Hyperthyroidism

Hyperthyroidism Microchapters
Patient Information
Overview
Classification
Differentiating hyperthyroidism from other diseases
Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [2]Omar Elshafei, MD[3] 'For the WikiDoc patient information for this topic, click here

Overview

Thyroid hormones are responsible for regulating the basal metabolic rate of the body and influence oxygen consumption by peripheral tissues. Over secretion of thyroid hormones can lead to a wide variety of syndromes depending on the cause of the hyperthyroidism. Thyrotoxicosis is the clinical syndrome produced by excess circulating thyroid hormone from any source, whereas hyperthyroidism is the subset of thyrotoxicosis in which the excess arises from increased hormone synthesis and secretion by the thyroid gland itself; the distinction determines whether antithyroid drugs can be effective. Hyperthyroidism can be due to hyperactivity of the thyroid gland itself (primary hyperthyroidism) or due to abnormalities in the pituitary gland or the hypothalamus causing irregularities in the upper control of the gland. Hyperthyroidism can also be classified according to the results of iodine uptake study into high uptake, high or normal uptake, and low uptake, and according to biochemical severity into overt hyperthyroidism, subclinical hyperthyroidism, and thyroid storm. Graves' disease is the most common cause worldwide, followed by toxic multinodular goiter and toxic adenoma; the relative frequency of these causes varies with dietary iodine intake, with nodular autonomy predominating in iodine-deficient regions and Graves' disease predominating in iodine-replete regions. Hyperthyroidism must be differentiated from other diseases that cause insomnia, anxiety, and hypertension such as pheochromocytoma, generalized anxiety disorder, and essential hypertension. The pathophysiology and the compilation of symptoms and signs differ between the different diseases causing high thyroid activity. Evaluation begins with measurement of serum TSH together with free T4 and total T3; when the cause is not evident from the history and examination, measurement of thyrotropin receptor antibodies, radioactive iodine uptake with scintigraphy, or thyroid ultrasound with color flow Doppler establishes the etiology. Untreated or inadequately controlled hyperthyroidism is associated with atrial fibrillation, heart failure, osteoporosis, fracture, and excess mortality. Definitive treatment of Graves' disease comprises antithyroid drugs, radioactive iodine, or thyroidectomy, while autonomously functioning nodular disease is managed with radioactive iodine or surgery; beta blockers provide symptomatic control in all forms of thyrotoxicosis. Thyroid storm is a life-threatening decompensation of thyrotoxicosis that requires intensive care and multimodal therapy.

Classification

Thyrotoxicosis is classified along three complementary axes: the mechanism of hormone excess (thyrotoxicosis with versus without hyperthyroidism), the biochemical severity (overt, subclinical, or thyroid storm), and the radioactive iodine uptake (RAIU) pattern. The axes are not interchangeable; applied together they establish etiology and determine whether antithyroid drug therapy is appropriate.

Thyrotoxicosis Versus Hyperthyroidism

• Thyrotoxicosis is the clinical syndrome produced by excess circulating thyroid hormone from any source.
• Hyperthyroidism is the subset of thyrotoxicosis in which the excess arises from increased thyroid hormone synthesis and secretion by the thyroid gland.
• The distinction is treatment-defining: thionamides act by inhibiting hormone synthesis and are therefore ineffective in destructive and exogenous thyrotoxicosis.

Mechanistic Classification

The American Thyroid Association describes four mechanisms of thyrotoxicosis: excessive stimulation by trophic factors, constitutive activation of hormone synthesis, passive release of preformed hormone from a damaged gland, and an extrathyroidal hormone source.

Mechanistic classification of thyrotoxicosis

Category	Mechanism	Representative causes	Typical RAIU
Thyrotoxicosis with hyperthyroidism	Excessive stimulation by trophic factors	Graves disease (TSH-receptor antibodies); gestational thyrotoxicosis and trophoblastic disease (hCG); TSH-producing pituitary adenoma	High or normal
Thyrotoxicosis with hyperthyroidism	Constitutive activation of thyroid hormone synthesis	Toxic adenoma and toxic multinodular goiter (somatic TSH-receptor mutations); familial nonautoimmune hyperthyroidism (germline TSH-receptor mutations)	High or normal
Thyrotoxicosis with hyperthyroidism	Iodine-driven increase in synthesis	Iodine-induced hyperthyroidism (Jod-Basedow); type 1 amiodarone-induced thyrotoxicosis	Low, despite genuine hyperfunction, because the expanded iodine pool dilutes tracer uptake
Thyrotoxicosis without hyperthyroidism — destructive	Passive release of preformed hormone from inflammatory destruction	Subacute thyroiditis (painful); painless thyroiditis; postpartum thyroiditis; radiation thyroiditis; immune checkpoint inhibitor-induced thyroiditis; type 2 amiodarone-induced thyrotoxicosis	Low or absent
Thyrotoxicosis without hyperthyroidism — exogenous or ectopic	Extrathyroidal hormone source	Factitious thyrotoxicosis; iatrogenic levothyroxine overreplacement; struma ovarii; metastatic differentiated thyroid carcinoma	Low or absent

Biochemical Classification

Thyrotoxicosis exists on a continuum of severity that is categorized biochemically.

Biochemical categories of thyrotoxicosis

Category	TSH	Free T4	T3	Comment
Overt hyperthyroidism	Suppressed, usually undetectable	Elevated	Elevated or normal	Elevated free T4 and/or T3 with suppressed TSH
Subclinical hyperthyroidism	Low or suppressed	Normal	Normal	Subclassified as grade 1 (TSH 0.1–0.4 mIU/L), which accounts for 65–75% of cases, and grade 2 (TSH <0.1 mIU/L)
T3 thyrotoxicosis	Suppressed	Normal	Elevated	May represent early or mild Graves disease, or autonomous nodular disease
Thyroid storm	Suppressed	Thyrotoxic range	Thyrotoxic range	A clinical diagnosis of systemic decompensation superimposed on biochemical thyrotoxicosis; hormone concentrations do not define the diagnosis

Subclinical hyperthyroidism should be confirmed with repeat thyroid function testing at 3 to 6 months before the diagnosis is established, to exclude transient TSH suppression. The distinction between endogenous subclinical hyperthyroidism (from autonomous thyroid disease) and exogenous subclinical hyperthyroidism (from levothyroxine overreplacement) is clinically important, as natural history and management differ.

