11/14/24, 10\:40 AM Thyrotoxicosis and Hyperthyroidism

Thyrotoxicosis and Hyperthyroidism

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Key points ⚡
Succinct notes to superpower your revision
Thyrotoxicosis\: clinical manifestation of excess thyroid hormone action at the tissue level due to high circulating thyroid
hormone concentrations.
Hyperthyroidism\: subset of thyrotoxicosis with excess thyroid hormone synthesis and secretion by the thyroid gland.
Most common cause\: Graves' disease (autoimmune condition).
Thyroid anatomy\: located at C5-T1, consists of a central isthmus and two lobes, sits anterior to the trachea with four
parathyroid glands on the posterior surface.
Thyroid physiology\: thyroid hormones (T , T ) produced from follicular cells, regulated by hypothalamic-pituitary-thyroid
3 4
axis, in
Causes\:
Graves' disease\: anti-TSHR autoantibodies stimulate excess T /T production.
3 4
Toxic multinodular goitre\: physiologically active nodules secrete thyroid hormones.
Iodine excess\: increased iodine levels enhance thyroid hormone production.
Iatrogenic\: drugs like amiodarone, levothyroxine.
Viral infection\: subacute De Quervain’s thyroiditis causing transient thyrotoxicosis.
Postpartum thyroiditis\: transient thyrotoxicosis followed by hypothyroidism.
Symptoms\: recent unintended weight loss, increased appetite, diarrhoea, heat intolerance, over-activity, restlessness,
tremor, palpitations, irritability, muscle weakness, loss of libido, oligomenorrhoea.
Clinical examination\: thin/brittle hair, warm/moist skin, irregular/fast heart rate,
erythema, lid lag, goitre.
Graves' disease speci
Investigations\:
Thyroid function tests\: increased T , T , decreased TSH (primary thyrotoxicosis); increased TSH (secondary thyrotoxicosis).
3 4
Autoantibodies\: anti-TSHR (Graves'), anti-TPO, anti-Tg.
Imaging\: Doppler ultrasound to con
Management\:
Beta-blockers (e.g., propranolol) for symptomatic relief.
Block and replace therapy (carbimazole + levothyroxine).
Radioiodine therapy for Graves' disease, toxic multinodular goitre.
Thyroidectomy for malignancy, goitre causing compression, or unsuitable/unsuccessful other treatments.
Complications\:
Thyroid storm\: severe adrenergic symptoms, high mortality.
Cardiac complications\: atrial
Graves' ophthalmopathy\: potential visual acuity deterioration.
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Introduction

Thyrotoxicosis is the clinical manifestation of excess thyroid hormone action at the tissue level due to inappropriately high
circulating thyroid hormone concentrations.
Hyperthyroidism is a subset of thyrotoxicosis, referring speci
the thyroid gland.
The most common cause of thyrotoxicosis is Graves' disease, an autoimmune condition that results in excess endogenous
production of thyroid hormones.
1

Aetiology

Anatomy

The thyroid gland is located within the neck at the level of the C5-T1 vertebrae.
It consists of a central isthmus and two lobes, to the left and the right. The gland sits anterior to the trachea with the four
parathyroid glands, which sit on the posterior surface of the thyroid gland.
2

Physiology

Thyroid hormones are produced from follicular cells of the thyroid gland. Production of these hormones is regulated via
the hypothalamic-pituitary-thyroid (HPT) axis (Figure 1).
Thyrotropin-releasing hormone (TRH) is released from the paraventricular nucleus of the hypothalamus. TRH binds to
pituitary receptors and causes the production of thyroid-stimulating hormone (TSH) from pituitary cells known as
thyrotrophs.
TSH subsequently binds to receptors on the thyroid gland and causes the production of thyroid hormones from the
thyroid follicular cells. These hormones are triiodothyronine (T ) and thyroxine (T ).
3 4
The HPT axis is regulated via negative feedback, at the level of the hypothalamus and the pituitary.
Excess concentrations of thyroid hormones feedback to both the hypothalamus and the pituitary to cause a reduction in
both TRH and TSH production. This decreases the rate of thyroid hormone production via the HPT axis. This physiological
regulation of the HPT axis is lost in thyrotoxicosis.
3
T is the main hormone produced from the thyroid gland, alongside smaller amounts of T . The majority of T 4 3 4
converted to T 3
when it reaches the target tissue (this is the most active form of the hormone).
4
is then
Thyroid hormones have a wide range of functions including in
oxidative phosphorylation).
Increased thyroid hormone concentration (seen in thyrotoxicosis) increases the basal metabolic rate. Thyroid hormones
also have a key role in physiological growth, including fetal growth (thyroid hormones mediate the growth of neuronal and
dendritic cells within the fetal central nervous system) and paediatric growth (thyroid hormones stimulate the expression of
the pituitary growth hormone).
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Figure 1. The hypothalamic-pituitary-thyroid (HPT) axis

