Seminar

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

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

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 Seminar

Alternative names Pathogenesis Clinical pointers

Thyrotoxicosis with hyperthyroidism
Graves’ disease
Toxic nodular goitre
Gestational hyperthyroidism
Gestational trophoblastic disease
Iodine-induced hyperthyroidism
Type 1 amiodarone-induced
thyrotoxicosis
Thyrotropinoma
Thyroid hormone resistance β*
Familial non-autoimmune
hyperthyroidism
Thyrotoxicosis without
hyperthyroidism
Thyroiditis
Lymphocytic thyroiditis
Subacute thyroiditis
Other forms of thyroiditis
Drug-induced
Traumatic
Radiation-induced
Bacterial, fungal
Exogenous thyroid hormone
Struma ovarii
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.
·· Increased thyroid hormone synthesis
and secretion by the thyroid
Basedow disease, diffuse toxic goitre Stimulating antibodies to TSH
receptor
Toxic adenoma, autonomous thyroid Single or multiple autonomous
adenoma, Plummer’s disease adenomas, somatic activating
mutations in TSH receptor
·· High values of hCG stimulating TSH
receptor
·· As for gestational hyperthyroidism
Jod-Basedow phenomenon Excess iodine substrate (usually in
gland with underlying autonomous
function)
·· As for iodine-induced
hyperthyroidism
TSHoma TSH secretion by pituitary adenoma
·· Mutation in TRb gene
·· Germline activating mutation in TSH
receptor
·· Increased circulating thyroid
hormones without increased
synthesis of thyroid hormone by the
thyroid
·· Inflammation leading to release of
stored thyroid hormone from thyroid
follicles
Silent thyroiditis, painless thyroiditis, Autoimmune thyroiditis
autoimmune thyroiditis, includes
post-partum thyroiditis
De Quervain thyroiditis, Viral or post-viral inflammation
granulomatous thyroiditis, viral or
post-viral thyroiditis, painful thyroiditis
·· ··
·· Various
·· Trauma, manipulation, palpation
·· Radiation thyroiditis
·· Bacterial or fungal infection
·· Excessive thyroid hormone use
(iatrogenic or factitious)
·· Ectopic thyroid hormone secretion
from ovarian teratoma
··
Diffuse goitre, thyroid bruit
(pathognomonic), ophthalmopathy
Asymmetric, irregular goitre; visible
or palpable nodule(s)
First trimester of pregnancy,
hyperemesis gravidarum, multiple
pregnancy
Hydatidiform mole, trophoblastic
tumour
History of excessive iodine or kelp
ingestion, radiographic contrast
exposure
Amiodarone treatment, underlying
thyroid disease
Pituitary tumour, elevated free T4
and (free)T3 with unsuppressed TSH
Attention deficit hyperactivity
disorder, tachycardia, diffuse goitre
··
··
··
Positive TPOAb, post-partum
presentation
Preceding viral illness; painful, tender
thyroid; negative TPOAb
··
··
··
··
··
··
Pelvic mass; very rare