Treatment of grade 1 subclinical hyperthyroidism (TSH 0.1–0.4 mIU/L) is not recommended in asymptomatic patients younger than 65 years without cardiovascular disease or osteoporosis, in whom observation with periodic reassessment is appropriate. Professional organizations generally recommend treatment in persons older than 65 years and in postmenopausal women, particularly when TSH is less than 0.1 mIU/L. Whether symptomatic younger patients, or those with cardiovascular risk factors, warrant intervention at a TSH of 0.1–0.4 mIU/L remains contested.

Assay characteristics, analytical interference, and biochemical patterns by etiology are addressed further under Diagnosis, below, and in Hyperthyroidism laboratory findings.

Classification by Radioactive Iodine Uptake

RAIU pattern is a principal tool for etiologic classification when the cause is not clinically apparent.

Etiologic classification by radioactive iodine uptake pattern

Uptake	Distribution	Representative causes	Note
Elevated	Diffuse	Graves disease	Extensive toxic multinodular goiter can produce a pseudo-diffuse pattern; TRAb negativity helps distinguish
Elevated	Focal, with suppressed surrounding parenchyma	Toxic adenoma
Elevated	Multifocal, alternating areas of increased and suppressed uptake	Toxic multinodular goiter
Low or absent	Not applicable	Thyroiditis of all types; factitious thyrotoxicosis; recent iodine excess (iodinated contrast, amiodarone, dietary); struma ovarii	Low uptake does not equate to thyroiditis
Low or absent despite increased synthesis	Not applicable	Type 1 amiodarone-induced thyrotoxicosis; iodine-induced hyperthyroidism (Jod-Basedow)	Tc-99m sestamibi scintigraphy can aid separation of type 1 from type 2 amiodarone-induced thyrotoxicosis

Etiology may be established by TRAb measurement, RAIU, or thyroid ultrasound with Doppler, depending on local availability and expertise; a thyroid scan is specifically recommended when nodularity is present or suspected. Comparative selection among these strategies is addressed in Differentiating hyperthyroidism from other diseases.

Classification Pitfalls

• Misclassifying destructive thyrotoxicosis as hyperthyroidism. Destructive thyrotoxicosis reflects passive release of preformed hormone rather than increased synthesis; assigning it to the wrong mechanistic category leads to thionamide exposure that cannot alter a self-limited process.
• Assuming that all suppressed TSH represents thyrotoxicosis. Nonthyroidal illness, pituitary or hypothalamic disease, and medications such as glucocorticoids and dopamine suppress TSH without thyrotoxicosis.
• Interpreting RAIU without an iodine exposure history. Recent iodinated contrast or amiodarone suppresses uptake even in genuine Graves disease or toxic nodular disease.
• Overlooking the total T3:T4 ratio. A total T3:T4 ratio (ng/μg) greater than 20 favors Graves disease or toxic nodular goiter, whereas a ratio less than 20 suggests destructive thyroiditis or factitious thyrotoxicosis from levothyroxine, in which the T4-predominant stored hormone pool is released.
• Underrecognizing subclinical hyperthyroidism in older adults. In patients older than 65 years, TSH less than 0.1 mIU/L is associated with significantly increased risk of atrial fibrillation, heart failure, fractures, and dementia.

Differentiating hyperthyroidism from other diseases

Hyperthyroidism must be differentiated from other diseases that cause anxiety, elevated blood pressure, and insomnia; such as essential hypertension, generalized anxiety disorder, and pheochromocytoma.

Disease	Prominent clinical features	Investigations
Hyperthyroidism	The main symptoms include: Palpitations Insomnia Anxiety Weight loss Heat intolerance Diarrhea Depending on the underlying diagnosis, the patient might have exophthalmos or goiter	The patient usually has elevated T3 and T4 TSH is suppressed in primary hyperthyroidism and is inappropriately normal or elevated in central hyperthyroidism Thyroid stimulating antibodies (TSI) and other TSH receptor antibodies are elevated in Graves’ disease and are the preferred first-line etiologic test when the cause is not clinically evident
Essential hypertension	Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: Headache Blurry vision Dyspnea Epistaxis Tinnitus Fatigue Drowsiness	The following routine laboratory tests are recommended before initiation of therapy for hypertension: 12-Lead electrocardiogram (ECG) Urinalysis, including urinary albumin excretion or albumin/creatinine ratio Blood glucose Blood hematocrit Serum electrolytes, especially potassium Serum calcium Lipid profile: Total cholesterol, LDL, HDL, triglycerides Creatinine or estimated GFR
Generalized anxiety disorder	According to DSM V, the following criteria should be present to fit the diagnosis of generalized anxiety disorder: The presence of sense of apprehension or fear toward certain activities for most of the days for at least 6 months Difficulty to control the apprehension Associated restless, fatigue, irritability, difficulty concentration, muscle tension or sleep disturbance (only one of these manifestations) The anxiety or the physical manifestations must affect the social and the daily life of the patient Exclusion of another medical condition or the effect of another administered substance Exclusion of another mental disorder causing the symptoms	-
Menopause	The perimenopausal symptoms are caused by an overall drop, as well as dramatic but erratic fluctuations, in the levels of estrogens, progestin, and testosterone. Some of these symptoms such as formication etc may be associated with the hormone withdrawal process. Vasomotor instability in the form of hot flushes, including night sweats and sleep disturbances Urogenital atrophy causing itching, dryness, bleeding, watery discharge, urinary frequency, urinary urgency, and urinary incontinence Skeletal symptoms in the form of osteoporosis (gradually developing over time), artharlgia, myalgia, and back pain Psychological manifestations such as mood disturbance, irritability, fatigue, memory loss and depression Sexual disorders: Decreased libido, vaginal dryness, problems reaching orgasm and dyspareunia	B-HCG should always be done first to rule out pregnancy, especially in women under the age of 45 years. FSH can be measured but it can be falsely normal or low. TSH, T3, and T4 should be assessed to rule out thyroid abnormalities. Prolactin can be measured to rule out prolactinoma, as a cause of menopause.
Opioid withdrawal disorder	According to DSM V, the following criteria should be present to fit the diagnosis of opioid withdrawal: Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e., several weeks or longer) or administration of an opioid antagonist after a period of opioid use. Development of three or more of the following criteria minutes to days after cessation of drug use: Dysphoric mood, nausea or vomiting, muscle aches, Lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. The signs or symptoms mentioned above must cause impairment of the daily functioning of the patient. The signs or symptoms mentioned above must not be attributed to other medical or mental disorders.	Urine drug screen to rule out any other associated drug abuse Routine blood work such as electrolytes and hemoglobin to rule out any associated disease explaining the symptoms
Pheochromocytoma	The hallmark symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include: Palpitations, especially in epinephrine producing tumors Anxiety often resembling that of a panic attack Sweating Headaches occur in 90 % of patients. Paroxysmal attacks of hypertension, but some patients have normal blood pressure It may be asymptomatic and discovered by incidence screening especially MEN patients Please note that not all patients with pheochromocytoma experience all classical symptoms.	Diagnostic lab findings associated with pheochromocytoma include: Elevated plasma, urinary catecholamines, and metanephrines Elevated urinary vanillyl mandelic acid