Causes of thyrotoxicosis

Graves' disease
Graves' disease is the most common cause of thyrotoxicosis and hyperthyroidism. This is an autoimmune condition
mediated via anti-TSH-Receptor (anti-TSHR) autoantibodies.
These autoantibodies bind to TSH-receptors on the thyroid gland and stimulate increased production of T and T 3 4
the thyroid gland, resulting in thyrotoxicosis.
from
Thyroxine receptors in the pituitary gland are activated by the excess hormone, resulting in the suppression of TSH release
due to negative feedback. The result is very high levels of circulating thyroid hormones and a low TSH level.
The prevalence of Graves' disease in the UK is 0.5%, typically presenting in patients between the ages of 40 and 60, and is
much more common in female patients. Graves' disease is also strongly associated with other auto-immune conditions
including type 1 diabetes mellitus, Addison’s disease and vitiligo.
4
Toxic multinodular goitre
Toxic multinodular goitre (TMG) is caused by the development of physiologically active nodules on the thyroid gland,
which are capable of secreting thyroid hormones. These nodules are not responsive to circulating TSH concentrations and
so, eventually cause thyrotoxicosis.
TMG is the second commonest cause of hyperthyroidism and most commonly a
a toxic multinodular goitre typically has a more insidious onset, in comparison to Graves' disease.
6
Iodine excess
Excess serum iodine concentrations can also cause thyrotoxicosis. This is because thyroid hormone production is
dependent upon iodine, so increased serum iodine concentrations allow increased production of the hormones.
Iodine excess can occur following the use of contrast media for imaging modalities or via the contamination of food.
1
Iatrogenic
Iatrogenic causes of thyrotoxicosis include the drugs amiodarone and levothyroxine.
Amiodarone contains iodine and increases iodine levels, increasing follicular thyroid hormone production. Levothyroxine is
used in the management of hypothyroidism where there is a de
increased serum hormone concentration.
1
Viral infection
Viral infections can predispose to a phenomenon known as ‘subacute De Quervain’s thyroiditis’
. This can cause a transient
rise in thyroid hormone production due to in
hormones into the circulation. subacute De Quervain’s thyroiditis presents with a painful lump in the neck, most commonly
between the ages of 20-50.
4
Patients may subsequently develop hypothyroidism if the thyroid gland tissue is damaged by the in
Postpartum thyroiditis
Postpartum thyroiditis presents with a transient acute phase of thyrotoxicosis, followed by a period of hypothyroidism.
This can occur 2 - 6 months following birth or miscarriage.
7

Clinical features

Thyrotoxicosis presents with a wide range of clinical features due to the overall increased basal metabolic rate.

History

Typical symptoms of thyrotoxicosis include\:
Recent unintended weight loss
Increased appetite
Diarrhoea
Heat intolerance (patients may appear underdressed for the weather)
Over-activity and restlessness
Tremor
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Palpitations
Irritability
Muscle weakness
Loss of libido
Oligomenorrhoea
Other important areas to cover in the history include\:
Past medical history\: autoimmune conditions (Graves' disease) or recent viral infection (De Quervain’s thyroiditis)
Family history\: family history of Graves' disease
Medication history\: use of amiodarone, levothyroxine, or recent use of contrast media
Obstetric history\: recent pregnancy or miscarriage

Clinical examination

A thyroid status examination should be performed in all patients presenting with symptoms suggestive of thyrotoxicosis.
Clinical features of thyrotoxicosis may include\:
1
Thin and brittle hair
Warm and moist skin
Irregular or fast heart rate
Fine tremor
Brisk re
Palmar erythema
Lid lag and lid retraction
Goitre (enlargement of the neck due to an enlarged thyroid gland)

