Seminar

Hyperthyroidism
Layal Chaker, David S Cooper, John P Walsh, Robin P Peeters

Lancet 2024; 403: 768–80 Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased
Published Online thyroid hormone synthesis and secretion, most commonly from Graves’ disease or toxic nodular goitre, whereas
January 23, 2024 thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The
https://doi.org/10.1016/
S0140-6736(23)02016-0
diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by
free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or
Department of Internal
Medicine (L Chaker MD PhD, within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection
Prof R P Peeters MD PhD) and of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for
Department of Epidemiology hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed
(L Chaker), Erasmus University
symptomatically or with glucocorticoid therapy. In Graves’ disease, first-line treatment is a 12–18-month course of
Medical Center, Rotterdam,
Netherlands; Department of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres.
Epidemiology, Harvard T H Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves’ disease
Chan School of Public Health, and toxic nodular goitre.
Boston, MA, USA (L Chaker);
Department of Medicine,
Division of Endocrinology, Introduction In this Seminar we discuss the epidemiology, cause,
Diabetes, and Metabolism, Thyrotoxicosis is the clinical manifestation of excess clinical presentations and complications, diagnosis, best
The Johns Hopkins University thyroid hormone action at the tissue level, whereas the treatment, and shifts in treatment preference. We also
School of Medicine, Baltimore,
MD, USA (Prof D S Cooper MD);
term hyperthyroidism refers to conditions of increased focus on future directions and research priorities.
Department of Endocrinology synthesis and secretion of thyroid hormone (although Hyperthyroidism in children is not discussed in this
& Diabetes, Sir Charles Gairdner the terms are often used interchangeably). The Seminar and is reviewed elsewhere.2,3
Hospital, Nedlands, WA, two main thyroid hormones are thyroxine (T4) and tri-
Australia
(Prof J P Walsh MD PhD);
iodothyronine (T3). T4 has minimal biological activity Epidemiology
Medical School, University of and serves as a prohormone, converted to the biologically The global epidemiology of thyroid disease is strongly
Western Australia, Crawley, active hormone T3 by intracellular deiodination in target related to population iodine status.4,5 In iodine-sufficient
WA, Australia (Prof J P Walsh) tissues. Under euthyroid conditions, direct thyroidal regions, overt and subclinical hyperthyroidism each
Correspondence to: secretion of T3 accounts for only about 20% of total daily affect about 0·5% of the population, with a combined
Prof Robin P Peeters,
Department of Internal
T3 production, with the remainder derived from peri­ incidence of about 50 cases per 100 000 per year6–8 and
Medicine, Erasmus University pheral conversion, but in hyperthyroidism the Graves’ disease accounting for most cases.9 In
Medical Center, 3000CA proportion can be higher because of increased iodine-deficient areas, the prevalence of hyperthyroidism
Rotterdam, Netherlands intrathyroidal conversion of T4 to T3. is higher: up to 10–15% for overt and subclinical
[email protected]
Overt hyperthyroidism is defined biochemically as hyperthyroidism combined, with toxic nodular goitre
suppressed serum concentrations of thyroid-stimulating being more common than Graves’ disease.10–12 Correction
hormone (TSH) with increased concentrations of of iodine deficiency by public health measures can result
free T4, or total or free T3. In mild cases, TSH is in a transient increase in the incidence of hyper­
su­ppressed but free T4 and T3 concentrations are within thyroidism, followed by a gradual decrease to levels
the reference range, which is termed subclinical recorded in iodine-sufficient regions.13,14
hyperthyroidism.1 The incidence of Graves’ disease in iodine-sufficient
Untreated hyperthyroidism can lead to serious adverse regions is 20–30 cases per 100 000 per year, with a peak in
effects on multiple organ systems and, rarely, to death. the third to fifth decades of life, and a female to male ratio
Optimum treatment depends on the underlying cause, of 5–6:1.9,10,15,16 The incidence of toxic nodular goitre ranges
with options including antithyroid drugs, radioactive from 3–6 cases per 100 000 per year in iodine-sufficient
iodine treatment, and thyroidectomy. areas to 20–40 cases per 100 000 per year in iodine-deficient
areas; it occurs predominantly after the age of 50 years,
and is also more common in females than males.9,10,12
Search strategy and selection criteria
We searched Embase, Medline, and Cochrane databases as Causes
See Online for appendix outlined in the appendix from database inception to Causes of thyrotoxicosis can be divided into those
Sept, 16, 2022, for articles related to hyperthyroidism. associated with hyperthyroidism (increased synthesis and
We selected all papers that were relevant to the topics of secretion of thyroid hormones by the thyroid) and those
epidemiology, clinical presentation and complications, without (release of stored thyroid hormone from the gland
diagnosis, and treatment, with a focus on the past 5 years. or extrathyroidal sources of thyroid hormone). In clinical
We supplemented the search with older important practice, Graves’ disease, toxic nodular goitre, and
publications, including clinical guidelines. thyroiditis are the most common conditions, with other
causes of thyrotoxicosis being rare by comparison (table 1).