Differentiating the causes of thyrotoxicosis

Cause of thyrotoxicosis	TSH receptor antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	↑	↑	Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules at thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	↓	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	↓	-
Amiodarone induced thyrotoxicosis-Type 1	-	Diffuse or nodular goiter	↓/Normal/↑	↓ but higher than in Type 2	High urinary iodine; iodine-induced excess synthesis in nodular goiter or latent Graves disease; thionamides, with sodium perchlorate for a few weeks in selected patients
Amiodarone induced thyrotoxicosis-Type 2	-	Normal	Absent	↓/absent	High urinary iodine; destructive thyroiditis in a normal gland; oral glucocorticoids are first-line
Central hyperthyroidism	-	Diffuse or nodular goiter	Normal/↑	↑	Inappropriately normal or high TSH
Trophoblastic disease	-	Diffuse or nodular goiter	Normal/↑	↑	-
Factitious thyrotoxicosis	-	Variable	Reduced/absent flow	↓	↓ Serum thyroglobulin
Struma ovarii	-	Variable	Reduced/absent flow	↓	Abdominal RAIU

Prominent features in the different causes of hyperthyroidism

Disease		Findings
Thyroiditis	Direct chemical toxicity with inflammation	Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.
	Radiation thyroiditis	Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
	Drugs that interfere with the immune system	Interferon-alfa is a well-known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.
	Immune checkpoint inhibitors	Immune checkpoint inhibitors cause a destructive thyroiditis that typically presents with a short thyrotoxic phase followed by hypothyroidism. Incidence differs by agent and is highest with combination PD-1 and CTLA-4 blockade.
	Lithium	Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves' disease.
	Palpation thyroiditis	Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during the physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism	Factitious ingestion of thyroid hormone	The diagnosis is based on the clinical features, laboratory findings, low or suppressed serum thyroglobulin, and 24-hour radioiodine uptake.
	Acute hyperthyroidism from a levothyroxine overdose	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Struma ovarii	Functioning thyroid tissue is present in an ovarian neoplasm.
	Functional thyroid cancer metastases	Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis		It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease. It is then followed by the development of hypothyroidism due to the infiltration of the thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.
Toxic adenoma and toxic multinodular goiter		Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation, most often driven by somatic activating mutations of the TSH receptor. Findings of single or multiple nodules are seen on physical examination or thyroid scan.
Iodine-induced hyperthyroidism		It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors		Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.

Epidemiology and Demographics

• Hyperthyroidism is common. Contemporary reviews report that it affects approximately 2.5% of adults worldwide, while pooled prevalence estimates restricted to biochemically confirmed disease give a global prevalence of 0.2–1.3%; the difference reflects differing case definitions and whether subclinical disease is included.
• Among patients with subclinical hyperthyroidism, grade 1 disease (TSH 0.1–0.4 mIU/L) accounts for 65–75% of cases, with the remainder having grade 2 disease (TSH <0.1 mIU/L).
• Hyperthyroidism of all causes is substantially more frequent in women than in men, and the incidence of Graves' disease peaks in the third to fifth decades, whereas toxic multinodular goiter is a disease of later life.
• Dietary iodine intake is the principal determinant of the distribution of etiologies. Comparative population surveys demonstrated a high incidence of multinodular toxic goitre in the elderly population of a low iodine intake area, contrasted with a high incidence of Graves' disease in the young in a high iodine intake area. Iodine deficiency therefore shifts the burden toward autonomous nodular disease, while iodine sufficiency and iodine supplementation shift it toward autoimmune disease.
• Amiodarone-associated thyroid dysfunction occurs in a substantial minority of treated patients, and amiodarone-induced thyrotoxicosis is relatively more frequent in iodine-deficient regions, whereas amiodarone-induced hypothyroidism predominates in iodine-replete regions.
• Thyroid dysfunction following immune checkpoint inhibitor therapy is now a recognized and increasingly frequent cause of drug-induced thyrotoxicosis, with incidence varying by regimen and highest with combination therapy.
• Agranulocytosis and pancytopenia during antithyroid drug therapy have been quantified in a retrospective cohort of 50,385 patients with Graves' disease, establishing these as rare but clinically important population-level risks.
• Thyroid storm is rare. Nationwide surveys conducted in Japan assembled detailed clinical data on 356 patients and formed the basis of formal, population-derived diagnostic criteria.

