Review

Hyperthyroidism: aetiology, pathogenesis, diagnosis,

management, complications, and prognosis
Wilmar M Wiersinga, Kris G Poppe, Grigoris Effraimidis

Lancet Diabetes Endocrinol Hyperthyroidism is a common condition with a global prevalence of 0·2–1·3%. When clinical suspicion of
2023; 11: 282–98 hyperthyroidism arises, it should be confirmed by biochemical tests (eg, low TSH, high free thyroxine [FT4], or high
Published Online free tri-iodothyonine [FT3]). If hyperthyroidism is confirmed by biochemical tests, a nosological diagnosis should be
February 24, 2023
done to find out which disease is causing the hyperthyroidism. Helpful tools are TSH-receptor antibodies, thyroid
https://doi.org/10.1016/
S2213-8587(23)00005-0 peroxidase antibodies, thyroid ultrasonography, and scintigraphy. Hyperthyroidism is mostly caused by Graves’
Department of Endocrinology
hyperthyroidism (70%) or toxic nodular goitre (16%). Hyperthyroidism can also be caused by subacute granulomatous
and Metabolism, Academic thyroiditis (3%) and drugs (9%) such as amiodarone, tyrosine kinase inhibitors, and immune checkpoint inhibitors.
Medical Center, University of Disease-specific recommendations are given. Currently, Graves’ hyperthyroidism is preferably treated with antithyroid
Amsterdam, Netherlands
drugs. However, recurrence of hyperthyroidism after a 12–18 month course of antithyroid drugs occurs in
(Prof W M Wiersinga MD PhD);
Endocrine Unit, CHU Saint- approximately 50% of patients. Being younger than 40 years, having FT4 concentrations that are 40 pmol/L or higher,
Pierre, Université Libre de having TSH-binding inhibitory immunoglobulins that are higher than 6 U/L, and having a goitre size that is
Bruxelles, Brussels, Belgium equivalent to or larger than WHO grade 2 before the start of treatment with antithyroid drugs increase risk of
(K G Poppe MD PhD);
recurrence. Long-term treatment with antithyroid drugs (ie, 5–10 years of treatment) is feasible and associated with
Department of Endocrinology
and Metabolic Diseases, Larissa fewer recurrences (15%) than short-term treatment (ie, 12–18 months of treatment). Toxic nodular goitre is mostly
University Hospital, Faculty of treated with radioiodine (¹³¹I) or thyroidectomy and is rarely treated with radiofrequency ablation. Destructive
Medicine, School of Health thyrotoxicosis is usually mild and transient, requiring steroids only in severe cases. Specific attention is given to
Sciences, University of
patients with hyperthyroidism who are pregnant, have COVID-19, or have other complications (eg, atrial fibrillation,
Thessaly, Larissa, Greece
(G Effraimidis MD PhD); thyrotoxic periodic paralysis, and thyroid storm). Hyperthyroidism is associated with increased mortality. Prognosis
Department of Endocrinology might be improved by rapid and sustained control of hyperthyroidism. Innovative new treatments are expected for
and Metabolism, Graves’ disease, by targeting B cells or TSH receptors.
Rigshospitalet, Copenhagen
University Hospital,
Copenhagen, Denmark Introduction daily T3 production is generated extrathyroidally from T4
(G Effraidimis) Thyrotoxicosis refers to a syndrome caused by excessive by deiodinases in extrathyroidal tissues such as the liver,
Correspondence to: thyroid hormones. Hyperthyroidism refers to excessive kidney, and brain. Thyroid hormone predominantly
Dr Grigoris Effraimidis, thyroid hormone production in the thyroid gland (ie, works by binding to nuclear T3 receptors that are present
Department of Endocrinology
thyrotoxicosis with hyperthyroidism), whereas excessive in almost all tissues. However, thyroid hormones can
and Metabolic Diseases, Larissa
University Hospital, Faculty of thyroid hormones derived from extrathyroidal sources also have non-genomic effects on plasma membranes
Medicine, School of Health or destructive thyrotoxicosis is known as thyrotoxicosis (eg, ion channels). Thyrotoxicosis is a common
Sciences, University of Thessaly, with­ out hyperthyroidism. However, the terms hyper­ condition: the estimated global prevalence of overt
Larissa 41500, Greece
thyroidism and thyrotoxicosis are often used almost hyperthyroidism (ie, elevated T4 or T3, or both) in iodine-
grigoris.effraimidis@gmail.
com interchangeably, as we do in in this Review. Thyroxine sufficient populations is 0·2–1·3%. In Europe, the
(T4) is produced by the thyroid gland and and considered prevalence of overt hyperthyroidism is 0·75%, and the
as the prohormone of tri-iodothyronine (T3). 80% of the annual incidence is 51 cases per 100 000 people per year.1
The prevalence and incidence of hyperthyroidism are
Symptoms Signs higher in historically iodine-deficient areas than in
iodine-sufficient area.
Metabolic Increased appetite Weight loss
Mood and cognition Nervousness; anxiety; depression; Hyperactivity; irratibility; emotional lability
disturbed sleep; poor concentration Clinical presentation
Neuromuscular Fatigue; weakness; tremor; periodic Brisk tendon reflexes; finger or tongue The typical patient with hyperthyroidism is a woman of
paralysis tremor, or both; muscle wasting reproductive age with symptoms such as nervousness,
Cardiovascular Palpitations; ankle oedema Tachycardia; irregular heartbeat; atrial heat intolerance, palpitations, and weight loss despite
fibrillation; systolic hypertension; heart failure increased appetite. Physical examination might reveal
Gastrointestinal Loose stools; nausea; diarrhoea Frequent bowel movements brisk tendon reflexes, fine finger tremor, moist skin,
Eyes Stare Upper lid retraction tachycardia, and goitre. The prevalence of these symptoms
Skeletal Fragility fractures Osteoporosis and signs in overt hyperthyroidism is greater than 50%.2
Respiratory Shortness of breath Dyspnoea; tachypnoea Less frequent systemic manifestations could happen in
Reproductive Irregular menses in women; Subfertility in women; gynaecomastia in all tissues because thyroid hormone stimulates
impaired libido in men men metabolism in general (table 1).
Skin Sweating; heat intolerance Warm and moist skin; onycholysis The clinical presentation of hyperthyroidism is modu­
lated by sex, age, and aetiology of hyperthyroidism.
Table 1: Symptoms and signs of systemic manifestations of hyperthyroidism
Hyperthyroidism is four to seven times more frequent in

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 Review

women than in men, irrespective of cause.3 It is most

common in women aged between 20 and 50 years. Clinical suspicion of hyperthyroidism

Hyperthyroidism in older adults (older than 65 years) is

usually oligosymptomatic and less severe than hyper­ Measure TSH
thyroidism in adults younger than 65 years, but older
adults with hyperthyroidism have a higher prevalence
of atrial fibrillation than younger adults with hyper­
thyroidism.4–6 Hyperthyroidism can present with lethargy Low TSH Normal or elevated TSH

(as opposed to the usual hyperkinesis and mental

alertness), which is known as apathetic thyrotoxicosis. Measure FT4 Hyperthyroidism excluded*
Severity is more pronounced in Graves’ hyperthyroidism
than in toxic adenoma or toxic multinodular goitre. Toxic
adenoma is more frequent between the ages of 30 and
Elevated FT4 Normal FT4
60 years, whereas toxic multinodular goitre tends to
occur after the age of 50. Toxic multinodular goitre occurs
more often in iodine-deficient areas than in iodine- Hyperthyroidism Measure FT3
sufficient areas.6 The clinical picture of thyrotoxicosis has
become less severe over the past four decades, which
could be caused by factors such as earlier diagnosis of
Elevated FT3 Normal FT3
hyperthyroidism (facilitated by the advent of sensitive
TSH assays), wider iodoprophylaxis, and a trend towards
declining rates of smoking.2,7 T3 toxicosis Subclinical hyperthyroidism