Table 1: Causes of thyrotoxicosis

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

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

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

Although this finding might relate to milder disease seen with atrial arrhythmias, and congestive heart failure,
in older adults, the index of suspicion for hyperthyroidism often with a precipitating event such as infection, surgery,
should be heightened in older people with unexplained or childbirth. It rarely is the initial presentation of
weight loss, atrial fibrillation or atrial flutter, palpitations, hyperthyroidism.
altered mood, and other non-specific complaints.52 Untreated hyperthyroidism is associated with various
Table 2 shows both typical and unusual symptoms adverse outcomes, especially in older individuals. In one
and signs of hyperthyroidism. Patients with Graves’ population-based study, the standardised mortality ratio
disease have additional findings that are highly specific was 1·14 (95% CI 1·04–1·24, p=0·002) compared with
to this condition and are diagnostically helpful (table 2). the general population.57 Cardiovascular adverse events
The most prevalent is thyroid eye disease, also known are most important, especially atrial fibrillation leading
as Graves’ ophthalmopathy or orbitopathy, with an to heart failure and embolic stroke.58 Such events are
overall prevalence of 25–40%53 among patients with more likely to occur in older patients with comorbidities
Graves’ hyperthyroidism. Other findings in patients including cardiovascular disease, hypertension, diabetes,
with Graves’ hyperthyroidism are less frequent and and valvular heart disease.58 Fractures are more common,
include thyroid dermopathy (pretibial myxedema), especially in postmenopausal women with hyper­
thyroid acropachy (clubbing of the nails), and other thyroidism, than in the general population, probably
autoimmune disorders such as thymic enlargement, because of increased bone turnover.59,60 Overall quality
splenomegaly, alopecia, vitiligo, pernicious anaemia, of life is diminished in individuals with untreated
and urticaria. hyperthyroidism,61 especially if they have concomitant
Thyroid storm, a severe exacerbation of hyperthyroidism Graves’ ophthalmopathy.62
associated with decompensation in one or more organ
systems, occurs in up to 0·2% of patients with Diagnosis of thyrotoxicosis
thyrotoxicosis54,55 and has a mortality rate of up to Overt thyrotoxicosis is characterised by increased serum
10–17% in people older than 60 years.56 Thyroid storm is a concentrations of free T4 and total or free T3, and
combination of signs and symptoms characterised by suppressed serum TSH, usually less than 0·01 mU/L.
many of the following: fever, altered mental status, Some patients have so-called T3 thyrotoxicosis, in which
See Online for appendix gastrointestinal and hepatic dysfunction, tachycardia free T4 concentrations are within range but T3 values are
raised. This occurrence is common in patients with
Symptoms* Signs* milder disease or early in the course of disease. In
