Hyperthyroidism
Hyperthyroidism is a common endocrine disorder in which the thyroid gland produces excessive amounts of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3), leading to an acceleration of the body's metabolic processes and affecting nearly every organ system.[1] This overproduction, also known as an overactive thyroid, disrupts normal regulation of heart rate, body temperature, digestion, and energy use, resulting in a hypermetabolic state that can cause significant morbidity if untreated.[2] The condition is classified as overt hyperthyroidism when thyroid-stimulating hormone (TSH) levels are low or suppressed alongside elevated T4 and T3, or subclinical when TSH is low but T4 and T3 remain normal.[3] The most prevalent cause worldwide is Graves' disease, an autoimmune condition where antibodies stimulate the thyroid to overproduce hormones, accounting for approximately 50-80% of cases in iodine-sufficient regions like the United States.[1][3] Other key etiologies include toxic multinodular goiter and toxic adenoma, where autonomous nodules in the thyroid gland independently secrete hormones, particularly in older adults or iodine-deficient areas.[2] Thyroiditis, an inflammation of the thyroid often triggered by viral infections, postpartum changes, or medications like amiodarone, can also release stored hormones temporarily.[3] Less common triggers involve excessive iodine intake, which overwhelms the gland's regulatory mechanisms, or rare pituitary tumors secreting excess TSH.[2] Risk factors include female sex (affecting women up to 10 times more than men), age over 60, family history of thyroid disorders, recent pregnancy, and smoking, which exacerbates Graves' disease.[1][3] Globally, hyperthyroidism impacts about 1-2% of the population, with subclinical forms being more prevalent than overt cases.[2] Symptoms typically develop gradually and include unintentional weight loss despite increased appetite, tachycardia or irregular heartbeat, nervousness, irritability, tremors, excessive sweating, heat intolerance, fatigue, muscle weakness, and menstrual irregularities in women.[1] In Graves' disease, patients may also experience eye problems such as bulging eyes (exophthalmos) or skin changes like pretibial myxedema.[2] Older adults might present atypically with apathy, depression, or unexplained heart failure rather than classic hypermetabolic signs.[3] Diagnosis involves blood tests measuring TSH, free T4, and T3 levels, often supplemented by thyroid scans or antibody tests to identify the underlying cause.[1] Untreated hyperthyroidism raises risks for serious complications, including atrial fibrillation, osteoporosis due to accelerated bone turnover, and, in rare cases, thyroid storm—a life-threatening surge of hormones with high mortality.[2] Treatment options are tailored to the cause, severity, and patient factors, encompassing antithyroid drugs like methimazole to inhibit hormone synthesis, beta-blockers for symptom relief, radioactive iodine ablation to destroy overactive thyroid tissue, or surgical thyroidectomy in select cases.[3] Early intervention is crucial to prevent long-term cardiovascular and skeletal damage.[1]Overview
Definition and Classification
Hyperthyroidism is defined as a condition characterized by excessive production of thyroid hormones by the thyroid gland itself, resulting in elevated circulating levels of thyroxine (T4) and/or triiodothyronine (T3).[3] This overproduction leads to thyrotoxicosis, the clinical syndrome of thyroid hormone excess that manifests as a hypermetabolic state affecting multiple organ systems.[2] In contrast, thyrotoxicosis can occur independently of hyperthyroidism when excess thyroid hormones are derived from exogenous sources, such as factitious thyrotoxicosis caused by surreptitious ingestion of thyroid hormone medications, or from the release of preformed hormones in conditions like thyroiditis, where the gland is inflamed and damaged rather than overactive.[4] Thyroid hormones T3 and T4 play essential roles in regulating basal metabolic rate, protein synthesis, and thermogenesis, influencing nearly every tissue in the body.[5] Under normal conditions, thyroid function is tightly controlled by the hypothalamic-pituitary-thyroid (HPT) axis: thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH), which in turn prompts the thyroid gland to synthesize and release T4 and T3; elevated thyroid hormone levels exert negative feedback on the hypothalamus and pituitary to suppress further TRH and TSH secretion.