Diagnosis Figure 1: Algorithm for the diagnosis of hyperthyroidism

If clinical suspicion of hyperthyroidism arises, thyroid Low TSH is below the TSH reference range of 0∙4–4∙0 mU/L; normal TSH is within the TSH reference range of
0∙4–4∙0 mU/L; and elevated TSH is is above the TSH reference range of 0∙4–4∙0 mU/L (reference range may differ
hormone excess must be confirmed or excluded by slightly between laboratories). FT3=free tri-iodothyronine. FT4=free thyroxine. T3=tri-iodothyronine. *Except the
biochemical tests (figure 1). TSH values within the rare TSH-secreting pituitary adenoma and resistance to thyroid hormone.
reference range (ie, 0·4–4·0 mU/L) accurately exclude
hyperthyroidism, the sole exceptions being the rare measure TSH-receptor antibodies whenever Graves’
TSH-producing pituitary adenoma and thyroid hormone disease is suspected.10,11 TSH-receptor antibodies can be
resistance associated with a normal or slightly increased assessed by immunoassays that detect binding of
TSH. Confirmation of low TSH concentration (ie, antibodies to the TSH receptors (ie, TSH-binding
<0·4 mU/L) should be followed by a free T4 (FT4) assay. inhibitory immunoglobulins [TBII]) or cell-based
Increased FT4 values confirm thyrotoxicosis, but an bioassays that also provide information on whether the
FT4 value that is within the normal range could indicate functional activity of these antibodies is stimulating or
either T3 toxicosis or subclinical hyper­thyroidism, which blocking.12 Sensitivity and specificity of current TBII
is defined as TSH concentration lower than 0∙4 mU/L assays for Graves’ disease are above 95%, and that of
and FT4 and free T3 (FT3) within their reference ranges. the bioassays approach 100%.11 Clinicians should know
Progression of subclinical hyper­ thyroidism (not which assay type is performed.
discussed in this Review, but see ETA guidelines8) to Next to TSH-receptor antibodies, thyroid imaging by
T3 toxicosis occurs in about 10% of all patients with either thyroid scintigraphy or ultrasound is the most
hyperthyroidism, especially in those with nodular goitre effective diagnostic test (table 2, figure 2). Thyroidal
(figure 1).6 The thyroid function tests are susceptible to uptake of radioiodine or other tracers (eg, technetium)
analytical interference by macro-TSH, antibodies, and will be enhanced in all conditions characterised by TSH-
the use of biotin.9 Fortunately, analytical interference receptor activation by either TSH-receptor antibodies,
rarely occurs, and the advice is to consult the human chorionic gonadotropin (hCG), or gain-of-function
biochemical lab in case of discrepancies between TSH mutations of TSH receptor and G-protein α-subunit (Gsα;
and FT4 or results that do not make sense. table 2). In contrast, the inflammation of destructive
If hyperthyroidism is confirmed, a nosological diag­ thyroiditis results in disruption of follicular architecture,
nosis should be made to assess the cause of thyrotox­ release of iodine-rich and hormone-rich follicular contents
icosis. Graves’ disease (ie, diffuse goitre) is the into the blood, and thyrotoxicosis. Radioiodine uptake will
most common cause, followed by toxic multinodular be low or absent, which is the case with extrathyroidal
goitre and solitary toxic adenoma.6 Sometimes the sources of excessive thyroid hormone (table 2). Thyroid
correct diagnosis is self-evident. For example, a diffuse ultrasonography (especially using colour flow Doppler
goitre with bruit or the presence of thyroid eye disease methodology) can also distinguish thyroid hyper­activity
(ie, Graves’ orbitopathy) strongly suggests Graves’ (increased vascularity in Graves’ hyper­ thyroidism,
hyperthyroidism. Nevertheless, it is recommended to toxic adenoma, and toxic multinodular goitre) from

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 Review

Prevalence* Diagnostic clue Preferred management†

Excessive TSH-receptor stimulation
·· Thyroid RAIU increased, ultrasonography ··
vascularity increased
Graves’ hyperthyroidism 70% TSH-receptor antibodies; Graves’ orbitopathy Antithyroid drugs
hCG-related thyrotoxicosis ·· Pregnancy; high serum hCG ··
Gestational transient thyrotoxicosis 2–3%‡ Hyperemesis gravidarum Wait-and-see
Familial gestational hyperthyroidism <0·1% Mutant TSH receptors, sensitive for hCG Antithyroid drugs
Hydatiform mole, choriocarcinoma <0·1% Trophoblast tumour Mole evacuation
TSH-producing pituitary adenoma <0·1% Serum TSH normal or increased; pituitary Trans-sphenoidal resection; somatostatin
tumour analogues
Autonomous thyroid hormone secretion
·· ·· Thyroid RAIU increased, ultrasonography ··
vascularity increased
Toxic multinodular goitre 10% Somatic activating TSH receptors or ¹³¹I therapy or thyroidectomy
mutations in Gsα
Solitary toxic adenoma 6% Somatic activating TSH receptors or ¹³¹I therapy or thyroidectomy
mutations in Gsα
Familial or sporadic non-autoimmune <0·1% Germline activating TSH receptor mutations Thyroidectomy and ¹³¹I therapy
hyperthyroidism
Destructive thyroiditis
·· Thyroid RAIU decreased, ultrasonography ··
vascularity decreased
Subacute de Quervain thyroiditis 3% Viral infection; pain in the neck; C-reactive Wait-and-see; non-steroidal anti-inflammatory
protein increased drugs; prednisone
Silent or painless thyroiditis; post-partum ·· Autoimmune thyroiditis; serum TPO Wait-and-see
thyroiditis antibodies; up to 1 year post partum
Acute suppurative thyroiditis <0·1% Bacterial, fungal, or parasitic infections Antibiotics, antifungals, or surgical drainage
Drug-induced thyroiditis 9% Drug history ··
Iodide-induced thyrotoxicosis ·· Iodine excess Wait-and-see
Amiodarone ·· Amiodarone Antithyroid drugs with or without perchlorate
for type 1 amiodarone-induced thyrotoxicosis;
prednisone for type 2 amiodarone-induced
thyrotoxicosis
Cytokines ·· Interferon alfa; IL-2 Wait-and-see
Tyrosine-kinase inhibitors ·· Sorafenib, vandetanib, axitinib Wait-and-see
Immune checkpoint inhibitors ·· Anti-CTLA4: ipilimumab, tremelimumab; anti- Wait-and-see
PD1: nivolumab, pembrolizumab; anti-PDL1:
atezolizumab, oravelumab, durvalumab
Extrathyroidal source of thyroid hormone
·· Thyroid RAIU decreased, ultrasonography ··
vascularity decreased
Thyrotoxicosis factitia ·· Excess thyroid hormone drug; serum Reduce dose of thyroid hormone drug
thyroglobulin decreased
Hamburger thyrotoxicosis ·· Beef neck meat contains thyroid tissue Stop eating contaminated beef
Struma ovarii ·· Ovary tumour with focal radioiodine uptake Ovarian surgery
Metastases of differentiated thyroid cancer ·· Functional metastases with radioiodine ¹³¹I therapy
uptake

Gsα=G-protein α-subunit. hCG=Human chorionic gonadotropin. RAIU=radioidoine uptake. *Prevalence among 1144 overt hyperthyroid patients, calculated from Goichot
and colleagues.6 †β-blockers can be considered in every suitable patient. ‡2–3% of all pregnancies.