Pathophysiology

Rgulation of thyroxin secretion - By CFCF; slightly modified by Geo-Science-International - This file was derived from Thyroid vector.svg:, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=47043638

• Thyroid hormones (T3 and T4) are regulating basal metabolic rate, influence oxygen consumption by tissues. They are crucial for normal development of the brain and growth of the body, especially in prepubertal period.
• Secretion of thyroid hormones follows upper control from the hypothalamus and the pituitary. Thyroid releasing hormone (TRH) acts on thyrotropes releasing cells in the pituitary causing them to release thyroid stimulating hormone (TSH).
• TSH acts on thyroid gland by binding to specific membrane receptors and activating an intracellular pathway involving cAMP that ends in the formation and secretion of thyroid hormones.
• Iodine is essential for the synthesis of thyroid hormones. The daily iodide need is about 100 mcg/day. Iodide is up taken through a special Na/I transporter found in the membrane of thyroid follicular cell. After the iodide uptake, it goes through a series of organic reactions ending in the formation of the two forms of thyroid hormones: T3 and T4. T3 and T4 remain stored in the thyroglobulin of the follicles and are released in response to further stimulation by TSH to the thyroid follicles.
• While T3 is 3 to 5 times more potent than T4, it represents only one-fourth of the total hormone secretion. T3 is thought to be the biologically active form of the of the two forms of the hormone. Most of the circulating T3 is due to peripheral conversion of T4 in the liver and peripheral tissues while only a small percentage is secreted directly from the thyroid gland itself.
• T3 and T4 act on nuclear receptors (DNA binding proteins) and cause the regulate the transcription of many proteins to regulate the metabolic rate of the body.
• The higher regulation of thyroxine secretion follows the negative feedback role, meaning that high levels of T3 and T4 will suppress TRH and TSH secretion and vice versa (Low levels of thyroxine will stimulate TRH and TSH secretion). This is useful in diagnosing the cause of hyperthyroidism (in secondary hyperthyroidism, where the pituitary or the hypothalamus are the sources of the disease, TSH will be inappropriately normal or high; while in primary hyperthyroidism where the gland is the source of the excess hormones, TSH will be low).
• Because the log-linear relationship between TSH and free T4 amplifies small changes in hormone concentration into large changes in TSH, TSH is the most sensitive single indicator of thyroid status in patients with an intact hypothalamic-pituitary axis; it is unreliable in central disease, in nonthyroidal illness, and during the first months after correction of long-standing thyrotoxicosis, when TSH suppression persists despite normalization of free T4 and T3.
• Graves' disease which is the most common cause of hyperthyroidism lies in the secretion of thyroid stimulating antibodies (TSI) that work on thyroid follicular cells causing an excessive uncontrolled release of the thyroxine. TSI responsible for many other aspects of the disease such as ophthalmopathy and the skin manifestations. This is thought to be due to the epitopic similarity between antigens on the surface of these cells and the thyroid receptors.
• In Graves' orbitopathy, orbital fibroblasts co-express the TSH receptor and the insulin-like growth factor 1 receptor, which form a functional signalling complex. Autoantibody-driven activation of this complex stimulates hyaluronan production and adipogenesis, expanding orbital fat and extraocular muscle volume; this mechanism is the rationale for insulin-like growth factor 1 receptor blockade as targeted therapy.
• Toxic nodular goiter involves the growth of a various number of nodules (ranging from one to tens). These nodules either bleed and undergo degeneration and fibrosis followed by calcification or they might have autonomous activity producing excess thyroxin. Autonomy most often results from somatic activating mutations of the TSH receptor, which render the affected follicular cells independent of TSH and therefore incapable of spontaneous remission.
• In destructive thyrotoxicosis, inflammation disrupts follicular integrity and preformed T3 and T4 leak passively into the circulation. Synthesis is not increased, radioactive iodine uptake is low or absent, thionamides are ineffective, and the thyrotoxic phase is self-limited and typically followed by a hypothyroid phase before recovery.
• Excess thyroid hormone increases resting heart rate, cardiac contractility, and cardiac output while reducing systemic vascular resistance; it also shortens the atrial refractory period, which underlies the association with atrial fibrillation. In bone, thyroid hormone excess accelerates bone remodelling with a net loss of bone mineral density.
• The majority of circulating T3 and T4 are bound to plasma proteins and thus not active (T4 is mostly bound to thyroxine binding globulin and T3 is mostly bound to transthyretin). Conditions that impair the production of thyroid binding globulins (such as pregnancy, liver failure, and certain drug administration) cause a change in the total serum thyroxine but the free T3 and T4 remain normal and the patient remain (this carries only laboratory significance).

Screening

• Universal population screening of asymptomatic, non-pregnant adults for hyperthyroidism is not recommended. Detection instead rests on targeted case finding, in which serum TSH is measured in patients whose clinical presentation or drug exposure confers elevated risk.
• Measurement of serum TSH is indicated in the following circumstances.

Targeted case finding for hyperthyroidism

Group	Rationale and testing approach
Unexplained atrial fibrillation or other unexplained tachyarrhythmia	Both overt and subclinical hyperthyroidism increase the risk of atrial fibrillation; measure TSH as part of the initial arrhythmia evaluation
Osteoporosis or low-trauma fracture, particularly in postmenopausal women	Thyroid hormone excess accelerates bone loss; unrecognized subclinical hyperthyroidism is a modifiable contributor
Unexplained weight loss, heat intolerance, palpitations, tremor, or proximal myopathy	Classical presentation; older patients may present with a paucity of adrenergic symptoms and predominant apathy, weight loss, or atrial fibrillation
Goiter, thyroid nodule, or orbitopathy found on examination	Structural or extrathyroidal signs warrant biochemical assessment regardless of symptoms
Patients starting or receiving amiodarone	Thyroid function should be assessed before initiation and monitored periodically during and after therapy, because dysfunction may appear at any time and may persist after withdrawal given the long half-life of the drug
Patients receiving immune checkpoint inhibitors, lithium, interferon, or tyrosine kinase inhibitors	Baseline and periodic thyroid function testing during therapy permits early detection of drug-induced thyroiditis
Patients receiving levothyroxine	Iatrogenic subclinical hyperthyroidism from overreplacement is a common and readily corrected cause of a suppressed TSH
Preconception, pregnancy, and postpartum	Thyroid function testing is directed by risk factors, which include known thyroid disease or prior thyroid surgery or radioactive iodine therapy, thyroid autoimmunity, goiter, symptoms of thyroid dysfunction, infertility or recurrent pregnancy loss, and a family history of autoimmune thyroid disease

• A suppressed TSH detected on case finding should be confirmed on a repeat sample together with free T4 and total T3, and, when values are within the reference range, repeated at 3 to 6 months before subclinical hyperthyroidism is diagnosed, in order to exclude transient suppression.