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Alternative names Pathogenesis Clinical pointers

Thyrotoxicosis with hyperthyroidism ·· Increased thyroid hormone synthesis ··
and secretion by the thyroid
Graves’ disease Basedow disease, diffuse toxic goitre Stimulating antibodies to TSH Diffuse goitre, thyroid bruit
receptor (pathognomonic), ophthalmopathy
Toxic nodular goitre Toxic adenoma, autonomous thyroid Single or multiple autonomous Asymmetric, irregular goitre; visible
adenoma, Plummer’s disease adenomas, somatic activating or palpable nodule(s)
mutations in TSH receptor
Gestational hyperthyroidism ·· High values of hCG stimulating TSH First trimester of pregnancy,
receptor hyperemesis gravidarum, multiple
pregnancy
Gestational trophoblastic disease ·· As for gestational hyperthyroidism Hydatidiform mole, trophoblastic
tumour
Iodine-induced hyperthyroidism Jod-Basedow phenomenon Excess iodine substrate (usually in History of excessive iodine or kelp
gland with underlying autonomous ingestion, radiographic contrast
function) exposure
Type 1 amiodarone-induced ·· As for iodine-induced Amiodarone treatment, underlying
thyrotoxicosis hyperthyroidism thyroid disease
Thyrotropinoma TSHoma TSH secretion by pituitary adenoma Pituitary tumour, elevated free T4
and (free)T3 with unsuppressed TSH
Thyroid hormone resistance β* ·· Mutation in TRb gene Attention deficit hyperactivity
disorder, tachycardia, diffuse goitre
Familial non-autoimmune ·· Germline activating mutation in TSH ··
hyperthyroidism receptor
Thyrotoxicosis without ·· Increased circulating thyroid ··
hyperthyroidism hormones without increased
synthesis of thyroid hormone by the
thyroid
Thyroiditis ·· Inflammation leading to release of ··
stored thyroid hormone from thyroid
follicles
Lymphocytic thyroiditis Silent thyroiditis, painless thyroiditis, Autoimmune thyroiditis Positive TPOAb, post-partum
autoimmune thyroiditis, includes presentation
post-partum thyroiditis
Subacute thyroiditis De Quervain thyroiditis, Viral or post-viral inflammation Preceding viral illness; painful, tender
granulomatous thyroiditis, viral or thyroid; negative TPOAb
post-viral thyroiditis, painful thyroiditis
Other forms of thyroiditis ·· ·· ··
Drug-induced ·· Various ··
Traumatic ·· Trauma, manipulation, palpation ··
Radiation-induced ·· Radiation thyroiditis ··
Bacterial, fungal ·· Bacterial or fungal infection ··
Exogenous thyroid hormone ·· Excessive thyroid hormone use ··
(iatrogenic or factitious)
Struma ovarii ·· Ectopic thyroid hormone secretion Pelvic mass; very rare
from ovarian teratoma
TSH=thyroid-stimulating hormone. T4=thyroxine. T3=tri-iodothyronine. TPOAb=thyroid peroxidase antibodies. *Not part of classic hyperthyroidism: mixed hyperthyroid
and hypothyroid state dependent on target tissue.

Table 1: Causes of thyrotoxicosis

Graves’ disease Graves’ disease has a high degree of heritability,

Graves’ disease forms part of the spectrum of autoimmune estimated at 60–80%.19,20 Common variants in immuno­
thyroid disease, with the pathogenesis involving complex regulatory genes (HLA-B, HLA-DR3, CD40, CTLA4,
interactions between genetic and environmental factors, FCRL3, IL2RA, PTPN22) and in genes encoding thyroid
resulting in loss of self-tolerance to thyroid antigens.17,18 A autoantigens (Tg, TSHR) increase susceptibility, but
key feature of Graves’ disease pathogenesis is a Th2 much of the heritability remains unaccounted for.17,21,22
immune response resulting in the production of IgG Smoking, iodine status, stress, pregnancy and the
antibodies that stimulate the TSH receptor on thyrocytes, postpartum phase, Yersinia enterocolitica infection, and
resulting in increased thyroid hormone synthesis and some drugs (panel) are established environmental factors,
secretion, follicular hyperplasia, and goitre. whereas other factors such as selenium status, gut