Table 2: Causes of hyperthyroidism, disease-specific diagnostic clues and preferred treatment

destructive thyroiditis and extrathyroidal thyrotoxicosis Aetiology and pathogenesis

(low or absent flow).10,11 Currently, ultrasound has become Excessive TSH-receptor stimulation
the preferred imaging procedure because it is very Graves’ hyperthyroidism
convenient and avoids the use of radioactivity.3,13 Thyroid Graves’ disease is a multisystem autoimmune disorder
scintigraphy could be useful before ¹³¹I therapy, especially characterised by stimulating TSH-receptor antibodies
for solitary toxic adenoma or toxic multinodular goitre.10,11 that bind to and activate the TSH receptors in

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 Review

thyroid follicular cells, orbital fibroblasts, and dermal

A Graves' hyperthyroidism
fibroblasts, which via cAMP and PI3 post-receptor
signalling pathways result in increased synthesis and
release of thyroid hormones (Graves’ hyperthyroidism),
swelling of extraocular muscles and orbital fat
(Graves’ orbitopathy), and pretibial myxo-oedema
(Graves’ dermopathy). Genomic immu­nisation with
the α-subunit of the TSH receptor induces hyper­
thyroidism but also extrathyroidal manifestations
such as Graves’ orbitopathy in experimental B Solitary toxic adenoma
animals.14,15 Graves’ orbitopa­ thy is not discussed in
this Review because guidelines have been published
in 2021.16 The annual incidence of Graves’ hyper­
thyroidism is 20–50 cases per 100 000 people per year,
with a peak between 30 and 50 years of age.17 The life­
time risk is 3∙0% for women and 0·5% for
men. The female preponderance in Graves’ disease is
incom­ pletely understood. Parity might be a risk
factor for Graves’ hyperthyroidism,18,19 and fetal C Toxic multinodular goitre

microchimerism (ie, persistence of fetal cells in mater­

nal tissues) and inactivation of the X chromosome in
early embryonic life are possibly involved.20,21 Both
genetic and environmental factors play a role in this
multifactorial disease. Twin studies suggest genetic
factors contribute 79% to the risk of developing
Graves’ disease.22 Polymorphisms in thyroid-specific
genes (ie, TSH-R and Tg) and immune-regulatory
D Destructive thyrotoxicosis
genes (ie HLA, FOXP3, CD25, CD40, CTLA4, and
PTPN22) are involved, with HLA-DR3 carrying the
highest risk.23 A positive family history of autoimmune
thyroid disease is present in about 50% of people with
Graves’ disease, with some evidence for genetic antic­
ipation (ie, younger age of onset in patients with
a positive family history).24,25 Environmental factors
are iodine, smoking, alcohol, stress, and infections.
Iodine fortification in iodine-deficient areas leads Figure 2: Thyroid imaging as a tool for the nosological diagnosis of hyperthyroidism.
to a small transient increase in the incidence of (A) Graves’ hyperthyroidism. Scintigraphy shows increased diffuse and homogeneous uptake of the
radioisotope (left panel). Ultrasonography shows very heterogeneous parenchyma without nodules; volume of
thyrotoxicosis, in older adults (older than 60 years)
right thyroid lobe is 14·2 mL and volume of left thyroid lobe 11·8 mL (middle panel). Ultrasound with colour
due to toxic nodular goitre and in younger people Doppler shows clear hyperaemia (right panel). (B) Solitary toxic adenoma: scintigraphy shows increased
(aged 20–39 years) possibly due to Graves’ hyper­ circumscribed uptake of radioisotope in the left thyroid lobe nodule with no uptake in the remainder of the thyroid
thyroidism.26 Iodine excess can sometimes lead to the gland (left panel). Ultrasonography shows a macronodule measuring 21 mm deep  × 20 mm  wide × 23 mm long
in the left lobe; volume of right thyroid lobe is 9·2 mL and volume of left thyroid lobe 15·2 mL (middle panel).
Jod-Basedow phenomenon, which occurs upon failure
Ultrasound with colour Doppler shows hypervascularity in the macronodule left (right panel). (C) Toxic
of normal protective mechanisms against iodine multinodular goitre. Scintigraphy shows two nodules with high uptake (hot) in the right lobe and two nodules
excess. Smoking is a clear risk factor for Graves’ with low uptake in the left thyroid lobe (left panel). Ultrasonography shows a hypoechoic macronodule measuring
hyperthyroidism: the odds ratio is 3·3 (95% CI 20 mm deep × 13 mm wide × 28 mm long in the upper right lobe and an isoechoic nodule of 7 mm deep
× 9 mm wide × 9 mm long in the lower part of the right lobe; volume of right thyroid lobe is 19·4 mL and volume
2·1–5·2) in current smokers compared with people
of left thyroid lobe 16·0 mL (middle panel). Ultrasound with colour Doppler shows hypervascularity in both
who have never smoked.27 The risk diminishes with nodules (right panel). (D) Destructive thyrotoxicosis. Scintigraphy shows faint uptake of the radioisotope in both
time and disappears 10–15 years after cessation of thyroid lobes (left panel). Ultrasonography shows a normal echostructure without nodules; volume of right
smoking. thyroid lobe is 4·4 mL and volume of left thyroid lobe 3·8 mL (middle panel). Ultrasound with colour Doppler is
normal in both thyroid lobes without increased velocities of the thyroid arteries (right panel). Images provided by
Moderate alcohol consumption seems to reduce the Dr Ringo Manta, Department of Nuclear Medicine, Saint Pierre University Hospital, Université Libre de Bruxelles,
risk of Graves’ hyperthyroidism.28 Strong circumstantial Brussels, Belgium.
evidence supports a causal relationship between severe
emotional stress and the onset of Graves’ hyperthy­
roidism.29 Infections have been implicated as a risk and epitopes of TSH-receptor antibodies, has not been
factor, without conclusive evidence. Yersinia enterocolitica linked to autoimmune hyperthyroidism.30,31 The possible
infection, despite cross-reactivity (ie, molecular mimicry) role of altered gut microbiota composition in the
between Yersinia enterocolitica outer membrane proteins development of autoimmune thyroid diseases is far

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 Review

from resolved.32 Graves’ hyperthyroidism can develop as TSH-secreting pituitary adenoma

part of the immune reconstitution syndrome when TSH-secreting pituitary adenoma is a rare disease
lymphocytes recover after induced severe lymphopoenia.33 usually presenting as a macroadenoma, which causes
Immune reconstitution syndrome could happen after visual field defects and headache, and mild
bone marrow or haematopoietic stem-cell transplantation, hyperthyroidism around the fifth or sixth decade of
during highly active antiretroviral therapy for HIV life.42 Concomitant hypersecretion of growth hormone
infection, and during alemtuzumab treatment for or prolactin occurs in 25% of patients with TSH-
multiple sclerosis. Up to 30% of patients treated with secreting pituitary adenoma. Diagnosis is often delayed,
alemtuzumab develop Graves’ hyperthyroidism, mainly especially in patients with a normal serum TSH value.
within 3 years after the last dose.34 Both stimulating and Similar thyroid function tests are found in resistance to
blocking TSH-receptor antibodies are observed in these thyroid hormone. A proper diagnosis of TSH-secreting
patients. The high incidence of Graves’ hyperthyroidism pituitary adenoma can be established by pituitary
in patients treated with alemtuzumab contrasts with the imaging, elevated serum concen­trations of glycoprotein
rare occurrence of Graves’ hyperthyroidism in patients α subunits, a blunted TSH response to TRH (TSH
treated with other drugs (table 2), which more commonly releasing hormone), and insuf­fi cient TSH suppression
cause transient destructive thyrotoxicosis frequently after exposure to exogenous T3.42
followed by a hypothy­ roid phase. Other autoimmune
diseases occur in 9·7% of patients with Graves’ Autonomous thyroid hormone secretion
hyperthyroidism, especially rheumatoid arthritis, Toxic multinodular goitre and toxic adenoma
pernicious anaemia, systemic lupus erythematosus, In toxic multinodular goitre and toxic adenoma there is
coeliac disease, Addison’s disease, and vitiligo.35 autonomous production and release of thyroid hormones
by thyrocytes, independent from TSH or TSH-receptor
Human chorionic gonadotropin-related thyrotoxicosis antibodies, due to constitutive activation of the TSH
Human chorionic gonadotropin (hCG) has some receptor or—less commonly—to somatic mutations in
thyroid-stimulating activity: 1 U of purified hCG is Gsα.43 The production and release of thyroid hormones
equivalent to 0∙0013 μU of human TSH as evident in by the autonomous nodules results in suppressed TSH,
vitro from de novo synthesised thyroid hormone release circumscribed uptake of radioisotopes in autonomous
in human thyroid follicles.36 hCG acts by binding to the nodules, but decreased uptake of radioisotopes in non-
TSH receptor and activating adenylyl cyclase. In normal autonomous thyroid tissue, and ultimately thyrotoxicosis
pregnancy, serum hCG peaks at 9–12 weeks of gestation, (figure 2). Thyroid autonomy develops slowly; the
coinciding with a decrease of serum TSH. TSH transition from euthyroidism to subclinical hyper­
concentrations lower than 0·2 mU/L are reported in thyroidism, T3-toxicosis, and finally overt hyper­
about 18% of pregnant women at a mean hCG of thyroidism could take decades.44 The pathogenesis can
52 400 IU/L.37 Higher hCG concentrations increase the start with iodine deficiency, which induces hyperplasia
risk of overt hyperthyroidism. At serum hCG and increases mutagenesis, leading to cell clones
concentrations higher than 200 000 IU/L, serum TSH containing somatic mutations featuring nodular
concentrations lower than or equal to 0·2 mU/L are transformation.43 Iodine fortification in iodine-deficient
observed in 67% of patients; at serum hCG areas initially increases thyrotoxicosis incidence, but
concentrations higher than 400 000 IU/L, serum TSH after approximately 10 years decreases the prevalence of
concentrations lower than or equal to 0·2 mU/L are goitre, thyroid autonomy, and hyperthyroidism.26,45
observed in 100% of patients. At serum hCG Activating germline TSH-receptor mutations can be
concentrations higher than 200  000 IU/L, elevated inherited in an autosomal dominant manner (ie, familial
serum FT4 is observed in 32% of patients; at hCG non-auto­ immune hyperthyroidism), or might occur
higher than 400  000 IU/L, elevated serum FT4 is sporadically as a de novo condition (ie, persistent
observed in 80% of patients.38 High hCG concentrations sporadic congenital non-autoimmune hyper­ thy­
roid­
occur in hyperemesis gravidarum, and a hCG ism).46 Patients have no signs of thyroid auto­immunity
concentration higher than 180 000 IU/L is associated (ie, no thyroid antibodies and no hypoechogenicity on
with clinically obvious gestational transient ultrasonography), and their goitre is initially diffuse but
thyrotoxicosis (prevalence 2–3%).37,39 Gestational can become nodular over time.
transient thyrotoxicosis usually resolves spontaneously
by 16 weeks of gestation when hCG concentration Destructive thyrotoxicosis
falls.39 Long-lasting and severe gestational thyrotoxicosis The typical triphasic course of destructive thyroiditis is
due to enhanced hCG sensitivity of a mutant TSH first a thyrotoxic episode of about 1–3 months, followed
receptor has been described occasionally.40 hCG by a more long-lasting hypothyroid period of up to
produced by some trophoblast tumours, particularly 6 months, which is then followed by a spontaneous
asialo-hCG, has potent TSH activity and could cause return to euthyroidism.47 The presenta­tion of destructive
overt hyperthyroidism when produced excessively.36,41 thyrotoxicosis varies greatly. Some patients have only