Natural History, Complications and Prognosis

Natural History

• Untreated overt hyperthyroidism is progressive and does not remit in autonomous nodular disease. Toxic adenoma and toxic multinodular goiter arise from constitutively activated follicular cells and therefore require definitive therapy; antithyroid drugs control but do not cure them.
• Graves' disease follows a relapsing and remitting course. In a randomized clinical trial of methimazole duration, hyperthyroidism recurred within 48 months of drug withdrawal in 15% (18/119) of patients treated long term, compared with 53% (65/123) of patients treated for a conventional course.
• Destructive thyrotoxicosis, including subacute thyroiditis, painless and postpartum thyroiditis, type 2 amiodarone-induced thyrotoxicosis, and immune checkpoint inhibitor-associated thyroiditis, is self-limited. A thyrotoxic phase of weeks to a few months is typically followed by a hypothyroid phase, with recovery in most but permanent hypothyroidism in a minority.
• Subclinical hyperthyroidism may resolve spontaneously, persist, or progress to overt disease; progression is more likely with grade 2 disease and with underlying nodular autonomy.

Complications

Complications of hyperthyroidism

System	Complication and supporting evidence
Cardiovascular	Atrial fibrillation, heart failure, angina, and pulmonary hypertension. In an individual participant data analysis of prospective cohorts, subclinical hyperthyroidism was associated with increased total mortality, coronary heart disease mortality, coronary heart disease events, and atrial fibrillation, with risks greatest when TSH was less than 0.10 mIU/L. A parallel individual participant data analysis from 6 prospective cohorts demonstrated an increased risk of heart failure events with subclinical thyroid dysfunction.
Skeletal	Accelerated bone turnover, reduced bone mineral density, osteoporosis, and fracture. In patients older than 65 years, TSH less than 0.1 mIU/L is associated with significantly increased risk of atrial fibrillation, heart failure, fractures, and dementia.
Ocular	Graves' orbitopathy with proptosis, diplopia, exposure keratopathy, and in the most severe cases dysthyroid optic neuropathy threatening sight. Smoking, uncontrolled thyroid dysfunction, and high TSH receptor antibody titres are recognized risk factors.
Neuropsychiatric	Anxiety, insomnia, emotional lability, tremor, and in older patients apathetic thyrotoxicosis. Dementia risk is increased in older adults with a markedly suppressed TSH.
Musculoskeletal and metabolic	Proximal myopathy, weight loss despite preserved or increased appetite, and thyrotoxic periodic paralysis in susceptible individuals.
Treatment-related	Agranulocytosis and pancytopenia with antithyroid drugs; hepatotoxicity, particularly with propylthiouracil; permanent hypothyroidism after radioactive iodine or thyroidectomy; and hypoparathyroidism or recurrent laryngeal nerve injury after thyroidectomy.
Life-threatening decompensation	Thyroid storm, characterized by multiple organ failure superimposed on severe thyrotoxicosis and usually precipitated by an intercurrent illness, surgery, trauma, or abrupt withdrawal of antithyroid therapy.

Prognosis

• With effective and sustained restoration of euthyroidism, prognosis is good and most complications are reversible or preventable. Prognosis worsens with the cumulative duration of untreated thyrotoxicosis.
• In a linked-record cohort study of primary therapy for Graves' disease, choice of first-line modality was examined against cardiovascular morbidity and mortality; the study supports early and durable control of thyrotoxicosis rather than any single modality as the principal determinant of cardiovascular outcome.
• Long-term follow-up using the Thyroid-Related Patient-Reported Outcome questionnaire and the 36-Item Short Form Health Status Survey found impaired quality of life after radioactive iodine therapy compared with antithyroid drugs or surgical treatment for Graves' hyperthyroidism, although the treatment groups differed in age and comorbidity.
• The relationship between radioactive iodine therapy and subsequent cancer mortality is disputed. A long-term follow-up of the Cooperative Thyrotoxicosis Therapy Follow-up Study reported a modest dose-related association between greater organ-absorbed dose and solid cancer mortality, while a subsequent systematic review and meta-analysis of the available cohorts found the overall evidence for an increased cancer risk after radioactive iodine treatment for hyperthyroidism to be limited and inconsistent. Current society guidance continues to regard radioactive iodine as an effective and acceptably safe definitive therapy, with individualized counselling.
• Thyroid storm carries the worst prognosis of any presentation of thyrotoxicosis. Analysis of the Japanese nationwide surveys found mortality in Japan to be approximately 11%, with multiple organ failure and acute heart failure the common causes of death.

Diagnosis

Diagnostic Approach

Evaluation proceeds in two steps: biochemical confirmation of thyrotoxicosis, then determination of its cause. Where the cause is not evident from the history and examination, measurement of TSH receptor antibodies, radioactive iodine uptake with scintigraphy, or thyroid ultrasound with color flow Doppler may each be used, selected according to local availability and expertise; a thyroid scan is specifically indicated when nodularity is present or suspected.

Clinical features of thyrotoxicosis: measure serum TSH with free T4 and total T3

Suppressed TSH with elevated free T4 and/or T3 confirms overt thyrotoxicosis; cause not evident from history and examination

Measure TSH receptor antibodies; if unavailable or discordant, obtain radioactive iodine uptake with scintigraphy or thyroid ultrasound with color flow Doppler

Antibodies positive, diffuse uptake, increased vascularity: Graves' disease

Antibodies negative, focal or multifocal uptake, nodules on ultrasound: toxic adenoma or toxic multinodular goiter

Antibodies negative, low or absent uptake, reduced vascularity: destructive, iodine-induced, exogenous, or ectopic thyrotoxicosis

History and Symptoms

• Cardinal symptoms include palpitations, heat intolerance, increased sweating, weight loss despite preserved or increased appetite, tremor, anxiety, insomnia, increased stool frequency or diarrhea, oligomenorrhea, and proximal muscle weakness.
• Older adults frequently present with a paucity of adrenergic symptoms, and may instead present with atrial fibrillation, weight loss, apathy, or worsening heart failure or angina.
• The history should specifically establish the duration and tempo of symptoms; a recent painful neck; recent pregnancy or delivery; exogenous thyroid hormone ingestion, including unregulated preparations and weight-loss products; recent iodinated contrast; and drug exposure to amiodarone, lithium, interferon, tyrosine kinase inhibitors, and immune checkpoint inhibitors.
• A family history of autoimmune thyroid disease and a personal or family history of other autoimmune disease supports Graves' disease.