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 Seminar

Lymphocytic thyroiditis (silent thyroiditis) is a painless,

Panel: Drugs associated with thyroiditis and autoimmune thyroiditis that can present with thyro­
thyrotoxicosis toxicosis. It is part of the spectrum of autoimmune
• Immune checkpoint inhibitors thyroid disease that encompasses post-partum thyroiditis
• PD-1 inhibitors: pembrolizumab, nivolumab, and clinical variants of Hashimoto’s disease, to which a
cemiplimab, dostarlimab range of names has been applied (table 1). By contrast
• PD-L1 inhibitors: atezolizumab, avelumab, with Graves’ disease, Th1 and Th17 immune responses
durvalumab predominate, with lymphocytic infiltration of the thyroid,
• CTLA-4 inhibitors: ipilumamb, tremelimumab lymphoid follicle formation, and thyroid follicular
• Cytokines atrophy. Most, but not all, affected individuals have
• Interferon-α, interleukin-2 circulating antibodies to the main autoantigens thyroid
• Tyrosine kinase inhibitors peroxidase enzyme (TPO) or thyroglobulin, or both.17,34
• Sunitinib, sorafenib Post-partum thyroiditis is a subtype, affecting about
• Lithium 5% of women in the first year post partum, about half of
• Amiodarone whom have thyrotoxicosis.35,36
• Type 2 amiodarone-induced thyrotoxicosis Subacute thyroiditis is characterised by thyroidal pain,
• Alemtuzumab (also associated with Graves’ disease) preceded or accompanied by fever and systemic
inflammatory symptoms. It is thought to be caused by
viral infection of the thyroid or a postviral inflammatory
microbiome, viral infection, and endocrine-disrupting state in genetically predisposed individuals (particularly
chemicals can also be involved.23–27 Similar to other HLA-B35 and HLA-B67 status), resulting in granu­
autoimmune diseases, skewed X chromosome inactiva­ lomatous change, giant cell formation, and a mixed
tion is probably an important contributor to the female monocytic and lymphocytic interfollicular infiltrate.33 It
predominance.28,29 Other epigenetic mechanisms, such as has an incidence of 2–5 cases per 100 000 per year, and
DNA methylation, provide a potential link between a female to male ratio of 3–7:1.12,37 Findings from
environmental factors, gene expression, and autoimmune epidemiological and virological studies have implicated
thyroid disease.30 several viruses including mumps, echoviruses, coxsackie
viruses, and SARS-CoV-2.27,38–41 Despite many case reports
Toxic nodular goitre of subacute thyroiditis after COVID-19 vaccination,42 a
Thyroid nodules are common in the general population, population-based study of 2·3 million vaccine recipients
particularly in the setting of iodine deficiency, which has a noted no increased risk of thyroiditis in the 56 days after
chronic stimulatory effect on the thyroid, resulting in vaccination compared with the pre-exposure period,
diffuse or nodular goitre and, ultimately, thyroidal suggesting that the association could be coincidental.43
autonomy.4,5,11,13 Genetic factors, female sex, and smoking Several drugs can cause thyroiditis (panel). Checkpoint
also contribute to nodule development.31 Functional inhibitor immunotherapy is now standard of care for
autonomy develops in about 5% of thyroid nodules, either many cancers: thyroiditis occurs in about 10% of treated
as solitary toxic adenomas or as part of multinodular patients,44,45 with higher rates in those with pre-existing
goitre. Activating mutations in the TSH receptor gene thyroid autoimmunity.46,47 Thyroiditis is more common
(TSHR; in up to 70% of autonomous nodules) and Gs with programmed cell death-1 (PD-1) inhibitors or
protein α subunit (GNAS; up to 30%) cause constitutive combination therapy than with programmed cell death-1
activation of cyclic AMP or protein kinase A signalling, ligand-1 (PD-L1) inhibitor or cytotoxic T lymphocyte
thereby stimulating thyroid hormone synthesis and antigen-4 (CTLA-4) inhibitor monotherapy.48 Thyrotoxicosis
secretion, resulting in hyperthyroidism.31 So-called second occurs in 3–5% of patients treated with interferon-α.49
hit mutations in the EZH1 gene provide a further stimulus
to thyrocyte proliferation in around 25% of cases.32 Clinical presentation and complications
The usual clinical presentation of hyperthyroidism
Thyroiditis signifies the hypermetabolic effects of thyroid hormone
Thyroiditis (thyroid inflammation) has many causes, excess at the cellular level, as well as enhanced
including infection, autoimmunity, drugs, systemic β-adrenergic activity. For reasons that remain uncertain,
disorders, environmental agents, and the post-partum signs and symptoms of hyperthyroidism vary greatly
period (table 1).33 Thyrotoxicosis is caused by unregulated among patients and are only roughly linked to circulating
release of stored thyroid hormone resulting from thyroid hormone concentrations.50 Some patients have
inflammatory or toxic damage to thyroid follicles. several complaints that seem out of proportion to their
Thyrotoxicosis is transient and self-limited, resolving apparent modest biochemical hyperthyroidism, whereas
after 1–4 months when stores of thyroid hormone have others are oligosymptomatic despite very high serum
been exhausted or the inflammatory process has hormone concentrations. Age is one factor, with older
subsided. individuals often having few hyperthyroid symptoms.51

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Although this finding might relate to milder disease seen the free fraction of T4 is preferred over the measurement
in older adults, the index of suspicion for hyperthyroidism of total T4, because it reflects the freely available
should be heightened in older people with unexplained hormone, which is unbound to proteins and ready to
weight loss, atrial fibrillation or atrial flutter, palpitations, enter tissues. Because of limitations of current free T3
altered mood, and other non-specific complaints.52 assays, either total or free T3 can be measured.
Table 2 shows both typical and unusual symptoms and In patients suspected of having Graves’ disease,
signs of hyperthyroidism. Patients with Graves’ disease particularly when they do not have Graves’ ophth­
have additional findings that are highly specific to this almopathy or other pathognomonic physical findings,
condition and are diagnostically helpful (table 2). The measurement of antibodies to the TSH receptor (TRAb)
most prevalent is thyroid eye disease, also known as is a key diagnostic. TRAb can be measured with
Graves’ ophthalmopathy or orbitopathy, with an overall immunoassays that simultaneously detect two categories
prevalence of 25–40%53 among patients with Graves’ of functional TRAb—ie, thyroid stimulating antibodies
hyperthyroidism. Other findings in patients with Graves’ and thyroid blocking antibodies, which sometimes co-
hyperthyroidism are less frequent and include thyroid exist in patients with Graves’ disease (figure). These
dermopathy (pretibial myxedema), thyroid acropachy immunoassays do not differentiate between thyroid
(clubbing of the nails), and other autoimmune disorders stimulating and thyroid blocking antibodies. For
such as thymic enlargement, splenomegaly, alopecia, approximately 5 years, novel automated bridge-based
vitiligo, pernicious anaemia, and urticaria. binding assays have become commercially available to
Thyroid storm, a severe exacerbation of hyperthyroidism more selectively, but not exclusively,63 measure thyroid
associated with decompensation in one or more organ stimulating antibodies.64 Either assay method provides
systems, occurs in up to 0·2% of patients with excellent diagnostic sensitivity and specificity.65
thyrotoxicosis54,55 and has a mortality rate of up to In patients in whom the cause of thyrotoxicosis is not
10–17% in people older than 60 years.56 Thyroid storm is a readily apparent, scintigraphy and radioisotope uptake
combination of signs and symptoms characterised by are useful to determine the cause. Radioisotopes of
many of the following: fever, altered mental status, iodine (¹²³I and ¹³¹I) or ⁹⁹-technetium are administered
gastrointestinal and hepatic dysfunction, tachycardia and subsequently detected in the thyroid gland by planar
with atrial arrhythmias, and congestive heart failure, imaging. In Graves’ disease, diffuse accumulation of the
often with a precipitating event such as infection, surgery,
or childbirth. It rarely is the initial presentation of Symptoms* Signs*
hyperthyroidism.
General Nervousness, insomnia, fatigue Anxiety, restlessness
Untreated hyperthyroidism is associated with various
Skin Diaphoresis, thinning hair Warm, moist skin, onycholysis, alopecia†,
adverse outcomes, especially in older individuals. In one acropachy†, urticaria*, vitiligo*
population-based study, the standardised mortality ratio Eyes Dry eye, eye protrusion, diplopia, Proptosis†, conjunctival injection†,
was 1·14 (95% CI 1·04–1·24, p=0·002) compared with photophobia chemosis†, decreased visual acuity†, lid
the general population.57 Cardiovascular adverse events lag†
are most important, especially atrial fibrillation leading Neck Anterior neck swelling, dysphagia Goitre
to heart failure and embolic stroke.58 Such events are Cardiovascular Palpitations, dyspnoea on exertion, Tachycardia, tachyarrhythmia, congestive
more likely to occur in older patients with comorbidities chest pain heart failure‡