[5] Hyperthyroidism is classified in several ways to guide diagnosis and management. Based on origin, it is primarily thyroidal (primary hyperthyroidism), arising from intrinsic thyroid dysfunction, or rarely central (secondary or tertiary), due to inappropriate TSH secretion from pituitary adenomas or hypothalamic disorders, respectively.[6] By severity, it is categorized as overt hyperthyroidism, marked by suppressed TSH levels alongside elevated free T4 and/or T3, or subclinical hyperthyroidism, featuring low TSH with normal thyroid hormone levels, which may be asymptomatic or produce milder effects like subtle tachycardia.[3] Etiologically, common forms include autoimmune causes such as Graves' disease, autonomous thyroid nodules like toxic multinodular goiter, and iodine-induced cases such as the Jod-Basedow phenomenon, where excess iodine exposure triggers hyperthyroidism in iodine-deficient individuals with underlying nodular thyroid disease.[7]Pathophysiology
Hyperthyroidism arises from excessive production or release of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3), disrupting the normal hypothalamic-pituitary-thyroid axis. This excess can result from increased synthesis, often driven by stimulation of the thyroid-stimulating hormone (TSH) receptor; accelerated release of preformed hormones due to glandular destruction. In the feedback loop, elevated free T4 and T3 levels suppress TSH secretion via negative feedback on the pituitary and hypothalamus, typically leading to low or undetectable TSH in overt hyperthyroidism, as described by the relationship TSH ∝ 1 / (T3 + T4) in simplified terms, where hormone levels inversely regulate pituitary output.[3][8][9] At the cellular level, thyroid hormone synthesis begins with iodide uptake into thyrocytes via the sodium-iodide symporter (NIS), powered by the sodium-potassium ATPase, followed by transport into the colloid by pendrin. Thyroid peroxidase (TPO) then oxidizes iodide to iodine using hydrogen peroxide and catalyzes its incorporation onto tyrosine residues in thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). TPO further facilitates the coupling of these iodotyrosines—MIT with DIT to yield T3, or two DIT molecules to produce T4—before proteolysis releases the hormones into circulation. Dysregulation, such as constitutive TSH receptor activation, amplifies these steps, leading to overproduction.[8][3] Systemically, excess thyroid hormones bind nuclear receptors, upregulating genes that increase basal metabolic rate by enhancing Na+/K+-ATPase activity, thereby elevating oxygen consumption and heat production across tissues. This mimics beta-adrenergic stimulation, promoting glycogenolysis, lipolysis, and cardiovascular effects like increased heart rate, independent of catecholamines. Additionally, T3 stimulates osteoclast activity via RANKL expression, accelerating bone resorption and reducing bone mineral density. In specific etiologies, such as Graves' disease, TSH receptor-stimulating antibodies (TRAb) chronically activate the receptor, driving autonomous synthesis; toxic adenomas exhibit somatic TSH receptor mutations that confer nodular independence from TSH; and destructive processes in subacute or postpartum thyroiditis release stored hormones without new synthesis, causing transient excess.[8][9][3]Clinical Presentation
Signs and Symptoms
Hyperthyroidism typically presents with a range of symptoms resulting from excess thyroid hormone, affecting multiple organ systems and varying in severity based on the degree of hormonal elevation. Common general symptoms include heat intolerance, unintentional weight loss despite increased appetite, fatigue, nervousness, irritability, and menstrual irregularities in women.[2][1] Cardiovascular manifestations are prominent and include tachycardia, palpitations, widened pulse pressure, and, in advanced cases, high-output heart failure due to increased metabolic demand.[3][10] Neuromuscular symptoms often involve fine tremor of the hands, proximal muscle weakness (myopathy), anxiety, irritability, hyperreflexia, and insomnia, reflecting heightened sympathetic activity.[1][3] Dermatological and gastrointestinal features encompass warm, moist skin, excessive sweating, thinning or brittle hair, hair loss, increased bowel frequency, and diarrhea, stemming from accelerated metabolism and gastrointestinal motility.[2][3] Ocular signs, generalizable across causes but more pronounced in Graves' disease, include lid lag and retraction, which may contribute to a staring appearance.[3][1] A goiter, or enlarged thyroid gland, is present in the majority of Graves' disease cases, the most common etiology of hyperthyroidism, often appearing as diffuse neck swelling.[1][11] In elderly patients, hyperthyroidism may manifest as apathetic hyperthyroidism, with subtler symptoms mimicking depression, such as weight loss, fatigue, apathy, and withdrawal, rather than classic hypermetabolic features.[2][3] Symptom intensity generally correlates with elevated free T4 and T3 levels, though extreme exacerbations like thyroid storm represent acute decompensation beyond typical presentations.[10]Thyroid Storm