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 Review

mild thyrotoxicosis or hypothyroidism, and for many thyrotoxicosis is super­imposed on latent Graves’ disease
patients the disease passes unnoticed. or nodular goitre, and is characterised by low to normal
Subacute granulomatous thyroiditis of De Quervain is radioiodine uptake, increased thyroid vascularity, and
rather common (present in 3% of all patients who have thyroid antibodies.53 Type 1 amiodarone-induced
thyrotoxicosis). Subacute granulomatous thyroiditis of thyrotoxicosis develops rather soon (ie, 3 months) after
De Quervain is often preceded by an upper respiratory starting amio­darone, whereas the more common type 2
tract infection and is probably caused by a viral infection amiodarone-induced thyrotoxicosis type (89% of all
of the thyroid gland. Subacute granulomatous thyroiditis patients with amiodarone-induced thyrotoxicosis)52
of De Quervain is characterised by pain in the neck, devel­ops later (median 30 months after starting
a tender thyroid on palpation, fever, malaise, high amiodarone). Type 2 amiodarone-induced thyrotoxicosis
erythrocyte sedimentation rate, and high C-reactive is characterised by sudden onset, suppressed radioio­
protein serum concentrations. Thyroglobulin (Tg) and dine uptake, absent hypervascularity, sponta­ neous
TPO antibodies can be positive in low titre. In contrast, remissions, and high likelihood of late hypothyroidism.
the silent painless thyroiditis and post-partum The rare presence of thyroid antibodies does not exclude
thyroiditis (occurring following 8–11% of all preg­ the possibility of type 2 amiodarone-induced thyro­
nancies) have an autoimmune aetiology; erythrocyte toxicosis.54 Amiodarone-induced thyro­ toxicosis might
sedimentation rate is within normal range and thyroid be preceded by subclinical hyperthyroidism, which can
antibodies are often persistent in high titre, associated remit spontaneously and does not always progress to
with a high rate of permanent hypothyroidism.47 overt amiodarone-induced thyro­ toxicosis.55 Therefore,
Thyrotoxicosis is usually asymptomatic. Acute suppu­ regular thyroid function testing during amiodarone
rative thyroiditis is a rare condition caused by bacterial, use has little value. Tyrosine-kinase inhibitors (TKIs)
fungal, or parasitic infections.48 Pyriform sinus fistula target multiple receptor tyrosine kinases, thereby
(located in 90% of patients on the left side) is the most inhibiting growth and spread of several cancers. TKIs
common route of infection and thyrotoxicosis seldom targeting VEGF and PDGF receptors cause transient
occurs. destructive thyrotoxicosis after approximately 6 weeks
Iodine-induced thyrotoxicosis is caused by high doses in 16% of patients, due to vascular damage. Hypothy­
of iodine from sources such as potassium iodide, roidism could occur after 5 months of treatment with
seaweed (eg, kelp tablets), and iodinated contrast media. TKIs.56 In patients who have had thyroidectomies, TKIs
Currently, iodinated contrast media are the most increase serum TSH, which necessitates an increase of
frequent cause of iodine-induced thyrotoxicosis. the daily levothyroxine dose due to increased type 3
Administration of 60–150 mL of contrast containing deiodinase activity.56,57 Immune checkpoint inhibitors
300 mg of iodine per mL delivers 18–45 g of iodine.49 counteract CTLA-4, PD-1, or PDL-1 (ie, the ligand of
The prevalence of overt hyperthyroidism after iodinated PD-1), which all play key roles in the maintenance of
contrast media is 0·1%, and develops 3–10 weeks immunological tolerance to self-antigens. Therefore,
after exposure.50 Risk factors for iodine-induced whereas immune checkpoint inhibitors can unleash
thyrotoxicosis are iodine deficiency and previous thyroid cytotoxic T cells to fight cancer, they can also trig­
autonomy (eg, latent Graves’ disease or nodular goitre). ger autoimmune manifestations.58 Immune check­point
Radioiodine uptake is usually low or suppressed in inhibitors induce destructive thyrotoxicosis, which
patients with iodine-induced thyrotoxicosis, but is occurs 4–6 weeks after initiation independent of
sometimes preserved in patients with underlying immune checkpoint inhibitor dosage, cancer subtype,
diffuse or nodular goitre (ie, Jod-Basedow phe­ or age. The reported incidence of thyrotoxicosis is
nomenon).51,52 Amiodarone-induced thyrotoxicosis devel­ 0·2–5·2% after anti-CTLA-4, 0·6–3·7% after anti-PD-1
ops in about 8% of patients taking this potent or anti-PDL-1, and 8·0–11·1% after a combination
anti-arrhyhmic drug, which generates huge iodine of both.57–60 Hypothyroidism induced by immune
excess. FT4 might be slightly increased by amiodarone check­point inhibitors could occur later, after 1–2 months,
itself, and therefore the biochemical diagnosis of and has a higher incidence than hyper­thyroidism. As in
amiodarone-induced thyro­toxicosis usually also requires all other conditions that predominantly result in
mea­ surement of FT3,which could be low due to destructive thyrotoxicosis, Tg antibodies, TPO anti­
inhibition of type 1 deiodinase activity in the liver and bodies, and even TSH-receptor antibodies might
non-thyroidal illness.53 If the biochemical picture is develop. However, actual cases of Graves’ hyper­
compatible with T4 toxicosis, a wait-and-see strategy thyroidism with increased radioiodine uptake and
might be considered depending on the clinical condition increased thyroid vascularity are rarely observed.61 The
of the patient. Amiodarone-induced thyro­ toxicosis is emergence of immune-related adverse events of
classified into two subtypes. Type 1 amiodarone-induced immune checkpoint inhibitors are associated with
thyrotoxicosis is relatively rare, making up 11% of all longer progression-free survival and overall survival
cases, which is much lower than the 60% prevalence of compared with patients with cancer who do not develop
this subtype 25 years ago.52 Type 1 amiodarone-induced these immune-related adverse events.62,63 Thyroid