including cardiovascular disease, hypertension, diabetes, Gastrointestinal Hyperdefecation, diarrhoea Abnormal liver function tests
and valvular heart disease.58 Fractures are more common, Metabolic Hyperphagia, weight loss, heat Cachexia, fever‡
sensitivity
especially in postmenopausal women with hyper­
Neuromuscular Muscle weakness, paralysis§ Hyper-reflexia, proximal muscle
thyroidism, than in the general population, probably weakness, muscle wasting, hypokalaemic
because of increased bone turnover.59,60 Overall quality periodic paralysis§
of life is diminished in individuals with untreated Skeletal ·· Low bone mass and fractures,
hyperthyroidism,61 especially if they have concomitant hypercalcaemia, hypercalciuria
Graves’ ophthalmopathy.62 Neurological Tremor Tremor, stupor‡, coma‡,
choreoathetosis§

Diagnosis of thyrotoxicosis Reproductive/sexual Oligo-amenorrhoea, decreased fertility Gynecomastia

in women, decreased libido in men
Overt thyrotoxicosis is characterised by increased serum
Haemopoietic ·· Leukopenia†, normochromic normocytic
concentrations of free T4 and total or free T3, and anaemia, splenomegaly†, thymic
suppressed serum TSH, usually less than 0·01 mU/L. enlargement†
Some patients have so-called T3 thyrotoxicosis, in which Psychiatric/cognitive Emotional lability, poor concentration, Depression, psychosis, irrational
free T4 concentrations are within range but T3 values are irritability behaviour
raised. This occurrence is common in patients with *Signs and symptoms of hyperthyroidism are less specific or might be absent in patients of older age. †Findings seen
milder disease or early in the course of disease. In in Graves’ disease. ‡Findings seen in thyroid storm. §References for rare findings are provided in the appendix.
subclinical hyperthyroidism, thyroid hormone values are Table 2: Signs and symptoms of hyperthyroidism, by system
within range but TSH is suppressed.1 Measurement of

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Suspected thyrotoxicosis?

Check serum TSH

High Normal Low

Check serum free T4 Consider other causes Check serum free T4

and (free)T3 for complaints. In some and (free)T3
cases TSHoma can
present with
high-normal TSH
concentrations

High Normal or low Low Normal* High

Consider: assay Overt or subclinical Central Subclinical Overt

interference, RTH, hypothyroidism hypothyroidism hyperthyroidism hyperthyroidism
FDH, TSHoma

Assess for other

pituitary hormone
Measure TRAbs
deficiencies, potential
use of glucocorticoids
or NTI

Positive Negative or
undetermined

Graves’ disease Scintigraphy†

Goitre Thyroiditis Other‡

Figure: Diagnostic workflow for suspected thyrotoxicosis

TSH=thyroid-stimulating hormone. T4=thyroxine. T3=tri-iodothyronine. NTI=non-thyroidal illness. RTH=resistance to thyroid hormone. FDH=familial
dysalbuminaemic hyperthyroxinaemia. TRAb=TSH receptor antibodies. *Central hypothyroidism can also present with low TSH concentrations and low to normal
concentrations of free T4 and T3. †Assessment of thyroid vascularity by colour flow Doppler is used in some centres. ‡See table 1 and panel.

radiotracer throughout the gland is seen with raised or thyroiditis, including silent and post-partum thyroiditis66
high to normal uptake, whereas uptake is usually very and amiodarone-induced thyroiditis.67
low or absent in thyroiditis. Tracer uptake is reduced in Laboratory diagnosis of thyrotoxicosis is usually
patients with iodine-induced hyperthyroidism because straightforward, but there are circumstances in which
of competition for uptake with the administered results cause diagnostic confusion. Analytical interference
radiotracer. In patients with toxic nodular goitre, from circulating heterophilic antibodies can affect TSH
scintigraphy can disclose areas of hyperfunction and measurements resulting in discordant thyroid function
hypofunction within the thyroid gland (so-called hot and tests (eg, increased thyroid hormones with unsuppressed
cold nodules). TSH). In assays using streptavidin-biotin detection
Thyroid ultrasound is indicated to define thyroid systems, ingestion of biotin supplements by patients can
nodules that are detected on physical examination or on cause concomitantly falsely raised thyroid hormone
scintigraphy. In some centres, assessment of thyroidal concentrations and falsely suppressed TSH, leading to
vascularity by ultrasound with colour flow Doppler is the erroneous diagnosis of thyrotoxicosis.68 Some
used in preference to thyroid scintigraphy to differentiate patients have spuriously increased immunoreactive
between Graves’ disease and other causes of thyro­ free T4 concentrations because of variant thyroid
toxicosis. Thyroidal blood flow is increased in Graves’ hor­­
mone binding proteins (familial dysalbuminaemic
disease, but is normal or low in various forms of hyper­thyroxinaemia),69,70 and in rare cases patients with