Thyroid storm, also known as thyrotoxic crisis, is a rare but life-threatening endocrine emergency characterized by an acute exacerbation of hyperthyroidism, resulting from a sudden and excessive release of thyroid hormones leading to multi-organ dysfunction.[12] It typically occurs in patients with underlying hyperthyroidism, such as Graves' disease, and represents a decompensated state rather than a distinct entity.[12] Common precipitants include infections (the most frequent trigger), surgery (thyroid or non-thyroid), trauma, iodine-containing contrast media, discontinuation of antithyroid therapy, and other stressors like parturition or burns.[12][13] Clinically, thyroid storm manifests with severe systemic symptoms, including high fever exceeding 102°F (38.9°C), often reaching 104–106°F (40–41.1°C); profound tachycardia greater than 140 beats per minute; and central nervous system alterations ranging from agitation and confusion to delirium or coma.[12] Gastrointestinal involvement is prominent, featuring nausea, vomiting, diarrhea, and occasionally jaundice due to hepatic dysfunction, while cardiovascular complications such as atrial fibrillation, heart failure, or shock may arise.[12] These features reflect a hypermetabolic crisis with heightened sympathetic activity.[13] Diagnosis relies on clinical assessment, as laboratory confirmation of hyperthyroidism alone is insufficient; the Burch-Wartofsky Point Scale provides a standardized scoring system, assigning points for thermoregulatory dysfunction (e.g., 30 points for temperature >104°F), central nervous system effects (e.g., 30 for coma), gastrointestinal symptoms (e.g., 20 for severe jaundice), and cardiovascular issues (e.g., 15 for severe congestive heart failure), among others, with a score greater than 45 indicating high likelihood of thyroid storm and 25–44 suggesting imminent risk.[12] Elevated free thyroxine (T4) and triiodothyronine (T3) levels with suppressed thyroid-stimulating hormone support the diagnosis but are not specific to the storm.[12] Pathophysiologically, thyroid storm arises from an abrupt surge in circulating thyroid hormones, often triggered by increased release or reduced binding to proteins during acute illness, coupled with enhanced end-organ sensitivity that amplifies sympathetic nervous system hyperactivity, mimicking catecholamine excess and leading to a hyperadrenergic state.[12][13] This cascade promotes widespread tissue oxygen demand, potentially culminating in multi-organ failure, including hepatic congestion, cardiac arrhythmias, and acute respiratory distress.[12] Despite prompt intervention, mortality from thyroid storm has decreased to approximately 1-6% with modern management as of 2025, primarily due to cardiovascular collapse or infection-related complications.[12][14] Its incidence is estimated at approximately 1.4 cases per 100,000 persons per year in females and 0.7 per 100,000 in males, with higher rates among hospitalized patients.[15]Causes
Autoimmune Causes
Autoimmune causes of hyperthyroidism primarily involve dysregulated immune responses targeting the thyroid gland, leading to excessive hormone production or release. The most common etiology is Graves' disease, an organ-specific autoimmune disorder characterized by the production of thyroid-stimulating immunoglobulins (TSI or TRAb) that bind to and activate the thyrotropin receptor (TSHR) on thyroid follicular cells, mimicking the action of thyroid-stimulating hormone (TSH) and causing diffuse glandular hyperplasia and hyperfunction.[16][11] These autoantibodies stimulate cyclic AMP production, promoting thyroid hormone synthesis and secretion, which accounts for 60-80% of hyperthyroidism cases in iodine-sufficient regions worldwide.[17][11] The pathogenesis of Graves' disease involves both humoral and cellular immunity, with B cells producing the pathogenic TRAb and T cells providing helper functions through cytokine release that amplify the autoimmune response.