General Nervousness, insomnia, fatigue Anxiety, restlessness
subclinical hyperthyroidism, thyroid hormone values are
Skin Diaphoresis, thinning hair Warm, moist skin, onycholysis, alopecia†,
within range but TSH is suppressed.1 Measurement of
acropachy†, urticaria*, vitiligo* the free fraction of T4 is preferred over the measurement
Eyes Dry eye, eye protrusion, diplopia, Proptosis†, conjunctival injection†, of total T4, because it reflects the freely available
photophobia chemosis†, decreased visual acuity†, lid hormone, which is unbound to proteins and ready to
lag† enter tissues. Because of limitations of current free T3
Neck Anterior neck swelling, dysphagia Goitre assays, either total or free T3 can be measured.
Cardiovascular Palpitations, dyspnoea on exertion, Tachycardia, tachyarrhythmia, congestive In patients suspected of having Graves’ disease,
chest pain heart failure‡
particularly when they do not have Graves’ ophth­
Gastrointestinal Hyperdefecation, diarrhoea Abnormal liver function tests
almopathy or other pathognomonic physical findings,
Metabolic Hyperphagia, weight loss, heat Cachexia, fever‡
sensitivity
measurement of antibodies to the TSH receptor (TRAb)
Neuromuscular Muscle weakness, paralysis§ Hyper-reflexia, proximal muscle
is a key diagnostic. TRAb can be measured with
weakness, muscle wasting, hypokalaemic immunoassays that simultaneously detect two categories
periodic paralysis§ of functional TRAb—ie, thyroid stimulating antibodies
Skeletal ·· Low bone mass and fractures, and thyroid blocking antibodies, which sometimes co-
hypercalcaemia, hypercalciuria exist in patients with Graves’ disease (figure). These
Neurological Tremor Tremor, stupor‡, coma‡, immunoassays do not differentiate between thyroid
choreoathetosis§
stimulating and thyroid blocking antibodies. For
Reproductive/sexual Oligo-amenorrhoea, decreased fertility Gynecomastia
in women, decreased libido in men approximately 5 years, novel automated bridge-based
Haemopoietic ·· Leukopenia†, normochromic normocytic
binding assays have become commercially available to
anaemia, splenomegaly†, thymic more selectively, but not exclusively,63 measure thyroid
enlargement† stimulating antibodies.64 Either assay method provides
Psychiatric/cognitive Emotional lability, poor concentration, Depression, psychosis, irrational excellent diagnostic sensitivity and specificity.65
irritability behaviour In patients in whom the cause of thyrotoxicosis is not
*Signs and symptoms of hyperthyroidism are less specific or might be absent in patients of older age. †Findings seen readily apparent, scintigraphy and radioisotope uptake
in Graves’ disease. ‡Findings seen in thyroid storm. §References for rare findings are provided in the appendix.
are useful to determine the cause. Radioisotopes of
Table 2: Signs and symptoms of hyperthyroidism, by system iodine (¹²³I and ¹³¹I) or ⁹⁹-technetium are administered
and subsequently detected in the thyroid gland by planar

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 Seminar

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.