Physical Examination

• Tachycardia, widened pulse pressure, warm moist skin, fine tremor, hyperreflexia, and lid lag and lid retraction occur in thyrotoxicosis of any cause.
• A diffuse, smooth, non-tender goiter, sometimes with a bruit, supports Graves' disease; a nodular gland supports toxic multinodular goiter or toxic adenoma; a painful, tender gland supports subacute thyroiditis.
• Graves' orbitopathy, thyroid dermopathy, and thyroid acropachy are specific to Graves' disease and, when present, obviate further etiologic testing.
• All patients with Graves' disease should be assessed for orbital involvement, with grading of activity and severity, and referred to a specialist centre when moderate-to-severe or sight-threatening disease is suspected.

Laboratory Findings

• Serum TSH is the initial test and is measured together with free T4 and total T3. Suppressed TSH with elevated free T4 and/or T3 defines overt thyrotoxicosis; suppressed TSH with normal free T4 and T3 defines subclinical hyperthyroidism.
• An inappropriately normal or elevated TSH in the presence of elevated free T4 should prompt evaluation for a TSH-secreting pituitary adenoma, resistance to thyroid hormone, and assay interference before the result is accepted at face value.
• TSH receptor antibodies are the preferred first-line etiologic test in most settings, are sensitive and specific for Graves' disease, and are additionally used to assess relapse risk before antithyroid drug withdrawal and to stratify fetal risk in pregnancy.
• A total T3:T4 ratio (ng/μg) greater than 20 favors Graves' disease or toxic nodular goiter, whereas a ratio less than 20 suggests destructive thyroiditis or factitious thyrotoxicosis from levothyroxine.
• A low or suppressed serum thyroglobulin distinguishes factitious or iatrogenic thyrotoxicosis, in which endogenous synthesis is suppressed, from destructive thyroiditis, in which thyroglobulin is released with preformed hormone.
• Baseline complete blood count with differential and a liver profile are obtained before starting antithyroid drugs, because mild leukopenia and transaminase elevation are common in untreated thyrotoxicosis and complicate later attribution of adverse effects.
• Assay interference should be considered whenever results are discordant with the clinical picture. Recognized causes include biotin supplementation, heterophile and anti-ruthenium antibodies, macro-TSH, and anti-T4 or anti-T3 autoantibodies; repeating the assay on a different platform or after biotin withdrawal resolves most cases.

Imaging and Other Diagnostic Studies

• Radioactive iodine uptake and scintigraphy. Quantifies fractional trapping and displays its distribution, separating diffuse hyperfunction, focal or multifocal autonomy, and low-uptake states. It is contraindicated in pregnancy and lactation, and is uninterpretable after recent iodine loading.
• Thyroid ultrasound with color flow Doppler. Demonstrates a hypoechoic gland with increased vascularity in Graves' disease and reduced or absent flow in destructive thyroiditis, and characterizes nodules. It carries no radiation exposure and is the preferred modality in pregnancy.
• Tc-99m sestamibi scintigraphy. Assists in distinguishing type 1 from type 2 amiodarone-induced thyrotoxicosis when conventional uptake studies are uninformative because of iodine loading.
• Orbital imaging. Computed tomography or magnetic resonance imaging of the orbits is indicated when dysthyroid optic neuropathy is suspected, when proptosis is markedly asymmetric, or before orbital decompression surgery.
• Electrocardiogram. Obtained in all patients with palpitations, irregular pulse, or known cardiac disease, to detect atrial fibrillation and other tachyarrhythmias.

Treatment

Initial Management

• Confirm thyrotoxicosis biochemically and establish the mechanism before committing to definitive therapy, because thionamides, radioactive iodine, and surgery are all inappropriate for destructive and exogenous thyrotoxicosis.
• Beta-adrenergic blockade is the first symptomatic measure in thyrotoxicosis of any cause. It is recommended in all older patients with symptomatic thyrotoxicosis and in any patient with a resting heart rate above 90 beats per minute or with coexistent cardiovascular disease. Atenolol and metoprolol permit once- or twice-daily dosing; propranolol in high doses additionally reduces peripheral conversion of T4 to T3.
• Where beta blockers are contraindicated, as in bronchospasm, a non-dihydropyridine calcium channel blocker such as verapamil or diltiazem may be used for rate control.
• Destructive thyrotoxicosis is managed supportively with beta blockers and, in subacute thyroiditis, analgesia with non-steroidal anti-inflammatory drugs or glucocorticoids; thionamides have no role.
• Assess for features of decompensation. Severe thyrotoxicosis accompanied by fever, central nervous system disturbance, congestive heart failure, tachyarrhythmia, or gastrointestinal and hepatic dysfunction should raise the possibility of thyroid storm and prompt immediate escalation to intensive care.
• Advise smoking cessation in all patients with Graves' disease, and confirm pregnancy status in all women of reproductive age before any definitive therapy is planned.

Medical Therapy

• Methimazole is the preferred antithyroid drug in essentially all non-pregnant patients, and carbimazole where methimazole is unavailable. Propylthiouracil is reserved for the first trimester of pregnancy, for thyroid storm, and for patients with minor adverse reactions to methimazole who decline radioactive iodine or surgery, because propylthiouracil carries a risk of severe and occasionally fatal hepatotoxicity.
• Starting dose is guided by the severity of biochemical thyrotoxicosis and by goiter size, and is then titrated to the lowest dose that maintains euthyroidism.
• Monitoring. Free T4 and total T3 are measured approximately 2 to 6 weeks after initiation and after each dose adjustment. Serum TSH may remain suppressed for several months after free T4 normalizes and should not be used alone to guide early titration.
• Adverse effects. Minor cutaneous reactions are the most frequent. Agranulocytosis and pancytopenia are rare but potentially fatal and have been characterized in a retrospective cohort of 50,385 patients with Graves' disease. Every patient must be instructed to stop the drug and obtain a white blood cell count with differential if fever or pharyngitis develops, and to seek assessment for jaundice, pale stool, dark urine, or right upper quadrant pain. Antineutrophil cytoplasmic antibody-associated vasculitis is an uncommon complication, more often reported with propylthiouracil.
• Routine surveillance blood counts are not a substitute for symptom-triggered testing, since agranulocytosis is typically abrupt in onset.
• Adjunctive agents. Inorganic iodine as saturated solution of potassium iodide or Lugol's iodine acutely inhibits hormone release and is used preoperatively and in thyroid storm. Glucocorticoids reduce T4 to T3 conversion, cholestyramine interrupts enterohepatic recirculation of thyroid hormone, and lithium may be used in selected refractory cases.
• In type 2 amiodarone-induced thyrotoxicosis, oral glucocorticoids are first-line therapy; in type 1, thionamides are used, combined for a few weeks with sodium perchlorate in selected patients to render the gland more sensitive to thionamides. The decision to continue or stop amiodarone should be individualized according to cardiovascular risk and taken jointly by cardiologists and endocrinologists.