[18][19] Genetic susceptibility plays a key role, with associations to human leukocyte antigen (HLA) alleles such as HLA-DR3, which influences antigen presentation and T-cell activation in thyroid tissue.[20] Environmental factors can trigger or exacerbate the disease in genetically predisposed individuals, including cigarette smoking, which increases risk by promoting oxidative stress and immune dysregulation; psychological stress, potentially via neuroendocrine pathways; and excess iodine intake, which may enhance autoantigen presentation.[21][22] Graves' disease exhibits a marked female predominance, with a female-to-male ratio of 5-10:1, likely influenced by estrogen-mediated immune modulation.[23][24] It is also associated with other autoimmune conditions, such as vitiligo and rheumatoid arthritis, reflecting shared genetic and immunological pathways that heighten overall autoimmunity risk.[25] In some cases, TSHR autoantibodies cross-react with orbital antigens, contributing to extrathyroidal manifestations like ophthalmopathy through shared immunogenic epitopes.[26] Other autoimmune etiologies include transient hyperthyroid phases in conditions like hashitoxicosis and postpartum thyroiditis. Hashitoxicosis represents an initial destructive hyperthyroid state in Hashimoto's thyroiditis, where antibody-mediated (anti-thyroid peroxidase or anti-thyroglobulin) inflammation causes follicular disruption and release of preformed thyroid hormones, typically resolving into hypothyroidism.[27][28] Postpartum thyroiditis, occurring in 5-10% of women within the first year after delivery, involves a similar autoimmune destructive process driven by rebound T-cell and antibody activity following pregnancy-induced immune suppression, often presenting with a hyperthyroid phase due to hormone leakage before progressing to hypothyroidism in many cases.[29][30] These conditions highlight the spectrum of autoimmune thyroiditis, where initial hyperthyroidism stems from glandular destruction rather than stimulation.Non-Autoimmune Causes
Non-autoimmune causes of hyperthyroidism encompass structural abnormalities in the thyroid gland, inflammatory conditions leading to hormone release, and exogenous factors that disrupt normal thyroid function. These differ from autoimmune etiologies by lacking antibody-mediated stimulation, instead involving autonomous hormone production or leakage of pre-formed hormones.[2] Toxic nodular goiter, also known as toxic multinodular goiter, arises from multiple autonomous thyroid nodules that independently produce excess thyroid hormone, often appearing as "hot" areas on scintigraphy with suppressed uptake in surrounding tissue. This condition is more prevalent in iodine-deficient regions, where the incidence is 1.5-18 cases per 100,000 person-years, compared to lower rates in iodine-sufficient areas. It typically affects older adults and develops gradually from longstanding non-toxic goiter.[31][9] Toxic adenoma refers to a single hyperfunctioning thyroid nodule that autonomously secretes thyroid hormones, accounting for approximately 5-10% of hyperthyroidism cases, particularly in iodine-deficient populations. These benign tumors suppress TSH levels and function independently of regulatory signals, leading to clinical hyperthyroidism without systemic autoimmunity. They are more common in women and often present as a palpable solitary nodule.[32][33] Thyroiditis variants represent inflammatory processes that cause transient hyperthyroidism through destructive release of stored thyroid hormones, rather than increased synthesis. Subacute thyroiditis, often viral in origin and associated with upper respiratory infections, presents with painful thyroid enlargement, fever, and elevated inflammatory markers; it affects women more frequently and resolves spontaneously in most cases. Silent thyroiditis, a painless form, involves lymphocytic infiltration and hormone leakage, commonly seen postpartum but also in non-pregnant individuals without evident autoimmunity. Drug-induced thyroiditis, triggered by agents like amiodarone or lithium, disrupts follicular integrity; amiodarone, for instance, can induce type 1 thyrotoxicosis via iodine excess in susceptible glands or type 2 through direct cytotoxicity.