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

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 Seminar
hyper­thyroxinaemia),69,70 and in rare cases patients with
thyroid autoimmunity might have circulating auto­
antibodies to T4 or T3 causing analytical interference.71
Although serum TSH is always subnormal in primary
hyper­thyroidism, two rare conditions present with
normal or raised serum concentrations of thyroid
hormone and unsuppressed serum TSH: TSH-secreting
pituitary tumours causing central thyrotoxicosis, and
resistance to thyroid hormone β, caused by mutations in
the thyroid hormone receptor β.72,73 Several common
clinical entities are associated with subnormal serum
TSH but normal or low concentrations of thyroid
hormones, including severe non-thyroidal illness, central
hypothyroidism, and high-dose glucocorticoid therapy.
Suppressed TSH with normal free T4 and T3 can also be
seen in early pregnancy.74,75 Ethnic differences can also be
important; up to 8% of healthy African Americans have
serum TSH concen­trations below the reference range
lower limit of 0·45 mU/L compared with White
Americans.76 Whether genetic predisposition or
environmental factors explain these differences is still
unclear.
Treatment
Relief of thyrotoxic symptoms (irrespective of cause) can
be achieved by β-adrenergic blocker therapy. The non-
selective β-blocker propranolol has long been used
(10–40 mg given three to four times a day), but longer
acting, selective β-1 blockers such as atenolol and
metoprolol are also effective. The preferred choice of
therapy in thyrotoxicosis with hyperthyroidism depends
on the underlying pathophysiology, but the most common
options are antithyroid drugs, radioactive iodine, and
thyroidectomy. In patients with toxic adenoma or
multinodular goitre, radioactive iodine treatment and
surgery have been the preferred options. However,
studies have shown that long-term, low-dose treatment
with antithyroid drugs is effective, especially in older
patients or those who are poor candidates for radioactive
iodine treatment or surgery.77 In Graves’ disease, all three
treatment options are effective, but antithyroid drugs may
be the patient-preferred approach.78 A cohort study of
1186 patients with Graves’ disease followed up for up to
10 years after treatment with radioactive iodine reported
lower quality of life than did those who had received
antithyroid drugs or surgery,79 whereas findings from an
earlier, smaller randomised controlled trial showed no
difference.80 Clinicians in Europe and the Asia-Pacific
region generally prefer antithyroid drugs as first-line
treatment.81,82 In the USA, treatment choices have shifted
in favour of antithyroid drugs over radioactive iodine in
the past two decades.83 Emerging evidence of the efficacy
and safety of long-term administration of antithyroid
drugs in patients with Graves’ disease might also
contribute to future treatment preferences.84 During the
COVID-19 pandemic, non-urgent surgery and radioactive
iodine treatment were curtailed in many countries,
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leading to a further shift towards the use of antithyroid
drugs. Table 3 shows the mode of action, contraindications,
and major side-effects for antithyroid drugs, radioactive
iodine, and thyroidectomy.
Antithyroid drugs
The thionamide antithyroid drugs include propylthiouracil,
carbimazole, and its metabolite methimazole. Carbimazole
and methimazole are generally preferred over pro­
pylthiouracil because of superior efficacy and tolerability,
and because their longer duration of action allows once
daily oral administration rather than twice or thrice daily
as for propylthiouracil.83,85 Patients with newly diagnosed
Graves’ hyperthyroidism can be treated for 12–18 months
with carbimazole and methimazole according to American
and European guidelines,78,86 after which they can be
discontinued if TSH serum is normal and TRAb is
negative. In case of persistent high TRAb on treatment or
relapse after treatment withdrawal, patients can choose
carbimazole and methimazole for a further 12 months (or
longer), or opt for definitive treatment with radioactive
iodine or thyroidectomy. A disadvantage of antithyroid
drugs is high relapse rates (about 50%) after a single
course, especially in the first 6 months after withdrawal.84,87,88
However, in a longitudinal study of 128 patients with
recurrent Graves’ disease, over 75% of those who received
a second course of treatment with antithyroid drugs had
long-term remission.89 Evidence shows that long-term
(5–10 years) or perhaps even lifelong treatment with low-
dose carbimazole and methimazole is a safe and an
effective option.84,90
The initial dose of antithyroid drug required depends
on the severity of hyperthyroidism and size of thyroid
gland.91 After initial control, which can take 1–3 months,
depending on the starting dose, antithyroid drugs can be
titrated to the lowest dose needed to maintain
euthyroidism. Alternatively, especially in difficult to
control disease, a so-called block and replace regimen
can be used in which antithyroid drugs are given in a
high dose to fully block thyroid function accompanied by
levothyroxine replacement to avoid hypothyroidism.78,86
Thyroid function should be checked 4–6 weeks after
starting treatment, with dose titration based on serum T4
and T3 concentrations, because serum TSH can remain
suppressed for several months.86 Overtreatment resulting
in hypothyroidism should be avoided, particularly in
Graves’ disease, because it can provoke or exacerbate
thyroid eye disease.92 Once patients achieve biochemical
euthyroidism, follow-up intervals can be extended to
2–4 months.
Minor side-effects occur in about 5% of patients,
including pruritus and gastrointestinal distress (table 3).
Major side-effects of antithyroid drugs are rare. There is
some evidence that serious side-effects are dose related
with carbimazole and methimazole, which has not been
reported for propylthiouracil.93 Agranulocytosis occurs in
less than 0·5% of patients, typically within the first
 Seminar