Procedural / Surgical Therapy

Confirmed Graves hyperthyroidism; symptoms controlled with beta blockers

Discuss antithyroid drugs, radioactive iodine, and thyroidectomy; individualize to comorbidity, goiter size, orbitopathy, pregnancy plans, access to care, and patient preference

Antithyroid drugs: methimazole titrated for 12 to 18 months, then measure TSH receptor antibodies before withdrawal

Radioactive iodine: avoid in pregnancy and lactation and in active moderate-to-severe orbitopathy; anticipate permanent hypothyroidism

Thyroidectomy: total or near-total, by a high-volume surgeon, after restoration of euthyroidism and preoperative potassium iodide

Selection among definitive treatment modalities

Modality	Preferred when	Avoid or use with caution when	Principal adverse effects
Antithyroid drugs	First presentation of Graves' disease; high likelihood of remission (mild disease, small goiter, low TSH receptor antibody titre); active orbitopathy; pregnancy; patient preference for avoiding radiation or surgery	Previous major adverse reaction to a thionamide; poor adherence or inability to attend for monitoring; toxic multinodular goiter or toxic adenoma, in which remission does not occur	Rash, arthralgia, hepatotoxicity (greater with propylthiouracil), agranulocytosis, vasculitis
Radioactive iodine	Toxic multinodular goiter and toxic adenoma; relapsed Graves' disease; high surgical risk; contraindication to thionamides	Pregnancy and lactation; planned pregnancy in the near term; active moderate-to-severe or sight-threatening orbitopathy; inability to comply with radiation protection instructions; suspected thyroid malignancy	Permanent hypothyroidism; transient radiation thyroiditis; worsening of orbitopathy, for which prophylactic glucocorticoids are given to at-risk patients; disputed long-term cancer mortality signal
Thyroidectomy	Large compressive goiter; suspected or confirmed thyroid malignancy; coexisting primary hyperparathyroidism; moderate-to-severe orbitopathy; need for rapid, definitive control; women planning pregnancy in the near term; low radioactive iodine uptake	Substantial anaesthetic or surgical risk; absence of a high-volume thyroid surgeon	Permanent hypothyroidism; transient or permanent hypoparathyroidism; recurrent laryngeal nerve injury; bleeding; scar

• Radioactive iodine therapy. The therapeutic aim in Graves' disease is ablation of thyroid function with resulting hypothyroidism, rather than euthyroidism, since a euthyroid target is associated with higher rates of persistent or recurrent hyperthyroidism. Activity may be selected empirically or by dosimetry; the European Association of Nuclear Medicine guideline details patient preparation, empirical and dosimetric approaches, applied activity, radiation protection requirements, and follow-up after administration.
• A pregnancy test is mandatory in women of reproductive potential before administration, and conception should be deferred after treatment in accordance with local radiation protection guidance.
• Antithyroid drugs are usually withheld for several days before and restarted several days after radioactive iodine in patients who require them, and beta blockers are continued through the peri-treatment period.
• Patients with risk factors for progression of orbitopathy, particularly smokers and those with high TSH receptor antibody titres or pre-existing eye disease, should receive prophylactic oral glucocorticoids with radioactive iodine, or be offered an alternative modality.
• Thyroidectomy. Total or near-total thyroidectomy is the operation of choice for Graves' disease and is performed after restoration of euthyroidism with methimazole. Preoperative potassium iodide is given in Graves' disease to reduce thyroid blood flow and intraoperative blood loss. Serum calcium and vitamin D should be assessed and repleted preoperatively, and the procedure should be performed by a high-volume thyroid surgeon to minimize the risk of hypoparathyroidism and recurrent laryngeal nerve injury.

Long-Term Management

• After a conventional course of antithyroid drugs. Treatment is continued for 12 to 18 months, after which TSH receptor antibodies are measured; persistently elevated titres predict relapse and favour either continued drug therapy or definitive treatment, whereas normalized titres support a trial of withdrawal.
• Long-term low-dose antithyroid drug therapy is now an evidence-supported alternative to definitive treatment. In a randomized clinical trial, methimazole was given for 95 ± 22 months in the long-term group and 19 ± 3 months in the conventional group. Fourteen patients experienced cutaneous reactions and 2 experienced liver enzyme elevations during the first 18 months of treatment, and no further methimazole-related reactions were observed despite therapy for up to another 118 months. Hyperthyroidism recurred within 48 months after methimazole withdrawal in 15% (18/119) of long-term patients versus 53% (65/123) of conventional group patients.
• After relapse. Options are a further course of antithyroid drugs, long-term low-dose therapy, radioactive iodine, or thyroidectomy, chosen with the patient.
• After definitive therapy. Hypothyroidism is expected after radioactive iodine and after total or near-total thyroidectomy. Thyroid function is checked at short intervals in the first months and, once levothyroxine replacement is stable, at least annually thereafter.
• Following remission. Lifelong periodic measurement of serum TSH is appropriate, since relapse may occur years later and since hypothyroidism may supervene.
• Comorbidity surveillance. Rate and rhythm control and anticoagulation decisions in atrial fibrillation follow standard cardiovascular criteria; bone mineral density should be assessed in patients with prolonged thyrotoxicosis, in postmenopausal women, and in older men.
• Counselling on outcomes. Patients should be informed that quality of life may remain impaired after treatment, that impairment has been reported to be greater after radioactive iodine than after antithyroid drugs or surgery in long-term follow-up, and that the evidence on cancer mortality after radioactive iodine is disputed.