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 Review

function tests (ie, TSH, FT4) are recommended before pancreatitis due to this treatment (six in total),
treatment and every 3–6 weeks in the early methimazole remains the preferred antithyroid drug
phase of treatment. The frequency of these tests can outside the settings of thyroid storm and early
be decreased at later stages depending on thyroid pregnancy. Patients should be informed to stop
hormones concentrations and their trend. 60 antithyroid drugs pending a complete blood count in
the case of sore throat with fever. The efficacy of
Thyrotoxicosis due to extrathyroidal source of thyroid granulocyte colony-stimulating factor in the treatment
hormone of agranulocytosis has not been proven.71 Monitoring
Thyrotoxicosis factitia refers to surreptitious ingestion liver function and white-cell count before starting
of excess thyroid hormone.64 The hallmark is low to treatment with antithyroid drugs or during treatment is
suppressed serum thyroglobulin. Outbreaks of so- generally not recommended.10,11
called Hamburger thyrotoxicosis have been observed by ¹³¹I causes thyroid cell damage and death. ¹³¹I dose is
the consumption of ground beef prepared from neck either fixed (eg, 10 mCi or 370 MBq) or calculated on
trimmings containing thyroid tissue.65 Struma ovarii is the basis of goitre size and radioiodine uptake. ¹³¹I
a teratoma containing ectopic thyroid tissue, which can should not be used in active Graves’ orbitopathy, during
become autonomous and cause hyperthyroidism.66 pregnancy, and during breastfeeding. Hypothyroidism
Characteristics are low thyroidal radioiodine uptake but develops eventually in most patients.10 A meta-analysis
intensely focal radioiodine uptake in a pelvic mass. of cancer risk after ¹³¹I therapy for hyperthyroidism
Thyrotoxicosis due to functioning metastases of describes the overall pooled cancer risk after exposure
differentiated thyroid cancer is rare.67 to ¹³¹I therapy versus non-exposure as not statistically
significant, although a linear dose-response association
Management between ¹³¹I therapy and solid cancer mortality is
Treatment modalities observed.72 These findings suggest that radiation-
Non-selective β-adrenergic antagonists alleviate induced cancer risks following ¹³¹I therapy for
thyrotoxic symptoms and signs. The clinical response hyperthyroidism are small, and might only be detectable
to β-blockers is independent of their effect on serum T3. at higher concentrations of the administered dose. To
Propranolol (10–40 mg, 3–4 times per day) can be used, advise patients, one could say the risk of cancer from
or long-acting β-blockers or cardioselective β-blockers ¹³¹I therapy is seemingly small enough to be
such as atenolol and metoprolol might be preferred. 10 indistinguishable from the risk of cancer that patients
Antithyroid drugs reduce thyroid hormone synthesis treated with antithyroid drugs or surgery have.73
by inhibition of thyroid peroxidase. The preferred Thyroidectomy ensures rapid restoration of
antithyroid drug is methimazole. Carbimazole is euthyroidism at the expense of a low rate (1–2%) of
a prodrug of methimazole and propylthiouracil is more adverse events (eg, postoperative bleeding, wound
toxic than methimazole.10,11 The starting dose of infection, hypoparathyroidism, and recurrent laryngeal
methimazole depends on the severity of nerve damage with voice problems). Complication rate
hyperthyroidism: 5–10 mg per day is recommended for is lower in in patients operated by surgeons who are
FT4 concentrations 1∙0–1∙5 times the upper limit of skill and experienced.10,11
normal, 10–20 mg per day for FT4 concentrations
1∙5–2∙0 times the upper limit of normal, and 30–40 mg Disease-specific management
per day for FT4 concentrations 2∙0–3∙0 times the upper Management of Graves’ hyperthyroidism
limit of normal. After about 4 weeks, the methimazole Antithyroid drugs, ¹³¹I, and thyroidectomy are the
dose is titrated according to FT4 and FT3 concentrations. three treatment options for Graves’ hyperthyroidism.
The usual methimazole dose to maintain euthyroidism Antithyroid drugs (specifically methimazole) are
is 2·5–10∙0 mg per day. Alternatively, the high initial currently the treatment of choice.10,11,74 However, ¹³¹I or
dose (ie, 20–40 mg methimazole per day) can be surgery, might be preferred in particular conditions like
maintained and levothyroxine can be added (the so- liver disease, congestive heart failure, large thyroid
called block-and-replace regimen). The superiority of nodule, suspicion of thyroid cancer, old age with
the block-and-replace approach over the titration comorbidities, or periodic paralysis.10,11 For both patients
approach has not been shown.68 Most side-effects of and clinicians, remission rate is an important deter­
antithyroid drugs occur in the first 3 months. Skin rash minant of treatment choice but antithyroid drugs
and arthralgia are common (1∙0–5∙0%); abnormalities remain the most preferred treatment option.75 Although
in taste or smell and agranulocytosis are rare clinicians prefer ¹³¹I over surgery, patients express
(0·2–1·0%); and hepatotoxicity, cholestatic jaundice, a negative attitude towards ¹³¹I. American but not
and lupus-like vasculitis are very rare (<0·1%).11 In 2019, European guidelines state that, if ¹³¹I is chosen, the
acute pancreatitis was recognised as another side-effect goal of treatment is to render the patient hypothyroid.10,11
of methimazole (but not of propylthiouracil).69,70 In view Relapse rates after antithyroid drugs are 52–53%,
of the very few reported patients who developed 8–15% after ¹³¹I, and 0–10% after thyroidectomy.76,77

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 Review

Total thyroidectomy is preferred over subtotal

thyroidectomy due to its association with a lower rate of Calculate GREAT score (maximum 6 points)

recurrent hyperthyroidism.78 A long-term follow-up

study published in 2009 of patients randomly assigned
to receive antithyroid drugs, ¹³¹I, or surgery found no 0–1 point(s) GREAT class 1 2–3 points GREAT class 2 4–6 points GREAT class 3
differences in quality of life.79 In contrast, a 2019 study
found that patients treated with ¹³¹I had a worse quality
of life than those treated with antithyroid drugs or Recommend antithyroid drugs Recommend either antithyroid Recommend ablation (131I or
drugs or ablation surgery)
surgery.80 The major difference between the studies is
the larger sample size and the use of the validated
Points
ThyPRO questionnaire in the 2019 study.80,81 Weight 100 GREAT Class 1, 16%
gain during treatment is a frequent outcome that is Age (years) GREAT Class 2, 44%
unwanted by many patients.82 Over a mean follow-up of ≥40 0 GREAT Class 3, 68%
<40 1 80
2 years, patients treated with antithyroid drugs gained
FT4 (pM)
5·2 kg, patients treated with ¹³¹I gained 4·8 kg, and

Recurrence rate (%)