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thyroid autoimmunity might have circulating auto­ drugs. Table 3 shows the mode of action, contraindications,
antibodies to T4 or T3 causing analytical interference.71 and major side-effects for antithyroid drugs, radioactive
Although serum TSH is always subnormal in primary iodine, and thyroidectomy.
hyper­thyroidism, two rare conditions present with
normal or raised serum concentrations of thyroid Antithyroid drugs
hormone and unsuppressed serum TSH: TSH-secreting The thionamide antithyroid drugs include propylthiouracil,
pituitary tumours causing central thyrotoxicosis, and carbimazole, and its metabolite methimazole. Carbimazole
resistance to thyroid hormone β, caused by mutations in and methimazole are generally preferred over pro­
the thyroid hormone receptor β.72,73 Several common pylthiouracil because of superior efficacy and tolerability,
clinical entities are associated with subnormal serum and because their longer duration of action allows once
TSH but normal or low concentrations of thyroid daily oral administration rather than twice or thrice daily
hormones, including severe non-thyroidal illness, central as for propylthiouracil.83,85 Patients with newly diagnosed
hypothyroidism, and high-dose glucocorticoid therapy. Graves’ hyperthyroidism can be treated for 12–18 months
Suppressed TSH with normal free T4 and T3 can also be with carbimazole and methimazole according to American
seen in early pregnancy.74,75 Ethnic differences can also be and European guidelines,78,86 after which they can be
important; up to 8% of healthy African Americans have discontinued if TSH serum is normal and TRAb is
serum TSH concen­trations below the reference range negative. In case of persistent high TRAb on treatment or
lower limit of 0·45 mU/L compared with White relapse after treatment withdrawal, patients can choose
Americans.76 Whether genetic predisposition or carbimazole and methimazole for a further 12 months (or
environmental factors explain these differences is still longer), or opt for definitive treatment with radioactive
unclear. iodine or thyroidectomy. A disadvantage of antithyroid
drugs is high relapse rates (about 50%) after a single
Treatment course, especially in the first 6 months after withdrawal.84,87,88
Relief of thyrotoxic symptoms (irrespective of cause) can However, in a longitudinal study of 128 patients with
be achieved by β-adrenergic blocker therapy. The non- recurrent Graves’ disease, over 75% of those who received
selective β-blocker propranolol has long been used a second course of treatment with antithyroid drugs had
(10–40 mg given three to four times a day), but longer long-term remission.89 Evidence shows that long-term
acting, selective β-1 blockers such as atenolol and (5–10 years) or perhaps even lifelong treatment with low-
metoprolol are also effective. The preferred choice of dose carbimazole and methimazole is a safe and an
therapy in thyrotoxicosis with hyperthyroidism depends effective option.84,90
on the underlying pathophysiology, but the most common The initial dose of antithyroid drug required depends
options are antithyroid drugs, radioactive iodine, and on the severity of hyperthyroidism and size of thyroid
thyroidectomy. In patients with toxic adenoma or gland.91 After initial control, which can take 1–3 months,
multinodular goitre, radioactive iodine treatment and depending on the starting dose, antithyroid drugs can be
surgery have been the preferred options. However, titrated to the lowest dose needed to maintain
studies have shown that long-term, low-dose treatment euthyroidism. Alternatively, especially in difficult to
with antithyroid drugs is effective, especially in older control disease, a so-called block and replace regimen
patients or those who are poor candidates for radioactive can be used in which antithyroid drugs are given in a
iodine treatment or surgery.77 In Graves’ disease, all three high dose to fully block thyroid function accompanied by
treatment options are effective, but antithyroid drugs may levothyroxine replacement to avoid hypothyroidism.78,86
be the patient-preferred approach.78 A cohort study of Thyroid function should be checked 4–6 weeks after
1186 patients with Graves’ disease followed up for up to starting treatment, with dose titration based on serum T4
10 years after treatment with radioactive iodine reported and T3 concentrations, because serum TSH can remain
lower quality of life than did those who had received suppressed for several months.86 Overtreatment resulting
antithyroid drugs or surgery,79 whereas findings from an in hypothyroidism should be avoided, particularly in
earlier, smaller randomised controlled trial showed no Graves’ disease, because it can provoke or exacerbate
difference.80 Clinicians in Europe and the Asia-Pacific thyroid eye disease.92 Once patients achieve biochemical
region generally prefer antithyroid drugs as first-line euthyroidism, follow-up intervals can be extended to
treatment.81,82 In the USA, treatment choices have shifted 2–4 months.
in favour of antithyroid drugs over radioactive iodine in Minor side-effects occur in about 5% of patients,
the past two decades.83 Emerging evidence of the efficacy including pruritus and gastrointestinal distress (table 3).
and safety of long-term administration of antithyroid Major side-effects of antithyroid drugs are rare. There is
drugs in patients with Graves’ disease might also some evidence that serious side-effects are dose related
contribute to future treatment preferences.84 During the with carbimazole and methimazole, which has not been
COVID-19 pandemic, non-urgent surgery and radioactive reported for propylthiouracil.93 Agranulocytosis occurs in
iodine treatment were curtailed in many countries, less than 0·5% of patients, typically within the first
leading to a further shift towards the use of antithyroid 3 months of treatment, and can present with fever or