Graves' disease

TSHR autoantibodies.
There are some clinical features of thyrotoxicosis which are speci
Clinical features of Graves' disease may include\:
4,8
Thyroid eye disease (Graves' ophthalmopathy)\: conjunctival injection, aching at the back of the eye, diplopia, gradual
proptosis (exophthalmos), lid retraction, lid lag, chemosis (oedema of the eye)
Thyroid acropachy\: clubbing or swelling of the digits
Pretibial myxoedema\: oedema of the pretibial portion of the leg (just above the lateral malleolus)
Figure 2. Thyroid eye disease
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Figure 3. Thyroid acropachy
Figure 4. Pretibial myxoedema

Investigations

Thyroid function tests

The key laboratory investigation for the diagnosis of any thyroid condition is thyroid function tests (TFTs) which
include serum levels of TSH, T and T .
3 4
In most cases of thyrotoxicosis, the pattern of TFTs will re
thyroid gland and a decreased production of pituitary TSH.
This is because the HPT axis will attempt to correct the excess thyroid hormone production via negative feedback\:
Increased T and T
3 4
Decreased TSH
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If thyrotoxicosis is due to a rarer pituitary cause, then there will be an increased production of pituitary TSH, causing the
increased production of thyroid hormones. The pattern of TFT results will be as follows\:
9
Increased T and T
3 4
Increased TSH
See the Geeky Medics guide for a more detailed overview of thyroid function test interpretation.

Autoantibodies

The presence of thyroid autoantibodies suggests there is an underlying autoimmune disease causing thyrotoxicosis. The
presence of anti-TSHR antibodies is highly suggestive of Graves' disease.
10
Other autoantibodies suggestive of autoimmune thyroid disease include anti-thyroid-peroxidase (anti-TPO) antibodies and
anti-thyroglobulin (anti-Tg) antibodies. These are non-speci
hyperthyroidism (Graves' disease) and hypothyroidism (Hashimotos' disease).
4

Imaging

Doppler ultrasound may be used to image the thyroid gland, to con
11

Management

Beta-blockers

Beta-blockers (commonly propranolol) are indicated in the management of thyrotoxicosis to provide symptomatic relief
from the typical adrenergic symptoms (palpitations, tachycardia, tremor).
4,12

Block and replace

The block and replace management regime is commonly used for the management of hyperthyroidism in adults and is
the
Block and replace involves blocking the excess thyroid hormone production from the thyroid gland and replacing this
with the correct concentration of exogenous thyroid hormones.
Carbimazole is used to block thyroid hormone production and levothyroxine is used to replace thyroid hormones (these
medications are administered simultaneously). Patients require ongoing monitoring of their TFTs and their FBC (due to the
risk of agranulocytosis associated with carbimazole).
In most patients with Graves' disease, a block and replace management regime can induce remission.
12

Radioiodine

Radioiodine is a de
If radioiodine is deemed unsuitable for patients with Graves' disease (e.g. due to pregnancy or malignancy), block and
replace therapy is typically used as a second-line management option.
If radioiodine is deemed unsuitable for patients with a toxic multinodular goitre, thyroid surgery is used as a second-line
management option.
Radioiodine can also be used second-line in patients with hyperthyroidism in whom block and replace has been
unsuccessful.
2
With radioactive iodine, measures must be taken following treatment to prevent any harm coming to those in close
contact with the patient. Patients must be advised against prolonged contact with children (including their own) and
pregnant women.
Female patients must also be advised against becoming pregnant within the next six months following treatment and male
patients must be advised against fathering children for the next four months following treatment.
12

Surgery

Thyroidectomy (complete removal of the thyroid gland) may be considered for the management of hyperthyroidism.
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Thyroidectomy is indicated in cases of thyroid malignancy, or where a thyroid goitre is causing compression of
surrounding structures. Thyroidectomy may also be considered if other treatment options are unsuitable or unsuccessful.
12
Removal of the thyroid gland will result in a lack of circulating thyroid hormones in these patients. Therefore, they will need
to be started on long term thyroid hormone replacement, most commonly levothyroxine.
4

Complications

Thyroid storm

A serious complication of thyrotoxicosis is the onset of a thyroid storm, which involves excessive adrenergic activity
secondary to thyrotoxicosis.
Clinical features of a thyroid storm may include\:
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Palpitations
Tachycardia (often greater than 140 beats per minute)
Tremor
Nausea and vomiting
Abdominal pain
Reduced level of consciousness
Confusion/agitation
Seizures
Thyroid storm is associated with high mortality.