[34][35][36] Exogenous causes stem from external thyroid hormone or iodine overload, mimicking endogenous hyperthyroidism biochemically but with low or absent thyroidal radioiodine uptake. Iatrogenic hyperthyroidism results from excessive levothyroxine dosing in hypothyroidism treatment, emphasizing the need for regular TSH monitoring to prevent overdose. Factitious hyperthyroidism, or thyrotoxicosis factitia, involves surreptitious ingestion of thyroid hormone preparations, often for weight loss or psychological reasons, and is characterized by suppressed thyroglobulin levels. Iodine excess, from supplements, contrast agents, or medications like amiodarone, can precipitate hyperthyroidism in predisposed individuals with underlying nodular disease, as high iodine loads overwhelm the gland's regulatory mechanisms.[2][3] Rare non-autoimmune causes include gestational trophoblastic disease, where markedly elevated human chorionic gonadotropin (hCG) from molar pregnancies or choriocarcinomas cross-reacts with the TSH receptor, stimulating thyroid hormone production; this can occur in up to 20-50% of complete hydatidiform mole cases with hCG levels exceeding 100,000 IU/L.[37][38][39] Rarely, TSH-secreting pituitary adenomas (TSHomas) cause central hyperthyroidism by autonomous TSH production, accounting for less than 1% of cases.[40]Diagnosis
Laboratory Tests
The diagnosis of hyperthyroidism begins with biochemical confirmation through thyroid function tests, typically prompted by symptoms such as unexplained weight loss or palpitations.[2] The primary screening test is serum thyroid-stimulating hormone (TSH), which is suppressed in hyperthyroidism due to negative feedback from excess thyroid hormones.[41] A TSH level below 0.1 mU/L is highly suggestive of hyperthyroidism, particularly when accompanied by elevated free thyroxine (T4) or triiodothyronine (T3).[42] Overt hyperthyroidism is characterized by low TSH with elevated free T4 and/or total T3 levels, confirming excess thyroid hormone production.[43] In subclinical hyperthyroidism, TSH is low or undetectable while free T4 and T3 remain within normal ranges, often representing an early or mild form of the condition.[44] Some cases, particularly in Graves' disease, exhibit T3-predominant hyperthyroidism, where T3 levels are disproportionately elevated compared to T4.[24] To identify the underlying etiology, antibody assays are essential. Thyrotropin receptor antibodies (TRAb), including thyroid-stimulating immunoglobulins (TSI), are positive in over 90% of Graves' disease cases and confirm autoimmune stimulation of the thyroid.[44] In contrast, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies may be elevated in destructive thyroiditis, indicating autoimmune-mediated thyroid damage rather than overproduction.[45] Ancillary laboratory tests provide supportive evidence and assess complications. A complete blood count (CBC) often reveals mild anemia due to increased red blood cell turnover, while leukocytosis with a left shift may occur in thyroid storm, a severe manifestation of hyperthyroidism.[46] Liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are frequently elevated in 15-76% of untreated cases, reflecting direct effects of excess thyroid hormones on hepatic function.[47] Hypercalcemia, resulting from accelerated bone turnover and resorption, is observed in up to 20% of patients and can contribute to symptoms like fatigue.[48] In amiodarone-induced hyperthyroidism, measurement of reverse T3 (rT3) is useful; elevated rT3 levels with high T4 but relatively low T3 help distinguish type 2 (destructive thyroiditis-like) from type 1 (iodine-induced overproduction).[49] These tests collectively guide differentiation from other causes, with further imaging reserved for etiological confirmation.[43]Imaging and Other Studies
Thyroid scintigraphy serves as a primary imaging modality for evaluating the etiology of hyperthyroidism by assessing thyroid gland function and structure through the administration of radiotracers such as iodine-123 (123I) or technetium-99m pertechnetate (99mTc-pertechnetate).[50][51] In Graves' disease, this test typically reveals diffusely increased radioiodine uptake, often exceeding 30% at 24 hours, reflecting enhanced thyroid activity, whereas uptake is low or suppressed in destructive thyroiditis due to impaired hormone synthesis.[50][52] The scan also distinguishes hyperfunctioning "hot" nodules, indicative of toxic adenomas, from non-functioning "cold" nodules that may warrant further evaluation for malignancy.[53] Additionally, whole-body scintigraphy can detect ectopic thyroid tissue, such as in struma ovarii, contributing to hyperthyroidism in rare cases.