends on the cause. Therefore, it is of substantial importance to establish the etiology following the diagnosis of the clinical syndrome.

Management of thyrotoxicosis and pregnancy: Review of the current literature and an update of the care pathway.

Pregnancy can be complicated by hyperthyroidism or thyrotoxicosis. Diagnosis is founded on an increase in free thyroid hormones and low TSH. The most frequent etiologies are Graves' disease, an autoimmune disease linked to stimulatory anti-TSH receptor antibodies, and non-autoimmune gestational hyperthyroidism linked to the TSH-like activity of the chorionic growth hormone (hCG). During pregnancy, thyrotoxicosis can entail maternal, obstetrical and fetal or neonatal complications. Graves' hyperthyroidism may be responsible for fetal and neonatal hyperthyroidism due to placental transfer of stimulatory anti-TSH receptor antibodies. During pregnancy, treatment of thyrotoxicosis must restore normal thyroid function in the mother without affecting fetal thyroid function. The recent reassessment of the prevalence of teratogenic effects in children of women treated with antithyroid drugs in the first weeks of gestation should orient the care pathway before and during pregnancy for women of child-bearing age with hyperthyroidism linked to Graves' disease.

Thyrotoxic myopathy: research status, diagnosis, and treatment.

Thyrotoxic myopathy is hyperthyroidism accompanied by muscle lesions. It is recognized as the general term for a group of symptoms with several main manifestations of several hyperthyroidism patients in the course (e.g. muscle weakness, muscle paralysis, or pain). From the clinical perspective, it may only be manifested as muscle-related symptoms. The symptoms of high metabolic syndrome (e.g. thyrotoxicosis) are absent, obscured, or relatively delayed, so it can be easily misdiagnosed. Accordingly, patients experiencing the first symptom of myopathy should concentrate on the possibility of thyrotoxic myopathy. Given the clinical characteristics, thyrotoxic myopathy can be devided into chronic thyrotoxic myopathy, thyrotoxicosis with periodic paralysis, acute thyrotoxic myopathy, hyperthyroidism with myasthenia gravis, as well as infiltrating exophthalmos with ophthalmoplegia. In this paper, we review thyrotoxic myopathy research status, diagnoses, and treatments.

Thyrotoxicosis-Induced Cardiomyopathy Complicated by Refractory Cardiogenic Shock Rescued by Extracorporeal Membrane Oxygenation.

BACKGROUND Thyrotoxicosis-induced cardiomyopathy is a rare but potentially life-threatening condition that occurs in less than 1% of thyrotoxic individuals. Severely impaired left ventricular systolic function can lead to an overt cardiogenic shock requiring mechanical circulatory support. Abnormal cardiac structure and function are potentially reversible after achievement of euthyroid state. CASE REPORT We present a case of a 53-year-old patient with a diagnosis of thyrotoxicosis-induced acute heart failure. Transthoracic echocardiography revealed a mildly dilated left ventricle and severely reduced systolic function with ejection fraction of 20%. Subsequently, the patient developed refractory cardiogenic shock, which was treated with the use of extracorporeal membrane oxygenation (ECMO). After early intensive treatments to achieve euthyroid state, the clinical status significantly improved. Echocardiography prior to discharge showed improvement of left ventricular ejection fraction to 40%. The anti-TSH receptor was positive and Grave's disease was diagnosed. The patient eventually returned to baseline functional status and could return to basic activities of daily living without limitations. CONCLUSIONS Early diagnosis of cardiac involvement in patients with thyrotoxicosis is critical. Promptly delivered intensive treatment with rapid achievement of euthyroid state can reverse cardiac dysfunction and improve patient outcomes. The use of ECMO can be considered as a "bridge" to recovery of cardiac function after restoration of euthyroid state.

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.

Therapeutic plasmapheresis for the treatment of thyrotoxicosis: A retrospective multi-center study.

BACKGROUND AND AIMS: Thyroid storm and severe thyrotoxicosis remain among the most frequent endocrine emergencies, and first-line hyperthyroidism treatment is not always an option. Since the first report in 1970, plasmapheresis is a second-line treatment for severe or otherwise untreatable thyrotoxicosis when rapid euthyroidism is desired. METHODS: We present a retrospective study of the experience in treating thyrotoxicosis with plasmapheresis between 2012 and 2020 in two specialized centers in Colombia. We register the demographic and clinical characteristic and compare the thyroid hormones and other biochemical measurements before and after treatment. RESULTS: Data from 19 patients was obtained, 58% female with a median age of 35 years (IQR 23.5), and most of them with Graves' disease. The most frequent indication for plasmapheresis was thyroid storm. A median of 4 (IQR 2) sessions lead to a significant reduction in FT4 (P .0001) and TT3 (P < .0003) with a nonsignificant decrease in beta-blocker (P .7353) dose, no change in hepatic enzymes, and no adverse events. After plasmapheresis, thyroidectomy was performed in 10 patients. CONCLUSIONS: Plasmapheresis is an effective and safe treatment option for reducing circulating thyroid hormones in severe thyrotoxicosis when other forms of treatment are contraindicated or in case of urgent thyroid and non-thyroid surgery. It is limited by its cost and the need for highly specialized resources.

Thyrotoxicosis and dilated cardiomyopathy in developing countries.