Cardiac complications

Cardiac complications of thyrotoxicosis include\:
4
Atrial
previously described as well as rate control (e.g. beta-blocker) and anticoagulation (e.g. Warfarin or Apixaban).
Heart failure\: this is more prevalent in elderly patients with hyperthyroidism, secondary to cardiomyopathy occurring in
long-term thyrotoxicosis.
Angina\: should be considered in hyperthyroid patients presenting with exertional chest pain.

Graves' ophthalmopathy

It is important to inform patients of the complications of Graves' ophthalmopathy. In some instances, this can also cause
deterioration of visual acuity if the optic nerve is a
14

References

Text references

Parveen K, Michael C. K u m a r a n d C l a r k' s C l i n i c a l M e d i c i n e . 9 ed. London\: Elsevier; 2017.
Moore K, Dalley A, Agur A. C l i n i c a l l y O r i e n t e d A n a t o m y . 7 ed\: Lippincott Williams and Wilkins 2013. 1168 p.
Rhoades R, Bell D. M e d i c a l P h y s i o l o g y . 4 ed. Philadelphia\: Lippincott Williams & Wilkins 2013. p. 621-8.
Wilkinson I, Raine T, Wiles K, Goodhart A, Hall C, O'Neil H. O x f o r d H a n d b o o k o f C l i n i c a l M e d i c i n e . 10 ed. Oxford\: Oxford
University Press; 2017.
Kim HY, Mohan S. R o l e a n d M e c h a n i s m s o f A c t i o n s o f T h y r o i d H o r m o n e o n t h e S k e l e t a l D e v e l o p m e n t . Bone Res.
2013;1(2)\:146-61.
BMJ Best Practice. T o x i c m u l t i n o d u l a r g o i t r e . 2019. Available from\: [LINK].
NICE CKS. H y p e r t h y r o i d i s m . 2020. Available from\: [LINK].
Jadidi J, Sigari M, Efendizade A, Grigorian A, Lehto SA, Kolla S. T h y r o i d a c r o p a c h y \: A r a r e s k e l e t a l m a n i f e s t a t i o n o f
a u t o i m m u n e t h y r o i d d i s e a s e . Radiol Case Rep. 2019;14(8)\:917-9.
Starr O, Tidy C. T h y r o i d F u n c t i o n T e s t s . 2020. Available from\: [LINK].
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BMJ Best Practice. G r a v e s' d i s e a s e . 2020. Available from\: [LINK].
NICE. H y p e r t h y r o i d i s m \: D i a g n o s i s . 2020. Available from\: [LINK].
NICE. H y p e r t h y r o i d i s m \: M a n a g e m e n t . 2020. Available from\: [LINK].
Newson L, Bonsall A. H y p e r t h y r o i d C r i s i s ( T h y r o t o x i c s t o r m ) . 2015. Available from\: [LINK].
Foundation BT. T h y r o i d E y e D i s e a s e . 2019. Available from\: [LINK].

Image references

Figure 1. Geeky Medics. T h e h y p o t h a l a m i c- p i t u i t a r y-t h y r o i d ( H P T ) a x i s .
Figure 2. Jonathan Trobe, M.D. T h y r o i d e y e d i s e a s e . License\: [CC-BY]. Available from\: [LINK]
Figure 3. Herbert L. Fred, MD and Hendrik A. van Dijk. T h y r o i d a c r o p a c h y . License\: [CC-BY]. Available from\: [LINK]
Figure 4. Herbert L. Fred, MD and Hendrik A. van Dijk. P r e t i b i a l m y x o e d e m a . License\: [CC-BY]. Available from\: [LINK]

Reviewer

Dr Peter King
Reader in Molecular Endocrinology

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Contents

Introduction
Aetiology
Clinical features
Investigations
Management
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