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

Table 3: Treatments for thyrotoxicosis with hyperthyroidism

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

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 Seminar
radioactive iodine is contraindicated in patients with
Graves’ disease with severe orbitopathy, and gluco­
corticoid prophylaxis is recommended in those with mild
orbitopathy or judged at risk of de-novo thyroid eye
disease (those who smoke, with severe or unstable
hyperthyroidism, and with high serum TRAb) when
receiving radioactive iodine.100 Untreated hypothyroidism
after radioactive iodine should be avoided since this
treatment can elicit or worsen thyroid eye disease. Other
contraindications to radioactive iodine therapy include
pregnancy (or pregnancy planned in the next 6 months),
breastfeeding,86 and inability to adhere to radiation safety
precautions. Finally, although findings from several
studies showed no difference in cancer incidence or
mortality with radioactive iodine in general or between
fixed and calculated radioiodine activity regimens,102,103
some evidence suggests a dose-dependent positive
association between RAI and solid cancer mortality;104
however, findings are controversial.
Thyroidectomy
Thyroidectomy can be regarded as first-line treatment for
toxic nodular goitre and as definitive treatment for Graves’
disease, particularly when other treatments are ineffective,
not tolerated, or contraindicated (eg, radioactive iodine
therapy in severe orbitopathy); in patients with (suspected)
malignant nodules, large goitres, or concurrent
primary hyperparathyroidism; or when thyroidectomy is
the patient’s preference. For Graves’ disease, total
thyroidectomy is generally more effective than subtotal
thyroidectomy, with equal rates of complications, and
therefore preferred. Antithyroid drugs should be used to
achieve euthyroidism before surgery and replaced by
levothyroxine treatment postoperatively. Pretreatment
with Lugol’s iodine or potassium iodide decreases
intraoperative blood loss for patients with Graves’ disease
and is recommended in clinical practice guidelines.78,86 For
toxic nodular goitre, hemithyroidectomy or total thy­
roidectomy might be appropriate depending on the
number and distribution of thyroid nodules. Surgical
complications are infrequent (1–2%), particularly when
undertaken by high-volume thyroid surgeons (ie, those
doing >25–50 thyroidectomies per year).105–107 Complications
include postoperative bleeding, hypocalcaemia (usually
transient) due to hypoparathyroidism, and recurrent
laryngeal nerve injury, with a risk for each of around 1%.
Special circumstances
Subclinical hyperthyroidism
Roughly between a third and a quarter of patients with
subclinical hyperthyroidism have a serum TSH less than
0·1 mU/L, which is regarded as more severe subclinical
hyperthyroidism.86,108 In patients with serum TSH
between 0·1 mU/L and 0·4 mU/L (mild subclinical
hyperthyroidism), TSH concentrations normalise during
follow-up in 20–30% of individuals over 4·5–5 years. In
patients with a TSH concentration less than 0·1 mU/L,
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thyroid dysfunction usually persists or progresses to overt
hyperthyroidism.109,110 In addition to the risk of developing
overt hyperthyroidism, older patients with subclinical
hyperthyroidism have increased risks of cardiovascular
disease (atrial fibrillation, heart failure, coronary heart
disease, and stroke), bone loss, fractures, and dementia.1
This risk has led to clinical practice recommendations to
treat severe and possibly mild subclinical hyperthyroidism
in people older than 65 years, despite little high-quality
evidence of therapeutic benefits. When treatment is
started, the goal is to normalise serum TSH concen­
trations.86,108 Similar to overt hyperthyroidism, treatment
depends on the underlying condition, comorbidities, and
patient preference.
Hyperthyroidism in pregnancy
During a normal pregnancy, pronounced changes in
thyroid physiology occur. The pregnancy hormone human
chorionic gonadotropin (hCG, which is a weak agonist of
the TSH receptor), stimulates thyroid hormone secretion
leading to higher circulating T4 concentrations and
a concomitant decrease in serum TSH. Therefore,
pregnancy-specific TSH reference ranges are required to
diagnose thyroid dysfunction in pregnant women.75
Gestational hyperthyroidism due to very high concen­
trations of hCG occurs in about 1–3% of pregnancies; it is
usually transient and does not require treatment.111 In
about half of cases, gestational hyperthyroidism is
associated with hyperemesis gravidarum. De-novo
pathological hyperthyroidism during pregnancy (mainly
due to Graves’ disease and toxic nodules) is much less
common, with a frequency of about 0·2%.112
Overt hyperthyroidism during pregnancy is associated
with adverse pregnancy and neonatal outcomes, including
increased risk of miscarriage, stillbirth, pre-eclampsia, pre-
term birth, and low birthweight.111 Most published studies
do not have data for treatment, but available evidence
suggests that cautious treatment of hyper­ thyroidism
during pregnancy improves outcomes,113 and that women
who receive adequate antenatal care do not have increased
risks.114 Excessive maternal thyroid hormones could affect
fetal development,115 and overt hyperthyroidism during
pregnancy should be treated. However, antithyroid drug
treatment in early pregnancy, especially in weeks 5–11,
carries a small risk of teratogenic side-effects with
differences in pattern and severity generally in favour of
propylthiouracil over carbimazole and methimazole.116
Ideally, women with hyperthyroidism planning pregnancy
would receive definitive therapy before pregnancy. In case
of de-novo pathological hyperthyroidism during pregnancy,
the lowest effective dose of antithyroid drug should be
used (as monotherapy rather than so-called block and
replace), with frequent monitoring of mother and fetus,
and propylthiouracil preferred to carbimazole and
methimazole during the first trimester. A more detailed
discussion on the treatment of hyperthyroidism in
pregnancy is available elsewhere.36,111