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Mode of action Usual starting dose Contraindications Advantages Disadvantages Adverse events
Antithyroid drugs Inhibition of thyroid Methimazole*: 10–30 mg, Previous major adverse No radiation exposure. No High relapse rate (about Minor pruritus (<5%).
(methimazole, hormone synthesis by once a day. Carbimazole: reactions to antithyroid adverse effect on Graves’ 50% after one course). Gastrointestinal distress
carbimazole, and preventing iodination and 15–40 mg, once a day. drugs. Severe liver orbitopathy. No risk of Long-term compliance. (<1%). Major
propylthiouracil) coupling of tyrosine Propylthiouracil: disease. surgery or anaesthesia. No Long therapy duration. agranulocytosis (<0·5%).
residues. Propylthiouracil 100–400 mg, 2–3 times a Propylthiouracil hospitalisation required. Use Hepatotoxicity (<0·1%).
additionally decreases T4 to day. preferred in first during pregnancy and Vasculitis (<0·1%).
T3 conversion by inhibiting trimester of pregnancy. breastfeeding possible. Low Pancreatitis.†
type 1 deiodinase. risk of subsequent
hypothyroidism. Chance of
remission.
Radioactive Radiation-induced Fixed radioiodine activity Pregnancy and High cure rate. No risk of Risk factor for exacerbating Exacerbation or
iodine thyrocyte destruction. of 185, 370, or 555 MBq. breastfeeding. Short- surgery or anaesthesia. hyperthyroidism, Graves’ development of Graves’
Calculated radioiodine term planning to Moderate costs compared orbitopathy. Slow control of orbitopathy (15–30%).
activity based on thyroid conceive or father a with surgery (especially hyperthyroidism. Frequent Radiation thyroiditis.
gland weight and child. Severe thyroid fixed-activity radioactive permanent hypothyroidism. Increased risk of solid-
percentage update on eye disease. iodine therapy). Avoid pregnancy cancer mortality.†
scintigraphy. 6–12 months after
radioactive iodine. Radiation
exposure. Need for pre-
treatment with antithyroid
drugs. Relief of
hyperthyroidism not
achieved in about 10% of
patients.
Thyroidectomy Removal of the thyroid Total thyroidectomy Frail or elderly patients Rapid control of High-volume surgeons not Bleeding or haematoma.
gland. (preferred). Subtotal with serious hyperthyroidism. Definitive always available. Surgery- Laryngeal nerve injury
thyroidectomy (in specific comorbidities. treatment. Possible in severe related risks and (1–2%).
cases). Pregnancy.†‡ thyroid eye disease. No hospitalisation. Permanent Hypoparathyroidism
radiation exposure. hypothyroidism. Need for related hypocalcaemia
Preferred in patients with pre-treatment with (1–2%). Anaesthesia
coexisting compressive antithyroid drugs or complications.
symptoms, (suspect) thyroid potassium/Lugol’s iodine.
malignancy, and Cosmetic burden (permanent
hyperparathyroidism. scar).§ High costs.
*Initial dose for hyperthyroidism control. In titration therapy methimazole is typically administered at a dose of 2·5–10 mg per day. †Adverse events suggested but not confirmed because of conflicting evidence.
‡With the exception of second trimester pregnancy, which is a contraindication. §Scarless thyroidectomy is available in some centres.

Table 3: Treatments for thyrotoxicosis with hyperthyroidism

sore throat, or both. Patients should be alerted for the radioiodine uptake. In the first weeks after treatment, T4
occurrence of these symptoms and, if agranulocytosis is and T3 concentrations can transiently increase, but
confirmed, antithyroid drugs should be discontinued ultimately hypothyroidism occurs in 50–85% of treated
permanently. Hepatoxicity, cholestatic or hepatocellular, patients with Graves’ disease97 and is more common with
occurs in less than 0·1% of patients, and is generally high administered radioactive iodine activities. Relief of
more severe with propylthiouracil than with carbimazole hyperthyroidism after radioactive iodine therapy is not
and methimazole, particularly in children and in the first achieved in roughly 10% of patients after initial treatment
3 months of therapy,85 with cases of fatal liver failure and depends on the underlying cause.98 Radioactive iodine
reported. For that reason, propylthiouracil received a so- can be administered as a definitive treatment option, but
called black box warning from the US Food and Drug the effects are not immediate. It can reduce goitre volume
Administration, recommending use only in specific up to 60% in multinodular goitre, depending on the initial
circumstances. Finally, in 2020, the European Medicines size.98 Carbimazole and methimazole or β blockers are
Agency issued a warning of increased risk of acute typically prescribed before radioactive iodine to control
pancreatitis in patients given carbimazole and hyperthyroidism and reduce risk for post-treatment
methimazole, although evidence for this effect is exacerbation, especially in older patients and those with
conflicting.94–96 severe hyperthyroidism. They should be stopped at least
3–7 days before ¹³¹iodine administration and may be
Radioactive iodine therapy restarted 3–7 days later and continued until euthyroidism
Radioactive iodine is first-line treatment in many cases of occurs.99
toxic adenoma and toxic multinodular goitre, especially for Side-effects include neck tenderness and development
older patients with comorbidities incurring higher surgery or worsening of pre-existing thyroid eye disease,
risk. It can be administered either as a fixed activity or especially in people who smoke.100,101 Therefore,
calculated activity on the basis of thyroid size and the 24 h radioactive iodine is contraindicated in patients with