[54] Ultrasound provides detailed anatomical assessment of the thyroid, particularly useful for characterizing nodules and evaluating parenchymal changes in hyperthyroidism.[55] In Graves' disease, color Doppler ultrasonography often demonstrates markedly increased intrathyroidal vascularity, known as the "thyroid inferno" pattern, which correlates with disease activity.[56] For nodular hyperthyroidism, the Thyroid Imaging Reporting and Data System (TIRADS) scoring system stratifies nodules based on ultrasound features like composition, echogenicity, margins, calcifications, and shape to estimate malignancy risk and guide biopsy decisions.[57][58] Computed tomography (CT) or magnetic resonance imaging (MRI) is employed when evaluating large goiters or retrosternal extension, providing critical information on tracheal compression, vascular involvement, and surgical planning.[59][60] These modalities are particularly valuable in cases where ultrasound is limited by anatomy or when assessing compressive symptoms. Positron emission tomography (PET), typically with 18F-fluorodeoxyglucose (FDG), is rarely indicated but may be used in suspected thyroid malignancy or to evaluate incidentalomas detected on other imaging.[61][62] Functional tests like thyrotropin-releasing hormone (TRH) stimulation, which provoke a blunted or absent thyroid-stimulating hormone (TSH) response in overt hyperthyroidism, have largely been supplanted by more sensitive laboratory assays and are now rarely performed.[63][64]Subclinical Hyperthyroidism
Subclinical hyperthyroidism is defined as a persistently suppressed serum thyroid-stimulating hormone (TSH) level, typically below 0.1 mU/L, accompanied by normal levels of free thyroxine (T4) and triiodothyronine (T3).[42] This condition reflects mild thyroid hormone excess without overt clinical symptoms, distinguishing it from manifest hyperthyroidism.[65] Its prevalence in the general population ranges from 0.5% to 2%, with higher rates observed in older adults and regions with iodine deficiency.[42] In the United States, subclinical hyperthyroidism affects approximately 0.7% to 1.4% of individuals overall, rising to 1% to 8% among those over 65 years.[9][42] The condition carries several health risks, particularly in vulnerable populations. It is associated with a 2- to 3-fold increased risk of atrial fibrillation, especially when TSH is below 0.1 mU/L and in patients over 60 years, contributing to higher rates of cardiovascular events such as coronary heart disease and stroke.[42][66] Bone health is also affected, with accelerated bone loss and a higher incidence of osteoporosis and fractures in postmenopausal women.[67] Additionally, subclinical hyperthyroidism has been linked to cognitive decline, reduced quality of life, and increased overall mortality, though these associations are more pronounced with prolonged duration and lower TSH levels.[42] Recent data emphasize that cardiovascular risks escalate significantly with TSH suppression below 0.1 mU/L, independent of other factors.[66] Progression to overt hyperthyroidism occurs at a rate of 2% to 5% per year on average, though this can reach up to 7% annually in cases with very low TSH or underlying Graves' disease, and is higher among the elderly.[65] Conversely, spontaneous normalization of TSH levels happens in up to 12% of cases per year.[68] Routine screening for subclinical hyperthyroidism is not recommended by major guidelines, including for high-risk groups such as individuals over 65 years; however, if detected through testing prompted by symptoms or other indications, evaluation and management are advised.[42][69] Management focuses on risk stratification rather than universal treatment. Intervention with antithyroid medications or other therapies is recommended for patients over 65 years with TSH below 0.1 mU/L, or those with comorbidities such as atrial fibrillation, heart disease, or osteoporosis, to mitigate associated risks.[65] For milder cases (TSH 0.1-0.4 mU/L) or younger patients without symptoms, periodic monitoring of TSH levels every 6 to 12 months is sufficient, with reassessment for progression or complications.[42] This approach balances potential benefits against treatment side effects, guided by clinical guidelines from endocrine societies.[66]Treatment
Antithyroid Medications