BACKGROUND: Thyrotoxicosis is the state of thyroid hormone excess. But, in sub-Saharan Africa (SSA), specifically Northern Ethiopia, scientific evidence about thyrotoxicosis and its cardiac complications like dilated cardiomyopathy is limited. Therefore, this study aimed to explore the thyrotoxicosis presentation and management and identify factors associated with dilated cardiomyopathy in a tertiary hospital in Northern Ethiopia. METHODS: An institution-based cross-sectional study was conducted in Ayder Comprehensive Specialized Hospital from 2017 to 2018. Data from 200 thyrotoxicosis cases were collected using a structured questionnaire. After describing variables, logistic regression was conducted to identify independent predictors of dilated cardiomyopathy. Statistical significance was declared at p < 0.05. RESULTS: Mean age at presentation of thyrotoxicosis was 45 years and females accounted for 89 % of the cases. The most frequent etiology was multinodular toxic goiter (51.5 %). As well, the most common symptoms and signs were palpitation and goiter respectively. Thyroid storm occurred in 6 % of the cases. Out of 89 patients subjected to echocardiography, 35 (39.3 %) of them had dilated cardiomyopathy. And, the odds of dilated cardiomyopathy were higher in patients who had atrial fibrillation (AOR = 15.95, 95 % CI:5.89-38.16, p = 0.001) and tachycardia (AOR = 2.73, 95 % CI:1.04-7.15, p = 0.040). All patients took propylthiouracil and 13.0 % of them experienced its side effects. Concerning ß-blockers, propranolol was the most commonly (78.5 % of the cases) used drug followed by atenolol (15.0 %). Six patients underwent surgery. CONCLUSIONS: In developing countries like Ethiopia, patients with thyrotoxicosis have no access to methimazole which is the first-line anti-thyroid drug. Besides, they greatly suffer from dilated cardiomyopathy (due to late presentation) and side effects of propylthiouracil. Therefore, we recommend that patients should get adequate health information about thyrotoxicosis and anti-thyroid drugs including their side effects. Additionally, hospitals and other concerned bodies should also avail of TSH tests and methimazole at an affordable cost. Furthermore, community awareness about iodized salt and iodine-rich foods should be enhanced.

Amiodarone-induced type 2 thyrotoxicosis.

The authors present a case of a 55-year-old gentleman with a medical history of atrial fibrillation on amiodarone who presented with weight loss, palpitations and exertional dyspnoea. Thyroid function tests revealed thyrotoxicosis with a free thyroxine (T4) of 117 pmol/L and a thyroid-stimulating hormone (TSH) of <0.008 mIU/L. Interleukin-6 level was low. The negative TSH-receptor antibody status, the presence of a small thyroid gland with heterogeneous echotexture and decreased internal vascularity on ultrasound together with the relatively quick drop in free T4 and free tri-iodothyronine (T3) levels once prednisolone therapy was added to carbimazole suggested that this was typical of amiodarone-induced thyrotoxicosis (AIT) type 2. Subsequently, carbimazole was discontinued and treatment with prednisolone was continued. This case highlights that AIT management may be challenging and it is of paramount importance to establish the type of AIT present as this will guide management and is key to improving prognosis.

Therapeutic plasma exchange with albumin as a valuable method of preparing thyrotoxic patients for a life-saving thyroidectomy.

Hyperthyroidism affects approximately 1.2% of the population and its routine treatment includes antithyroid drugs (ATDs), radioiodine and surgery. Management of patients with resistance or contraindications to ATDs who require thyroidectomy may be challenging. We present the experience of our department in preparing thyrotoxic patients for life-saving thyroidectomy by using therapeutic plasma exchange (TPE) with albumin: one patient with Graves' disease and previous history of agranulocytosis and cholestatic jaundice after ATDs and two patients with amiodarone-induced thyrotoxicosis. Five to six TPEs were applied to each patient resulting in a decrease of fT3 by 57% to 83%, fT4 by 21% to 60% and decrease/normalization of total thyroid hormones. All patients underwent surgery successfully. In case of drug-resistant thyrotoxicosis or contraindications to ATDs, TPE can be a valuable tool in preparing patients for surgery. Albumin used as a replacement fluid appears to be effective in ameliorating clinical and laboratory symptoms of thyrotoxicosis.

Amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis (AIT) are not uncommon endocrinopathies. Clinicians are sometimes faced with difficult diagnostic and therapeutic situations. The disease pathophysiology is partially understood, explaining the lack of predictive factors for occurrence. Different international recommendations for their management have been published: the most recent in 2018 by the European Thyroid Association (ETA) (Ross et al., 2016; Bartalena et al., 2018). The purpose of this paper is to present the essential concepts for their management and to review the literature since 2018.

Testing, Monitoring, and Treatment of Thyroid Dysfunction in Pregnancy.

Both hyperthyroidism and hypothyroidism can have adverse effects in pregnancy. The most common causes of thyrotoxicosis in pregnancy are gestational transient thyrotoxicosis and Graves' disease. It is important to distinguish between these entities as treatment options differ. Women of reproductive age who are diagnosed with Graves' disease should be counseled regarding the impact of treatment options on a potential pregnancy. Although the absolute risk is small, antithyroid medications can have teratogenic effects. Propylthiouracil appears to have less severe teratogenicity compared to methimazole and is therefore favored during the first trimester if a medication is needed. Women should be advised to delay pregnancy for at least 6 months following radioactive iodine to minimize potential adverse effects from radiation and ensure normal thyroid hormone levels prior to conception. As thyroid hormone is critical for normal fetal development, hypothyroidism is associated with adverse obstetric and child neurodevelopmental outcomes. Women with overt hypothyroidism should be treated with levothyroxine (LT4) to a thyrotropin (thyroid-stimulating hormone; TSH) goal of <2.5 mIU/L. There is mounting evidence for associations of maternal hypothyroxinemia and subclinical hypothyroidism with pregnancy loss, preterm labor, and lower scores on child cognitive assessment. Although there is minimal risk of LT4 treatment to keep TSH within the pregnancy-specific reference range, treatment of mild maternal thyroid hypofunction remains controversial, given the lack of clinical trials showing improved outcomes with LT4 treatment.