Thyroiditis
Thyrotoxicosis caused by thyroiditis is usually transient
and self-limiting, regardless of cause, and often no
treatment is required. β blockers provide symptomatic
relief, but antithyroid drugs are ineffective and not
indicated. For subacute painful thyroiditis, first-line
treatment is a non-steroidal anti-inflammatory drug
(NSAID), with glucocorticoid treatment used if symptoms
are severe or the patient does not respond to NSAID.
Prednisolone or prednisone 30–40 mg daily for 1–2 weeks
followed by dose tapering is widely used,86,117 although
lower initial doses (15–20 mg) can be effective.117,118
Thyrotoxicosis is often followed by hypothyroidism,
which can be transient or permanent. In subacute
thyroiditis, most patients recover normal thyroid
function, whereas in lymphocytic thyroiditis (including
post partum), hypothyroidism can be long lasting (eg,
6–12 months) or permanent in 10–40% of cases.35
Levothyroxine replacement is indicated if hypothyroidism
is severe or symptomatic, with consideration of a trial of
withdrawal of therapy after 6–12 months. Thyroiditis
caused by checkpoint inhibitor immunotherapy is
followed by permanent hypothyroidism in most cases.44,119
Iodine-induced hyperthyroidism
Excessive iodine intake can cause hyperthyroidism. It
occurs mainly in patients with pre-existing thyroid
disease (autonomous thyroid nodules or latent Graves’
disease) as a result of the Jod-Basedow phenomenon
(thyroid hormone hypersecretion in response to excess
iodine substrate), but can occur in individuals with no
evidence of underlying thyroid disease. Nowadays,
iodine-induced hyperthyroidism occurs most often after
exposure to iodinated radiographic contrast120 or
treatment with the iodine-containing antiarrhythmic
drug amiodarone, but it has also been described after
ingestion of kelp, high-dose iodine supplements, topical
disinfectant use, and food contamination. Amiodarone-
induced thyrotoxicosis can be due to the Jod-Basedow
phenomenon, called type 1 amiodarone-induced thyro­
toxicosis, but more commonly it is due to drug-induced
thyroiditis, termed type 2 amiodarone-induced thyro­
toxicosis.121 Typically, type 1 amiodarone-induced thyro­
toxicosis presents after only a few months to 1 year of
therapy in previously euthyroid patients who have thyroid
nodules or latent Graves’ disease. By contrast, type 2
amiodarone-induced thyrotoxicosis usually develops
several years after drug therapy was initiated. It is
characterised clinically by a non-tender, non-enlarged
thyroid gland, with absence of thyroid nodules or
evidence of thyroid autoimmunity, and low parenchymal
blood flow on thyroid sonography. It can be difficult to
distinguish between the two types on clinical grounds,
and both forms can coexist.
Type 1 amiodarone-induced thyrotoxicosis is treated
with high doses of antithyroid drugs but thyroidectomy
might be necessary in patients who do not adequately
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Seminar
respond. Radioactive iodine treatment is usually not
feasible because of the high intrathyroidal concentrations
of iodine from the amiodarone, which has a half-life of
100 days.121 As with any thyroiditis, type 2 amiodarone-
induced thyrotoxicosis resolves over time, and ultimately
can result in transient or permanent hypothyroidism.
However, its presentation can be very severe and often
requires glucocorticoid therapy for several months.121
Discontinuation of amiodarone can hasten recovery
from both types of amiodarone-induced thyrotoxicosis,
but is not always possible because of the underlying
cardiac condition.122 Since amiodarone is generally used
in patients with severe cardiovascular disease or tachya­
rrhythmias, or both, amiodarone-induced thyrotoxicosis
is associated with high mortality, especially in patients
with underlying left ventricular dysfunction.123
Future directions
Therapeutic options for Graves’ disease have remained
much the same over the past 80 years. Despite
improvements in delivery and safety, current treatment
methods have important limitations, particularly high
relapse rates after withdrawal of antithyroid drugs and
hypothyroidism after radioactive iodine therapy or surgery.
In the past decade, novel potential treatments for Graves’
disease have emerged with different mechanisms of
action: restoration of immune tolerance (immuno­
modulatory TSHR peptides), counteracting TSH-receptor
signalling (TRAb blockers, small molecular TSHR
antagonists), modulating B-cell function and activation
(rituximab, iscalimab, belimumab), and inhibition of
IgG recycling by neonatal Fc receptor blockade
(rozanolixizumab, efgartigimod).124,125 Published clinical
studies with these treatments are small and include mainly
open-label phase 1 and 2 studies.126 Findings from large,
randomised multicentre trials are awaited to confirm these
promising but preliminary results.