Antithyroid medications (ATDs), also known as thionamides, represent a cornerstone of first-line pharmacological therapy for hyperthyroidism, particularly in cases like Graves' disease, by reversibly inhibiting thyroid hormone synthesis to restore euthyroidism.[70] These agents are preferred initially due to their non-ablative nature, allowing for potential remission without permanent thyroid ablation.[71] The primary ATDs are methimazole (MMI) and propylthiouracil (PTU). Methimazole is the preferred agent in most non-pregnant adults, with an initial dose of 10-30 mg daily, titrated based on clinical response and thyroid function tests.[70] Propylthiouracil is recommended at 300-600 mg daily for severe hyperthyroidism or during the first trimester of pregnancy, where it is favored over methimazole due to a lower risk of congenital anomalies.[72] After the first trimester, switching to methimazole is often advised to minimize PTU-related risks.[73] Both drugs exert their primary effect by inhibiting thyroid peroxidase, the enzyme essential for iodination of tyrosine residues and coupling to form thyroxine (T4) and triiodothyronine (T3) within the thyroid gland.[74] Uniquely, PTU also blocks peripheral deiodination of T4 to the more active T3 by inhibiting 5'-deiodinase, providing an additional benefit in acute hyperthyroid states like thyroid storm.[72] Treatment regimens involve dose titration to achieve normalization of thyroid-stimulating hormone (TSH) and free T4 levels, typically within 4-8 weeks, followed by maintenance dosing.[75] Therapy duration is generally 12-18 months, after which discontinuation is attempted; remission rates in Graves' disease range from 30-50%, with predictors including lower pretreatment TSH receptor antibody levels and smaller goiter size.[76] Adverse effects necessitate vigilant monitoring. Agranulocytosis, a severe reduction in neutrophils, occurs in 0.2-0.5% of patients and requires immediate drug cessation upon symptoms like sore throat or fever; routine white blood cell monitoring is recommended, especially in the first 3 months.[77] Hepatotoxicity is more common with PTU than methimazole, potentially leading to liver failure in rare cases, prompting baseline and periodic liver function tests.[78] Pruritic rash affects up to 5% of users and often resolves with antihistamines or dose adjustment.[79] Recent studies from 2023-2025 have explored prolonged ATD use beyond 18 months, demonstrating safety and higher sustained remission rates—up to 60% with extended therapy—particularly in patients with fluctuating disease activity.[80] Additionally, mathematical models integrating patient-specific pharmacokinetics have been developed to predict free T4 trajectories and optimize dosing, enhancing precision in achieving euthyroidism while minimizing side effects.[81] For patients unsuitable for long-term ATD therapy, radioactive iodine serves as a definitive alternative, though it carries a risk of permanent hypothyroidism.[70] Symptomatic relief with beta-blockers may complement ATDs during titration.[82]Radioactive Iodine Therapy
Radioactive iodine therapy, utilizing iodine-131 (¹³¹I), serves as a definitive treatment for hyperthyroidism by ablating overactive thyroid tissue. The procedure involves oral administration of ¹³¹I in the form of a capsule or liquid, which is selectively taken up by the sodium-iodide symporter in thyroid follicular cells. Once absorbed, the isotope emits beta particles that damage and destroy thyroid follicles, leading to reduced hormone production over time. This non-invasive approach is typically performed on an outpatient basis, with patients advised to follow radiation safety precautions, such as limiting close contact with others for a few days to weeks post-treatment.[83] Dosing strategies for ¹³¹I therapy include fixed doses, commonly 10-15 mCi (370-555 MBq), or calculated doses based on thyroid gland size, radioiodine uptake, and desired therapeutic outcome. The goal is often to induce hypothyroidism in 80-90% of patients, as this ensures complete resolution of hyperthyroidism while allowing straightforward management with levothyroxine replacement. Fixed dosing is simpler and widely used for Graves' disease, while calculated approaches may be preferred for toxic nodules or multinodular goiter to minimize radiation exposure.[84][85] Indications for radioactive iodine therapy primarily include Graves' disease and toxic thyroid nodules, where it provides a durable cure by permanently reducing thyroid function. It is contraindicated in pregnancy and breastfeeding due to the risk of fetal or infant thyroid damage, with pregnancy delayed for at least 6-12 months afterward. Pretreatment with antithyroid drugs may be used to deplete thyroid hormone stores and prevent symptom exacerbation during therapy.