<40 0 60
patients who had thyroidectomies gained 10·3 kg.83
≥40 1
Thyroidectomy is asso­ ciated with a lower all-cause TBII (U/L)
mortality than antithyroid drugs or ¹³¹I.84 Thyroidectomy <6·0 0
40
or antithyroid drugs are associated with a decline in 6·0–19·9 1
TSH-receptor antibodies, but a sustained increase in ≥20·0 2 20
these antibodies is observed after ¹³¹I, putting the Goitre (WHO grade)
patient at risk of developing—or worsening of—Graves’ 0 or 1 0
0
orbitopathy and (in pregnancy) of fetal 2 or 3 2 0 6 12 18 24
hyperthyroidism.16 Guidelines therefore recommend Maximum 6 Time of follow up after withdrawal of antithyroid drugs (months)
that management choices should be considered by Figure 3: The GREAT score for predicting recurrence of Graves’ hyperthyroidism after antithyroid drug
patients and physicians together in a shared decision- therapy
making process.10,11 Figure adapted with permission from Vos XG and colleagues.85 FT4=free thyroxine. GREAT=Graves’ Recurrent
The common duration of antithyroid drug therapy is Events After Therapy. TBII=TSH-binding inhibitory immunoglobulins.
12–18 months; thereafter the drug is tapered to see if
the patient with Graves’ disease has gone into drugs before 1 year of treatment even if TSH-receptor
remission. Recurrent hyperthyroidism develops in antibodies have already become negative.
about 50% of patients, but is difficult to predict. Patients When recurrent hyperthyroidism develops, guidelines
who are younger than 40 years have FT4 concentrations traditionally recommend ¹³¹I or surgery because the
higher than or equal to 40 pmol/L, have TBII chance of remission after an extended course of
concentrations higher than or equal to 6 U/L, and have antithyroid drugs does not increase.10,11 However, this
a goitre size corresponding to WHO grade 2 or grade 3 finding might not be entirely true, and interest in long-
(measured before the start of treatment with antithyroid term treatment with antithyroid drugs has grown over
drugs) are good predictors for recurrences, as the past decade because they could have unexpected
summarised in the Graves Recurrent Events After long-term efficacy.90 Compared with a 53% rate
Therapy (GREAT) score (figure 3).85 When TSH- of recurrence after short-term treatment with
receptor antibody assays other than TBII are applied, antithyroid drugs (1–2 years), long-term treatment with
TSH-receptor antibody concentrations higher than antithyroid drugs (5–10 years) has a much lower
three times the upper limit of normal could be given recurrence rate of 15%.91 The maintenance dose for
the same score as TBII concentrations higher than or long-term treatment with antithyroid drugs is
equal to 6 U/L. The predictive value of the GREAT score 2·5–7·5 mg of methimazole per day, almost without
can be enhanced by adding HLA and PTPN22 major side-effects. Major side-effects occurred in 15 out
genotypes. The GREAT score has been externally of 1660 patients exposed to methimazole (mean
validated in several studies.86–88 During treatment with duration 5·8 years) for about 10 000 patient years.
antithyroid drugs, TBII concentrations could become 14 patients developed major side-effects within the first
lower or even undetectable, which increases the chance year of treatment and only one patient developed side-
of remission. Guidelines recommend to measure TBII effects after the first year.92–94 Long-term antithyroid
before stopping treatment with antithyroid drugs, and drug treatment seems a viable alternative to ablative
consider continuing antithyroid drugs if TBII therapies.90,95
concentrations remain high.10,11 According to a Cochrane
systematic review, maximum remission rates of Management of thyrotoxicosis with hyperthyroidism
50–55% are achieved at 12–18 months of treatment.89 Specific guidelines are available for the treatment of
Consequently it is not advised to discontinue antithyroid hyperthyroidism due to Graves’ disease (antithyroid

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 Review

drugs), immune reconstitution (antithyroid drugs), TSH- Specific conditions

secreting pituitary adenoma (neurosurgical resection or Pregnancy
somatostatin analogues) and familial or sporadic non- For women with hyperthyroidism who want to get
autoimmune hyperthyroidism (total thyroidectomy pregnant, it is recommended to postpone pregnancy until
followed by ¹³¹I; table 2).11,42,96,97 Gestational transient euthyroidism is reached and maintained for more than
thyrotoxicosis usually requires no treatment with 2 months after total thyroidectomy or treatment with
antithyroid drugs but in more severe cases propranolol antithyroid drugs and for at least 6 months after ¹³¹I.104 The
can be considered.39 Toxic multinodular goitre is treated incidence of neonatal hyperthyroidism among newborns
with near-total or total thyroidectomy or ¹³¹I, because of mothers with Graves’ disease who conceived within
recurrent hyperthyroidism after a course of antithyroid 2 years after ¹³¹I therapy has been reported to be 5·5%.105
drugs is the rule rather than the exception.10,98 ¹³¹I therapy No congenital malformations were observed if conception
is often preferred, but ¹³¹I-induced Graves’ hyper­ was postponed at least 6 months after ¹³¹I therapy
thyroidism develops in 5% of patients after 3–6 months (>925 MBq) for thyroid cancer.106
especially if TPO antibodies were positive before In pregnant women, the prevalence of pre-existing
treatment.10,99 10 years after a fixed dose of 15 mCi Graves’ hyperthyroidism is 0·5–1·3%, the prevalence of
(555 MBq), hyperthyroidism is cured in 94% of patients, new onset Graves’ hyperthyroidism is 0·05%, and the
with 60% developing euthyroidism and 34% developing prevalence of autonomous thyroid hormone secretion
hypothyroidism.100 Frequently, more than one dose of ¹³¹I is 0·1%.107 Serum TSH-receptor antibodies should be
is required, resulting in a higher rate of post-radioiodine measured at first presentation in pregnancy whenever
hypothyroidism. Solitary toxic adenoma is treated with a history of Graves’ disease is present, and again—if
lobectomy or ¹³¹I.10 The rate of hypothyroidism after elevated—at 18–22 weeks gestation.11,104
treatment with ¹³¹I is rather low because radioiodine Overt hyperthyroidism during pregnancy is associated
uptake in extranodular thyroid tissue is suppressed with hypertensive disorders, preterm delivery, small for
(figure 2B). Radiofrequency ablation is a safe and gestational age neonates, and intrauterine fetal death
effective alternative. Radiofrequency ablation normalises according to the current largest population-based
thyroid function in about 50% of medium-sized nodules study.11,104,108 However, statistically significant evidence
(>12 mL) and in more than 80% of small-sized nodules on the beneficial effect of medical treatment has only
(<12 mL).10,101,102 been shown for outcomes such as abruptio placentae,
fetal growth retardation, gestational diabetes,
Management of thyrotoxicosis without hyperthyroidism postpartum hemorrhage, and stillbirth.109
Destructive thyrotoxicosis is transient in nature, and Women should be informed about the slightly
usually requires only supportive care (table 2).10 Neck pain increased risk of birth defects associated with antithyroid
in subacute granulomatous thyroiditis can be quite drugs. Literature on congenital malformations is
substantial, necessitating non-steroidal, anti-inflam­matory complex. Facial dysmorphia, aplasia cutis, and choanal
drugs; if the pain persists after 2–3 days, prednisone or oesophageal atresia have been described after
(40 mg per day) offers fast pain relief.10,47 In mild iodine- exposure to carbimazole or methimazole. Face and neck
induced thyrotoxicosis, close monitoring will suffice. In cysts and urinary tract abnormalities (males only) have
more severe cases of thyrotoxicosis, antithyroid drugs, been described after exposure to propylthiouracil.110
eventually combined with perchlorate (not available in A meta-analysis published in 2022 found an anomaly
the USA), might be helpful.49 A similar management is rate of 61·5 per 1000 live births in the unexposed
recom­ mended in type 1 amiodarone-induced disease-free population. The excess number of anoma­
thyrotoxicosis: 40–60 mg of methimazole per day with or lies was 17·2 for exposure to carbimazole or methi­
without 500 mg perchlorate twice per day, and mazole, 9·8 for exposure to propylthiouracil, and 31·4
discontinuation of amiodarone.53 In contrast, prednisone for exposure to both car­bimazole or methimazole and
suffices for most patients with type 2 amiodarone-induced propy­lthiouracil.110 The high figure of 31·4 is a new
thyrotoxicosis, and amiodarone could even be continued. finding, and does not sup­ port current guidelines
However, patients with mixed types of amiodarone- recommending a switch from carbimazole or methi­
induced thyrotoxicosis or very severe amiodarone-induced mazole to propylthiouracil in the first trimester.11,104,110
thyrotoxicosis would probably benefit most from treatment The teratogenic risk appears to correlate with car­
with thyroidectomy.53,103 Thyrotoxicosis due to cytokines, bimazole or methimazole dose in the first trimester;
lithium, TKIs or immune checkpoint inhibitors are mostly hyperthyroidism by itself is not associated with these
mild and can be monitored and treated with β-blockers if anomalies.110,111
patients are symptomatic.10,60 The best treatment options To avoid or minimise exposure to antithyroid drugs,
for thyrotoxicosis of extrathyroidal origin are self- several strategies can be adopted.112 The first strategy
explanatory: reduce dose of thyroid hormone pills, stop is to replace carbimazole or methimazole with propy­
eating contaminated beef, ovarian surgery for struma lthiouracil before pregnancy, the second strategy is to
ovarii, and ¹³¹I therapy for functional metastases. stop treatment with antithyroid drugs as soon as