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Graves’ disease with severe orbitopathy, and gluco­ hyperthyroidism.109,110 In addition to the risk of developing
corticoid prophylaxis is recommended in those with mild overt hyperthyroidism, older patients with subclinical
orbitopathy or judged at risk of de-novo thyroid eye hyperthyroidism have increased risks of cardiovascular
disease (those who smoke, with severe or unstable disease (atrial fibrillation, heart failure, coronary heart
hyperthyroidism, and with high serum TRAb) when disease, and stroke), bone loss, fractures, and dementia.1
receiving radioactive iodine.100 Untreated hypothyroidism This risk has led to clinical practice recommendations to
after radioactive iodine should be avoided since this treat severe and possibly mild subclinical hyperthyroidism
treatment can elicit or worsen thyroid eye disease. Other in people older than 65 years, despite little high-quality
contraindications to radioactive iodine therapy include evidence of therapeutic benefits. When treatment is
pregnancy (or pregnancy planned in the next 6 months), started, the goal is to normalise serum TSH concen­
breastfeeding,86 and inability to adhere to radiation safety trations.86,108 Similar to overt hyperthyroidism, treatment
precautions. Finally, although findings from several depends on the underlying condition, comorbidities, and
studies showed no difference in cancer incidence or patient preference.
mortality with radioactive iodine in general or between
fixed and calculated radioiodine activity regimens,102,103 Hyperthyroidism in pregnancy
some evidence suggests a dose-dependent positive During a normal pregnancy, pronounced changes in
association between RAI and solid cancer mortality;104 thyroid physiology occur. The pregnancy hormone human
however, findings are controversial. chorionic gonadotropin (hCG, which is a weak agonist of
the TSH receptor), stimulates thyroid hormone secretion
Thyroidectomy leading to higher circulating T4 concentrations and
Thyroidectomy can be regarded as first-line treatment for a concomitant decrease in serum TSH. Therefore,
toxic nodular goitre and as definitive treatment for Graves’ pregnancy-specific TSH reference ranges are required to
disease, particularly when other treatments are ineffective, diagnose thyroid dysfunction in pregnant women.75
not tolerated, or contraindicated (eg, radioactive iodine Gestational hyperthyroidism due to very high concen­
therapy in severe orbitopathy); in patients with (suspected) trations of hCG occurs in about 1–3% of pregnancies; it is
malignant nodules, large goitres, or concurrent usually transient and does not require treatment.111 In
primary hyperparathyroidism; or when thyroidectomy is about half of cases, gestational hyperthyroidism is
the patient’s preference. For Graves’ disease, total associated with hyperemesis gravidarum. De-novo
thyroidectomy is generally more effective than subtotal pathological hyperthyroidism during pregnancy (mainly
thyroidectomy, with equal rates of complications, and due to Graves’ disease and toxic nodules) is much less
therefore preferred. Antithyroid drugs should be used to common, with a frequency of about 0·2%.112
achieve euthyroidism before surgery and replaced by Overt hyperthyroidism during pregnancy is associated
levothyroxine treatment postoperatively. Pretreatment with adverse pregnancy and neonatal outcomes, including
with Lugol’s iodine or potassium iodide decreases increased risk of miscarriage, stillbirth, pre-eclampsia,
intraoperative blood loss for patients with Graves’ disease pre-term birth, and low birthweight.111 Most published
and is recommended in clinical practice guidelines.78,86 For studies do not have data for treatment, but available
toxic nodular goitre, hemithyroidectomy or total thy­ evidence suggests that cautious treatment of hyper­
roidectomy might be appropriate depending on the thyroidism during pregnancy improves outcomes,113 and
number and distribution of thyroid nodules. Surgical that women who receive adequate antenatal care do not
complications are infrequent (1–2%), particularly when have increased risks.114 Excessive maternal thyroid
undertaken by high-volume thyroid surgeons (ie, those hormones could affect fetal development,115 and overt
doing >25–50 thyroidectomies per year).105–107 Complications hyperthyroidism during pregnancy should be treated.
include postoperative bleeding, hypocalcaemia (usually However, antithyroid drug treatment in early pregnancy,
transient) due to hypoparathyroidism, and recurrent especially in weeks 5–11, carries a small risk of teratogenic
laryngeal nerve injury, with a risk for each of around 1%. side-effects with differences in pattern and severity
generally in favour of propylthiouracil over carbimazole
Special circumstances and methimazole.116 Ideally, women with hyperthyroidism
Subclinical hyperthyroidism planning pregnancy would receive definitive therapy
Roughly between a third and a quarter of patients with before pregnancy. In case of de-novo pathological
subclinical hyperthyroidism have a serum TSH less than hyperthyroidism during pregnancy, the lowest effective
0·1 mU/L, which is regarded as more severe subclinical dose of antithyroid drug should be used (as monotherapy
hyperthyroidism.86,108 In patients with serum TSH rather than so-called block and replace), with frequent
between 0·1 mU/L and 0·4 mU/L (mild subclinical monitoring of mother and fetus, and propylthiouracil
hyperthyroidism), TSH concentrations normalise during preferred to carbimazole and methimazole during the
follow-up in 20–30% of individuals over 4·5–5 years. In first trimester. A more detailed discussion on the
patients with a TSH concentration less than 0·1 mU/L, treatment of hyperthyroidism in pregnancy is available
thyroid dysfunction usually persists or progresses to overt elsewhere.36,111

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Thyroiditis Radioactive iodine treatment is usually not feasible because