Long-term treatment with a low-dose antithyroid drug
is a feasible strategy to control hyperthyroidism and
avoid relapse, and seems to be safe and effective in both
Graves’ disease and toxic nodular goitre.127 In view of
upcoming novel immunomodulating and other targeted
drugs, long-term low-dose antithyroid drugs might
become an appealing option in Graves’ disease, while
awaiting the future availability of these therapies.
When choosing drug therapy, current guidelines advise
a course of antithyroid drugs for 12–18 months in
patients with Graves’ disease.78,86 However, although an
initial treatment course of 12–18 months is reasonable in
patients who respond quickly to treatment and who seem
likely to achieve remission, studies suggest opportunities
for a more individualised approach.84 In patients with a
low chance of remission upfront (eg, those who smoke or
have high TRAb titres) or those for whom a relapse
would be detrimental because of underlying other
abnormalities (eg, patients with heart disease), providing
definitive therapy or starting long-term antithyroid drug
9
 Seminar
therapy from the outset might be more appropriate.
Evidence suggests an increase in remission rate with
every additional year of antithyroid drug therapy.87,128
Achieving and maintaining euthyroidism or inducing
and treating hypothyroidism appear to reverse the
mortality excess seen in hyperthyroidism.129 In particular,
hypothyroidism induced by radioactive iodine followed
by T4 replacement reverses the increased risk of
cardiovascular disease and total mortality.57,102,130 However,
achieving euthyroidism with antithyroid drugs does not
necessarily reverse the increased mortality risk,131
probably because patients are not always euthyroid while
receiving antithyroid drugs and might relapse when
treatment is stopped.102 The effect of long-term treatment
with low-dose antithyroid drugs on risk of cardiovascular
disease and mortality is yet unknown, but could be more
favourable than shorter or repeated courses.
In some patients with autonomous benign thyroid
nodules, radiofrequency ablation might be an alternative
to current strategies. Findings from two single-centre
studies investigating radiofrequency ablation with a
moving-shot technique showed normalisation of TSH in
at least half of patients with a low complication rate
and improvement of local cervical discomfort.132,133 In
one study a second radiofrequency ablation led to a
normalisation of TSH in four of five patients.133
Patients frequently inquire about the role of dietary
supplements (eg, vitamin D, selenium, and omega 3 fatty
acids) for prevention or treatment of Graves’ disease.
Although several supplements have been investigated,
data are conflicting.134 The addition of dietary supplements
or traditional medicine to current strategies to enhance
efficacy or increase safety has also been studied. A meta-
analysis of 17 randomised controlled trials with
1536 participants showed that tripterygium glycosides
could enhance the effect of methimazole and prednisone
in treatment of hyperthyroidism, without increasing side-
effects.135 A network meta-analysis showed combination
of several regimens (including iodine, cholestyramine,
and immunosuppressants) with methimazole to be
efficacious in reducing free T3 and T4 values.136 Two meta-
analyses have been published in the same year comparing
radioactive iodine with lithium to radioactive iodine alone
for treatment of hyperthyroidism, but data for the
effectiveness of lithium as an adjunct to radioactive iodine
are inconclusive.137,138
Finally, in older patients, subclinical hyperthyroidism is
more prevalent than overt hyperthyroidism. Since several
individual participant meta-analyses of observational
studies have shown that patients with subclinical
hyperthyroidism have an increased risk of hip and other
fractures, osteoporosis, cardiovascular events, and
mortality, guidelines recommend treatment of subclinical
hyperthyroidism with a serum TSH concentration less
than 0·1 mU/L, independent of the presence of symptoms,
particularly in elderly patients.1,108 Although there is no
consensus regarding treatment for patients with mild
10 www.thelancet.com Published online January 23, 2024 https://doi.org/10.1016/S0140-6736(23)02016-0
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subclinical hyperthyroidism (serum TSH 0·1–0·4 mU/L),
a randomised controlled trial investigating this question
seems to be unlikely in the near future.
Contributors
LC and RPP drafted the outline for this Seminar, which was further
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
literature search, drafted separate sections of the manuscript, and
provided crucial input on all other sections of the manuscript. All
authors have verified the underlying data from the literature review.
Declaration of interests
We declare no competing interests.
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