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 Review

pregnancy is confirmed. The second strategy should be hospitalised patients with COVID-19, correlated with
followed by monitoring of thyroid function every elevation of IL-6 and C-reactive protein.117,119,120 If the
2 weeks during the first trimester, and every 4 weeks biochemical picture is compatible with T4 toxicosis,
during the second and third trimesters. Conditions for a wait-and-see strategy might be considered depending
stopping treatment with antithyroid drugs include on the clinical condition of the patient. New onset,
a stable, low dose of methimazole (5–10 mg) or relapse, or exacerbation of well controlled Graves’
propylthiouracil (100–200 mg); a long treatment period hyperthyroidism has been described in relation with
(>6 months); normal concentrations of TSH, absent COVID-19.116 COVID-19 might also be a precipitating
TSH-receptor antibodies, and no goitre.113 Discon­ factor for thyroid storm.121 To maintain control of Graves’
tinuation of treatment with antithyroid drugs is often hyperthyroidism during the COVID-19 pandemic, the
feasible at the end of the second trimester or in the block-and-replace regimen of antithyroid drugs might
third trimester due to the disappearance of maternal be chosen in view of scarce availability of biochemical
TSH-receptor antibodies.111 A third strategy could be testing during lockdowns, and one should also be
switching from methimazole to potassium iodide specifically attentive to the development of antithyroid
(10–30 mg) in the first trimester. However, almost half drug-induced neutropaenia.122
of women do not show antithyroid effects with iodide Vaccination against SARS-CoV-2 is rarely followed
excess, and more studies are needed in areas outside by subacute thyroiditis (mean time to symptoms is
Japan with a lower iodine intake.114 9 days) or Graves’ hyperthyroidism (mean time to
If treatment is necessary during the first trimester, symptoms is 15 days ).123,124 The underlying pathogenetic
propylthiouracil should be initiated (or carbimazole or mechanisms could be molecular mimicry or the
methimazole if propylthiouracil is not available). The autoimmune or inflammatory syndrome induced by
aim is to keep FT4 in the range of the upper limit of adjuvants. Patients with Graves’ hyperthyroidism that
normal with the lowest possible dose of antithyroid occurred within 4 weeks after COVID-19 vaccination,
drug. The block-and-replace regimen is contraindicated are older (51 years old), more likely to be male (40%),
in pregnancy in view of the risk on fetal hypothyroidism. and need lower doses of methimazole than patients
Propylthiouracil could be replaced by carbimazole or with Graves’ hyper­ thyroidism who did not receive
methimazole after the first trimester to reduce the risk a COVID-19 vaccination 4 weeks before the occurrence
of propylthiouracil-associated fulminant hepatic failure. of Graves’ hyperthyroidism (35 years old; male sex
However, firm evidence to support this recommendation 14%).125 There is no evidence that patients with
is scarce, and one might prefer to continue with a low hyperthyroidism are at greater risk of developing
dose of propylthiouracil. If thyroidectomy is indicated, COVID-19 or have worse prognosis due to COVID-19
it should be performed in the second trimester of than the general population.122
pregnancy.11,104 As symptomatic treatment, 10–40 mg
propranolol 3–4 times per day could be used, but long- Atrial fibrillation
term treatment and treatment after the fifth month TSH measurement is recommended in all patients
of pregnancy should be avoided in view of the risk of with atrial fibrillation, but only 3% of patients with new-
fetal bradycardia, intrauterine growth restriction, and onset atrial fibrillation develop hyper­ thyroidism.126–128
neonatal hypoglycaemia.115 In the post-partum phase, Atrial fibrillation will develop in 8% of patients within
small amounts of antithyroid drug enter breastmilk, 30 days after the diagnosis of hyperthyroidism. The risk
but daily doses of up to 250 mg of propylthiouracil or of of atrial fibrillation in patients with hyperthyroidism
20 mg of methimazole are considered safe. Antithyroid increases for people older than 60 years, and for those
drugs should be taken after having breastfed the with ischaemic heart disease, congestive heart failure,
child.11,104 or cardiac valvular disease.129
Hyperthyroidism is a correctable cause of atrial
COVID-19 fibrillation. At least 75% of patients with thyrotoxic atrial
SARS-CoV-2 binds to ACE2, which functions as fibrillation and no underlying cardiac or valvular disease
a receptor for the virus to enter the cell.116 ACE2 is will reverse spontaneously to sinus rhythm within
highly expressed in the thyroid gland, and patients with 3–6 months of antithyroid drug therapy.130,131 In addition
COVID-19 consequently might manifest changes in to antithyroid drugs, non-selective β-blockers such as
thyroid function such as thyrotoxicosis, hypothyroidism, propranolol can be used for rate control of atrial
and non-thyroidal illness syndrome.117,118 fibrillation.131 Current data do not reveal a higher risk
COVID-19-related thyrotoxicosis can occur after of stroke in patients with hyperthyroidism-related atrial
infection, in relation with the thyrotoxic phase of fibrillation than in patients with non-hyperthyroidism-
subacute thyroiditis.117 An atypical inflammatory form related atrial fibrillation.131,132 Nevertheless, data con­cerning
of thyroiditis without neck pain, characterised by low the use of anticoagulants to prevent thromboembolism in
serum TSH, normal or low FT3, and normal or elevated patients with hyperthyroidism-related atrial fibrillation is
FT4 (ie, T4 thyrotoxicosis) has been described in controversial and based on little evidence. To date, stroke

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 Review

prevention in hyperthyroidism-related atrial fibrillation with reduced K+ output.137 Loss-of-function mutations

should follow the same principles as in other patients with of the skeletal muscle-specific, inward-rectifying
atrial fibrillation. The CHA2DS2-VASc score can help to K+ (Kir2.6) channel have been associated with thyrotoxic
establish the risk of a thromboembolic event in a patient periodic paralysis. These mutations could explain
with non-valvular atrial fibrillation who has not used an how reduced outward K+ efflux in skeletal muscle,
anticoagulant. The score gives one point each to the from either channel mutations or inhibition by
presence of congestive heart failure, hypertension, age hormones (eg, adrenaline or insulin), can lead to
between 65 and 74 years, diabetes, and vascular disease, hypokalaemia and paradoxical depolarisation, which in
and two points each to being older than 75 years and turn inactivates Na+ channels and causes muscle
previous stroke. If the CHA2DS2-VASc score is 1 or higher, inexcitability and paralysis.137 Thyrotoxic periodic paraly­
early anticoagulation is recommended for patients with sis thus arises from the combination of thyrotoxicosis,
hyperthyroidism-related atrial fibrillation.126,131,132 Warfarin environmental factors, and genetic susceptibility.136 The
dosage should be adjusted cautiously because hyper­ degree of hypokalaemia varies, and normokalaemia
thyroidism enhances sensitivity to anticoagulant effects, does not exclude thyrotoxic periodic paralysis. In the
which can result in supratherapeutic international acute phase, thyrotoxic periodic paralysis must be
normalised ratio values and bleeding. Few data indicate treated with K+ to prevent the development of life-
that novel direct oral anticoagulants are not superior to threatening arrhythmias and respiratory complications
warfarin in terms of stroke or thromboembolism and to shorten the episode of paralysis. Nonselective
prevention, but might have a lower risk of major bleeding β-blockers can ameliorate and prevent recurrences of
than warfarin.133,134 paralytic attacks.135 Euthyroidism should be promptly
Hyperthyroidism-related atrial fibrilliation usually restored and stably maintained. It has been proposed
has a lower recurrence rate than non-thyrotoxic atrial that all patients with thyrotoxic periodic paralysis
fibrillation. Determinants of persistent arrhythmia are should receive ablative treatment of the thyroid gland.
older age (older than 55 years), longer pre-treatment Prophylactic potassium sup­ plementation is not
duration of atrial fibrillation, and uncontrolled hyper­ indicated when patients have euthyroidism.
thyroidism.130,131 Pharmacological or electrical cardio­
version is recommended in patients with persistent Thyroid storm
atrial fibrillation for at least 4 months after TSH Thyroid storm is a rare, acute, and life-threatening
normalisation.130,131 Anti-arrhythmic drugs should be form of thyrotoxicosis. Thyroid storm is associated with
used after successful cardioversion to reduce the risk of a mortality rate that is 12 times higher than the mortality
recurrent atrial fibrillation.130,131 Ablation of the thyroid rate of thyrotoxicosis without storm among patients
gland should be considered in case of recurrent admitted to hospital.138 Although the mortality rate
atrial fibrillation when the patient had developed associated with thyroid storm has been reduced over
euthyroidism.131 Consultation with a cardiologist might the past four decades, it remains high (up to 3·6% in
be required. the USA, 10% in Japan, and 17% in France).138–140
National surveys revealed the incidence of thyroid
Thyrotoxic periodic paralysis storm is 0·2 per 100 000 patients admitted to hospital
Thyrotoxic periodic paralysis is an uncommon, per year in Japan and 4·8–5·6 per 100 000 patients
dangerous, but reversible complication of hyper­ admitted to hospital per year in the USA.138,140 Thyroid
thyroidism, with a much higher frequency in men than storm develops in patients with hyperthyroidism who
in women (ratio 30:1) and a higher frequency in people have not received treatment or those who are non-
of Asian origin than in people not of Asian origin compliant to treatment. Thyroid storm is usually
(2∙0% vs 0·1%).135 Patients with thyrotoxic periodic precipitated by an acute event (eg, surgery, trauma,
paralysis present with acute attacks varying from mild infection, or iodine excess).
weakness to total paralysis, starting at night or in the A diagnosis of thyroid storm is made on the basis of
early morning, a few hours after a heavy or carbohydrate- clinical presentation that is compatible with
rich meal, alcohol abuse, or strenuous exercise with hyperthyroid symptoms and signs, because thyroid-
complete recovery within 72 h.136 The lower limbs are function tests in thyroid storm are similar to those in
affected first followed by the girdle muscles and then uncomplicated hyperthyroidism.140 Patients with thyroid
the upper limbs.135 The respiratory muscles are rarely storm present with an exaggeration of the usual
involved. Most patients have not been diagnosed with features of hyperthyroidism. The Burch-Wartofsky
hyper­thyroidism before the thyrotoxic periodic paralysis score has been developed to establish the likelihood of
attack, although these attacks develop only when the thyroid storm (table 3).141,142 A scoring system that is
patient is thyrotoxic.136 The hallmark is hypokalaemia slightly different from the Burch-Wartofsky score is
caused by thyroid hormone-induced Na+K+-ATPase used in Japan.140 It must be noted that a diagnosis of
pump activity with increased transport of K+ from the thyroid storm should be made on the basis of clinical
extracellular to the intracellular space, together judgement and the scores should be ancillary.