Thyrotoxicosis caused by thyroiditis is usually transient of the high intrathyroidal concentrations of iodine from
and self-limiting, regardless of cause, and often no the amiodarone, which has a half-life of 100 days.121 As with
treatment is required. β blockers provide symptomatic any thyroiditis, type 2 amiodarone-induced thyrotoxicosis
relief, but antithyroid drugs are ineffective and not resolves over time, and ultimately can result in transient or
indicated. For subacute painful thyroiditis, first-line permanent hypothyroidism. However, its presentation can
treatment is a non-steroidal anti-inflammatory drug be very severe and often requires glucocorticoid therapy
(NSAID), with glucocorticoid treatment used if symptoms for several months.121 Discontinuation of amiodarone can
are severe or the patient does not respond to NSAID. hasten recovery from both types of amiodarone-induced
Prednisolone or prednisone 30–40 mg daily for 1–2 weeks thyrotoxicosis, but is not always possible because of the
followed by dose tapering is widely used,86,117 although underlying cardiac condition.122 Since amiodarone is
lower initial doses (15–20 mg) can be effective.117,118 generally used in patients with severe cardiovascular
Thyrotoxicosis is often followed by hypothyroidism, disease or tachya­rrhythmias, or both, amiodarone-induced
which can be transient or permanent. In subacute thyrotoxicosis is associated with high mortality, especially
thyroiditis, most patients recover normal thyroid in patients with underlying left ventricular dysfunction.123
function, whereas in lymphocytic thyroiditis (including
post partum), hypothyroidism can be long lasting (eg, Future directions
6–12 months) or permanent in 10–40% of cases.35 Therapeutic options for Graves’ disease have remained
Levothyroxine replacement is indicated if hypothyroidism much the same over the past 80 years. Despite
is severe or symptomatic, with consideration of a trial of improvements in delivery and safety, current treatment
withdrawal of therapy after 6–12 months. Thyroiditis methods have important limitations, particularly high
caused by checkpoint inhibitor immunotherapy is relapse rates after withdrawal of antithyroid drugs and
followed by permanent hypothyroidism in most cases.44,119 hypothyroidism after radioactive iodine therapy or surgery.
In the past decade, novel potential treatments for Graves’
Iodine-induced hyperthyroidism disease have emerged with different mechanisms of
Excessive iodine intake can cause hyperthyroidism. It action: restoration of immune tolerance (immuno­
occurs mainly in patients with pre-existing thyroid modulatory TSHR peptides), counteracting TSH-receptor
disease (autonomous thyroid nodules or latent Graves’ signalling (TRAb blockers, small molecular TSHR
disease) as a result of the Jod-Basedow phenomenon antagonists), modulating B-cell function and activation
(thyroid hormone hypersecretion in response to excess (rituximab, iscalimab, belimumab), and inhibition of
iodine substrate), but can occur in individuals with no IgG recycling by neonatal Fc receptor blockade
evidence of underlying thyroid disease. Nowadays, (rozanolixizumab, efgartigimod).124,125 Published clinical
iodine-induced hyperthyroidism occurs most often after studies with these treatments are small and include mainly
exposure to iodinated radiographic contrast120 or open-label phase 1 and 2 studies.126 Findings from large,
treatment with the iodine-containing antiarrhythmic randomised multicentre trials are awaited to confirm these
drug amiodarone, but it has also been described after promising but preliminary results.
ingestion of kelp, high-dose iodine supplements, topical Long-term treatment with a low-dose antithyroid drug
disinfectant use, and food contamination. Amiodarone- is a feasible strategy to control hyperthyroidism and
induced thyrotoxicosis can be due to the Jod-Basedow avoid relapse, and seems to be safe and effective in both
phenomenon, called type 1 amiodarone-induced thyro­ Graves’ disease and toxic nodular goitre.127 In view of
toxicosis, but more commonly it is due to drug-induced upcoming novel immunomodulating and other targeted
thyroiditis, termed type 2 amiodarone-induced thyro­ drugs, long-term low-dose antithyroid drugs might
toxicosis.121 Typically, type 1 amiodarone-induced thyro­ become an appealing option in Graves’ disease, while
toxicosis presents after only a few months to 1 year of awaiting the future availability of these therapies.
therapy in previously euthyroid patients who have thyroid When choosing drug therapy, current guidelines advise
nodules or latent Graves’ disease. By contrast, type 2 a course of antithyroid drugs for 12–18 months in
amiodarone-induced thyrotoxicosis usually develops patients with Graves’ disease.78,86 However, although an
several years after drug therapy was initiated. It is initial treatment course of 12–18 months is reasonable in
characterised clinically by a non-tender, non-enlarged patients who respond quickly to treatment and who seem
thyroid gland, with absence of thyroid nodules or likely to achieve remission, studies suggest opportunities
evidence of thyroid autoimmunity, and low parenchymal for a more individualised approach.84 In patients with a
blood flow on thyroid sonography. It can be difficult to low chance of remission upfront (eg, those who smoke or
distinguish between the two types on clinical grounds, have high TRAb titres) or those for whom a relapse
and both forms can coexist. would be detrimental because of underlying other
Type 1 amiodarone-induced thyrotoxicosis is treated with abnormalities (eg, patients with heart disease), providing
high doses of antithyroid drugs but thyroidectomy might definitive therapy or starting long-term antithyroid drug
be necessary in patients who do not adequately respond. therapy from the outset might be more appropriate.

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 Seminar

Evidence suggests an increase in remission rate with a randomised controlled trial investigating this question
every additional year of antithyroid drug therapy.87,128 seems to be unlikely in the near future.
Achieving and maintaining euthyroidism or inducing Contributors
and treating hypothyroidism appear to reverse the LC and RPP drafted the outline for this Seminar, which was further
mortality excess seen in hyperthyroidism.129 In particular, developed by LC, DSC, JPW, and RPP. The literature search was done by
a medical librarian. LC, DSC, JPW, and RPP selected studies from the
hypothyroidism induced by radioactive iodine followed literature search, drafted separate sections of the manuscript, and
by T4 replacement reverses the increased risk of provided crucial input on all other sections of the manuscript. All
cardiovascular disease and total mortality.57,102,130 However, authors have verified the underlying data from the literature review.
achieving euthyroidism with antithyroid drugs does not Declaration of interests
necessarily reverse the increased mortality risk,131 We declare no competing interests.
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