[86][83] Common side effects include a transient flare of hyperthyroidism in 5-10% of patients, occurring shortly after administration due to initial hormone release from damaged cells, as well as inevitable hypothyroidism typically onsetting within 2-3 months. Other potential issues encompass salivary gland inflammation (sialadenitis) or dryness from radiation uptake in salivary tissues, and mild neck tenderness managed with analgesics. Long-term, patients require monitoring for hypothyroidism, which develops in the majority and necessitates lifelong thyroid hormone replacement.[84][83] Outcomes demonstrate remission of hyperthyroidism in 80-90% of patients after a single dose, with full effects manifesting over 2-6 months. Recent trends favor radioactive iodine over surgical options for most eligible cases, with surgery reserved for approximately 5-10% of patients due to its invasiveness. This therapy's efficacy and safety profile make it a cornerstone of definitive management, though repeated doses may be needed in 10-20% of non-responders.[87][84]Surgical Interventions
Surgical interventions for hyperthyroidism primarily involve thyroidectomy, a procedure that removes part or all of the thyroid gland to provide a definitive cure by eliminating the source of excess thyroid hormone production. This approach is particularly valuable when medical therapies fail or are contraindicated, offering rapid resolution of symptoms compared to other modalities. Thyroidectomy is typically performed under general anesthesia through a transverse incision in the neck, with careful preservation of the recurrent laryngeal nerves and parathyroid glands to minimize complications.[88][89] The choice of procedure depends on the underlying cause of hyperthyroidism. For Graves' disease, the most common etiology, total or near-total thyroidectomy is recommended to remove nearly all thyroid tissue, reducing the risk of recurrent hyperthyroidism to less than 1%. In contrast, for a solitary toxic nodule, a lobectomy—removal of the affected thyroid lobe along with the isthmus—may be sufficient, preserving the contralateral lobe to avoid hypothyroidism. These operations are ideally conducted by high-volume surgeons, defined as those performing more than 30 thyroidectomies annually, to optimize outcomes.[88][90][89] Indications for thyroidectomy include failure or intolerance to antithyroid medications, such as methimazole or propylthiouracil; large goiters causing compressive symptoms like dysphagia or airway obstruction; suspicion of thyroid malignancy based on fine-needle aspiration; moderate-to-severe Graves' ophthalmopathy, where radioactive iodine is contraindicated; and patient preference for a swift, permanent resolution of hyperthyroidism. It is also favored in scenarios like pregnancy with severe hyperthyroidism unresponsive to medications, as it avoids potential fetal risks from prolonged antithyroid drug exposure. Additionally, surgery is considered for young patients or those with contraindications to radioactive iodine, such as desire for future pregnancy.[90][88][91] Preoperative preparation is essential to mitigate risks, beginning with achieving a euthyroid state using antithyroid drugs (e.g., methimazole 10-40 mg daily) combined with beta-blockers (e.g., propranolol 10-40 mg three to four times daily) to control symptoms like tachycardia and prevent thyroid storm; this typically takes 6 weeks to 3 months. In the 7-10 days prior to surgery, potassium iodide—such as Lugol's solution (5-7 drops three times daily) or saturated solution of potassium iodide (1-2 drops three times daily)—is administered to decrease thyroid vascularity, thereby reducing intraoperative blood loss by up to 40%. Calcium and vitamin D supplementation may also be given prophylactically to address potential hypoparathyroidism. Antithyroid drugs are discontinued on the day of surgery, while beta-blockers are continued and tapered postoperatively.[91][90][88] Complications of thyroidectomy for hyperthyroidism, though generally low in experienced hands, are slightly elevated in Graves' disease due to the gland's increased friability and vascularity. The following table summarizes key complication rates from a large single-center study of 594 patients undergoing total thyroidectomy for Graves' disease:| Complication | Transient Rate | Permanent Rate |
|---|---|---|
| Recurrent laryngeal nerve palsy | 5.2% | 0.16% |
| Hypoparathyroidism (hypocalcemia) | 40.6% | 0.5% |
| Hematoma (requiring intervention) | - | 0.5% |
| Seroma | - | 1.8% |