Special Populations

Pregnancy, Preconception, and Postpartum

• Gestational transient thyrotoxicosis, driven by HCG cross-stimulation of the TSH receptor, must be distinguished from Graves' disease. It is typically associated with hyperemesis gravidarum, absent TSH receptor antibodies, and no goiter or orbitopathy, and is managed supportively rather than with thionamides.
• Propylthiouracil is preferred during the first trimester because of the higher risk of characteristic embryopathy with methimazole; transition to methimazole is generally made thereafter given the hepatotoxicity of propylthiouracil. The lowest effective dose is used, targeting free T4 at or slightly above the upper reference limit for pregnancy.
• TSH receptor antibodies should be measured in pregnant women with current or previously treated Graves' disease, because transplacental antibody transfer can cause fetal and neonatal hyperthyroidism even in mothers rendered euthyroid by prior radioactive iodine or surgery; elevated titres warrant fetal surveillance.
• Radioactive iodine is contraindicated in pregnancy and lactation. When definitive therapy is required before conception, thyroidectomy or radioactive iodine with an appropriate interval before conception is planned in advance.
• Postpartum thyroiditis should be considered in any woman presenting with thyrotoxicosis in the first postpartum year; it is destructive, self-limited, and does not respond to thionamides.

Children and Adolescents

• Methimazole or carbimazole is the antithyroid drug of choice; propylthiouracil is avoided outside exceptional circumstances because of the risk of severe hepatotoxicity in this age group.
• Remission rates with antithyroid drugs are lower than in adults, and longer courses are commonly used before definitive therapy is considered. When definitive therapy is required, thyroidectomy by a high-volume surgeon is generally preferred in younger children, with radioactive iodine an option in older children and adolescents.

Graves' Orbitopathy and Thyroid Eye Disease

• Restoration and maintenance of euthyroidism, smoking cessation, and selenium supplementation in selenium-deficient areas are recommended in all patients; local measures such as ocular lubricants and elevation of the head at night relieve mild disease.
• Moderate-to-severe active disease requires referral to a specialist centre. Intravenous methylprednisolone has been the established first-line immunosuppressive therapy; in a randomized, observer-masked, multicentre trial, the addition of mycophenolate to methylprednisolone improved response compared with methylprednisolone alone in active, moderate-to-severe disease.
• Blockade of the insulin-like growth factor 1 receptor with teprotumumab produced significant reductions in proptosis and clinical activity compared with placebo in a randomized, double-masked, placebo-controlled trial, and has since been positioned as a first-line option for moderate-to-severe active disease in some society guidance while others retain intravenous glucocorticoids as first-line; the two positions differ and are actively debated.
• Sight-threatening disease with dysthyroid optic neuropathy requires urgent high-dose intravenous glucocorticoids and, if the response is inadequate, urgent orbital decompression.
• Radioactive iodine may worsen orbitopathy; prophylactic oral glucocorticoids are given to at-risk patients or an alternative modality is selected.

Amiodarone-Associated Thyroid Dysfunction

• Thyroid function should be assessed before amiodarone is started and monitored periodically during and after therapy.
• Type 1 amiodarone-induced thyrotoxicosis is iodine-induced hyperthyroidism arising in nodular goiter or latent Graves' disease and is treated with thionamides, which may be combined for a few weeks with sodium perchlorate. Type 2 results from destructive thyroiditis in an otherwise normal gland and is treated with oral glucocorticoids. Mixed and indefinite forms occur and may require combined therapy.
• Whether to continue or stop amiodarone should be individualized according to cardiovascular risk stratification and decided jointly by cardiologists and endocrinologists. Total thyroidectomy is a valid option when medical therapy fails or when rapid restoration of euthyroidism is required.

Drug-Induced Thyrotoxicosis

• Immune checkpoint inhibitors cause destructive thyroiditis with a brief thyrotoxic phase, most often followed by permanent hypothyroidism. Management is supportive with beta blockers; thionamides are ineffective, and glucocorticoids are not routinely required for isolated thyroiditis. Incidence varies by regimen and is highest with combination therapy.
• Lithium, interferon, and tyrosine kinase inhibitors may each precipitate destructive thyroiditis or, less commonly, Graves' disease; management follows the underlying mechanism.

Older Adults and Subclinical Hyperthyroidism

• Treatment is recommended in persons older than 65 years and in postmenopausal women, particularly when TSH is less than 0.1 mIU/L, because of the associated risks of atrial fibrillation, heart failure, fracture, and dementia.
• Observation with periodic reassessment is appropriate for asymptomatic patients younger than 65 years with grade 1 disease and without cardiovascular disease or osteoporosis.
• Where subclinical hyperthyroidism results from levothyroxine overreplacement, dose reduction rather than antithyroid therapy is the correct intervention.

Thyroid Storm

• Thyroid storm is a clinical diagnosis of systemic decompensation superimposed on biochemical thyrotoxicosis; hormone concentrations do not define it. Population-derived diagnostic criteria were formulated from nationwide surveys and require thyrotoxicosis together with combinations of central nervous system manifestations, fever, tachycardia, congestive heart failure, and gastrointestinal or hepatic disturbance.
• Management is multimodal and delivered in an intensive care unit. Combined therapy with antithyroid drugs, inorganic iodine, corticosteroids, and beta-adrenergic antagonists has been associated with improved mortality; inorganic iodine is given after the thionamide to avoid substrate loading. Propylthiouracil is preferred in this setting for its additional inhibition of peripheral T4 to T3 conversion.
• Precipitants must be identified and treated, and organ failure in the central nervous system, the cardiovascular system, and the hepato-gastrointestinal tract managed concurrently.
• Plasmapheresis has been used successfully in refractory cases and in thyrotoxicosis from massive exogenous hormone exposure.
• Prognosis remains guarded; nationwide survey data place mortality in Japan at approximately 11%, with multiple organ failure and acute heart failure the common causes of death.

Case Studies

Case #1

Hyperthyroidism case study one