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 Review

Treatment for thyroid storm should be aggressive and

Points
includes specific treatment (targeting the thyroid
hormone excess) and supportive treatment (directed Temperature °F (°C)

against the precipitating event and systemic decom­ 99–99·9 (37·2–37·7) 5

pensation). Specific treatment includes thionamides 100–100·9 (37·8–38·2) 10
(500–1000 mg load of propylthiouracil, followed by 101–101·9 (38·3–38·8) 15
250 mg every 4 h; or 60–80 mg of methimazole per day), 102–102·9 (38·9–39·4) 20
β-blockers (propranolol, 60–80 mg every 4 h), iodine 103–103·9 (39·4–39·9) 25
(5 drops, equalling to 0∙25 mL or 250 mg, of saturated ≥104·0 (>40·0) 30
solution of potassium iodide orally every 6 h), and Central nervous system effects
glucocorticoids (300 mg load of hydrocortisone Absent 0
intra­
venously, followed by 100 mg every 8 h).10 Mild (agitation) 10
Propylthiouracil is preferred over methimazole due to Moderate (delirium, psychosis, extreme lethargy) 20
its additional inhibitory effect on T4 to T3 conversion. Severe (seizure, coma) 30
However, antithyroid drugs should be administrated 1 h Gastrointestinal–hepatic dysfunction
before potassium iodide.10 Supportive therapy includes Absent 0
cooling blankets, volume resuscitation, antibiotics, Moderate (diarrhoea, nausea or vomiting, abdominal pain) 10
nutritional support, respiratory care, and monitoring in Severe (unexplained jaundice) 20
intensive care units.10,11 In case of poor response, Cardiovascular dysfunction
plasmapheresis or plasma exchange and emergency Tachycardia
thyroidectomy could be considered.10 90–109 BPM 5
110–119 BPM 10
Prognosis 120–129 BPM 15
Long-term prognosis of hyperthyroidism has become 130–139 BPM 20
more understood in the past decade. In a large hospital- ≥140 BPM 25
based study with a mean follow-up of 11 years, Graves’ Atrial fibrillation 10
disease (hazard ratio [HR] 1·42, 95% CI 1·25–1·60) and Heart failure
toxic nodular goitre (1·22, 1·07–1·40) were both Absent 0
associated with increased all-cause mortality.143 Graves’ Mild (pedal oedema) 5
disease was associated with increased mortality due to
Moderate (bibasilar rales) 10
cardiovascular disease (1·49, 1·25–1·77) and lung
Severe (pulmonary oedema) 15
disease (1·91, 1·37–2·65), whereas toxic nodular goitre
Precipitating history
was associated with increased cancer mortality (1·36,
Negative 0
1·06–1·75). Another very large prospective study was
Positive 10
done in women who were certified as radiological
technologists between 1926 and 1982. Cause-specific A score ≥45 is highly suggestive of thyroid storm; scores between 25 and 44 points
mortality risks were compared according to self- support the diagnosis of thyroid storm; and scores of less than 25 points suggest
that thyroid storm is unlikely. Data are from Burch and Wartofsky.141 BPM=beats
reported thyroid status, with adjustments for regular per minute.
confounders and, in case of breast cancer, for family
history, duration of the use of hormone replacement Table 3: Scoring system for the diagnosis of thyroid storm
therapy and oral contraceptives, and organ doses from
radiation exposures.144 Women with hyperthyroidism A Danish register-based cohort study included
older than 60 years had an elevated risk of breast cancer 235 547 individuals who had at least one TSH mea­
mortality (2·04, 1·16–3·60), compared with women surement between 1995 and 2011 (7·3 years median
without thyroid disease. Other causes of cancer death follow-up).147 The authors defined hyperthyroidism
were not associated with hyperthyroidism. Breast when patients had at least two TSH values lower than
cancer and hyperthyroidism might be associated via 0·3 mU/L within 6 months, with at least 14 days
various mechanisms.145 between measurements. Mortality rates were recorded
In a study including 85 856 patients with hyper­ for treated and untreated patients with hyperthyroidism
thyroidism and 847 057 people in a matched population- compared with people in the control group with
based control group, with a mean follow-up of 9·2 years, euthyroidism. Cox regression analyses were controlled
the HR for all-cause mortality was highest in the first for age, sex, and comorbidities by using the Charlson
3 months after diagnosis of hyperthyroidism (HR 4·62, comorbidity index. An excess all-cause mortality
95% CI 4·40–4·85) and remained elevated during rate was noted in patients with untreated overt
long-term follow-up (>3 years).146 Sensitivity analysis for hyperthyroidism (HR 1·24, 95% CI 1·12 to 1·37) but not
gender and Graves’ disease as cause of hyperthyroidism in patients receiving treatment for hyper­ thyroidism
did not change the study results. (1·01, 0·92 to 1·10). The mortality was increased in

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 Review

receptor-specific immunotherapy using a soluble

Search strategy and selection criteria antigen (ie, TSH-receptor peptide ATX-GD-59) that
References for this Review were identified through searches aims to lead to tolerogenic immune responses.150,151
of PubMed for articles published from Jan 1, 2000, to Contributors
Oct 1, 2022, using the search terms “clinical presentation”, All authors have been involved in drafting the manuscript and revising
it critically for important intellectual content. All authors read and
“symptoms”, “signs”, “diagnosis”, “pathogenesis”, “nodular approved the final manuscript.
goitre”, “thyroiditis”, “treatment”, “atrial fibrillation”,
Declaration of interests
“management”, “prognosis”, “pregnancy”, “covid-19”. WMW has received consulting fees from Argenx BV. KGP has received
In addition, the terms “Graves’ disease”, “thyrotoxic periodic lecture fees from Berlin-Chemie, Merck, and IBSA, and served on
paralysis”, “thyroid storm”, “gestational transient Advisory Boards for Takeda. GE has received speaker honoraria from
thyrotoxicosis”, “radioactive iodine therapy”, and “antithyroid Novo Nordisk and has received sponsorship to attend meetings from
Amicus Therapeutics.
drugs” in combination with the terms “hyperthyroidism”, and
“thyrotoxicosis”. Articles resulting from these searches and References
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