What are the two commonest causes of hyperthyroidism?

URL of this page: https://medlineplus.gov/hyperthyroidism.html

Also called: Overactive thyroid

Hyperthyroidism, or overactive thyroid, happens when your thyroid gland makes more thyroid hormones than your body needs.

Your thyroid is a small, butterfly-shaped gland in the front of your neck. It makes hormones that control the way the body uses energy. These hormones affect nearly every organ in your body and control many of your body's most important functions. For example, they affect your breathing, heart rate, weight, digestion, and moods. If not treated, hyperthyroidism can cause serious problems with your heart, bones, muscles, menstrual cycle, and fertility. But there are treatments that can help.

What causes hyperthyroidism?

Hyperthyroidism has several causes. They include:

  • Graves' disease, an autoimmune disorder in which your immune system attacks your thyroid and causes it to make too much hormone. This is the most common cause.
  • Thyroid nodules, which are growths on your thyroid. They are usually benign (not cancer). But they may become overactive and make too much thyroid hormone. Thyroid nodules are more common in older adults.
  • Thyroiditis, inflammation of the thyroid. It causes stored thyroid hormone to leak out of your thyroid gland.
  • Too much iodine. Iodine is found in some medicines, cough syrups, seaweed and seaweed-based supplements. Taking too much of them can cause your thyroid to make too much thyroid hormone.
  • Too much thyroid medicine. This can happen if people who take thyroid hormone medicine for hypothyroidism (underactive thyroid) take too much of it.

Who is at risk for hyperthyroidism?

You are at higher risk for hyperthyroidism if you:

  • Are a woman
  • Are older than age 60
  • Have been pregnant or had a baby within the past 6 months
  • Have had thyroid surgery or a thyroid problem, such as goiter
  • Have a family history of thyroid disease
  • Have pernicious anemia, in which the body cannot make enough healthy red blood cells because it does not have enough vitamin B12
  • Have type 1 diabetes or primary adrenal insufficiency, a hormonal disorder
  • Get too much iodine, from eating large amounts of foods containing iodine or using iodine-containing medicines or supplements

What are the symptoms of hyperthyroidism?

The symptoms of hyperthyroidism can vary from person to person and may include:

  • Nervousness or irritability
  • Fatigue
  • Muscle weakness
  • Trouble tolerating heat
  • Trouble sleeping
  • Tremor, usually in your hands
  • Rapid and irregular heartbeat
  • Frequent bowel movements or diarrhea
  • Weight loss
  • Mood swings
  • Goiter, an enlarged thyroid that may cause your neck to look swollen. Sometimes it can cause trouble with breathing or swallowing.

Adults over age 60 may have different symptoms than younger adults. For example, they may lose their appetite or withdraw from other people. Sometimes this can be mistaken for depression or dementia.

What other problems can hyperthyroidism cause?

If hyperthyroidism isn't treated, it can cause some serious health problems, including:

  • An irregular heartbeat that can lead to blood clots, stroke, heart failure, and other heart problems
  • An eye disease called Graves' ophthalmopathy. It can cause double vision, light sensitivity, and eye pain. In rare cases, it can lead to vision loss.
  • Thinning bones and osteoporosis
  • Fertility problems in women
  • Complications in pregnancy, such as premature birth, low birth weight, high blood pressure in pregnancy, and miscarriage

How is hyperthyroidism diagnosed?

Your health care provider may use many tools to make a diagnosis:

  • A medical history, including asking about symptoms
  • A physical exam
  • Thyroid tests, such as

What are the treatments for hyperthyroidism?

The treatments for hyperthyroidism include medicines, radioiodine therapy, and thyroid surgery:

  • Medicines for hyperthyroidism include
    • Antithyroid medicines, which cause your thyroid to make less thyroid hormone. You probably need to take the medicines for 1 to 2 years. In some cases, you might need to take the medicines for several years. This is the simplest treatment, but it is often not a permanent cure.
    • Beta blocker medicines, which can reduce symptoms such as tremors, rapid heartbeat, and nervousness. They work quickly and can help you feel better until other treatments take effect.
  • Radioiodine therapy is a common and effective treatment for hyperthyroidism. It involves taking radioactive iodine by mouth as a capsule or liquid. This slowly destroys the cells of the thyroid gland that produce thyroid hormone. It does not affect other body tissues. Almost everyone who has radioactive iodine treatment later develops hypothyroidism. This is because the thyroid hormone-producing cells have been destroyed. But hypothyroidism is easier to treat and causes fewer long-term health problems than hyperthyroidism.
  • Surgery to remove part or most of the thyroid gland is done in rare cases. It might be an option for people with large goiters or pregnant women who cannot take antithyroid medicines. If you have all of your thyroid removed, you will need to take thyroid medicines for the rest of your life. Some people who have part of their thyroid removed also need to take medicines.

If you have hyperthyroidism, it's important not to get too much iodine. Talk to your health care provider about which foods, supplements, and medicines you need to avoid.

NIH: National Institute of Diabetes and Digestive and Kidney Diseases

  • Thyroidectomy - slideshow (Medical Encyclopedia) Also in Spanish

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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 specifically to excess thyroid hormone synthesis and secretion by 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

You might also be interested in our medical flashcard collection which contains over 1000 flashcards that cover key medical topics.

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 (T3) and thyroxine (T4).

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

T4 is the main hormone produced from the thyroid gland, alongside smaller amounts of T3. The majority of T4 is then converted to T3 when it reaches the target tissue (this is the most active form of the hormone).4

Thyroid hormones have a wide range of functions including influencing the basal metabolic rate (the rate of cellular 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).5

What are the two commonest causes of hyperthyroidism?
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 T3 and T4 from the thyroid gland, resulting in thyrotoxicosis.

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 affects older patients. Thyrotoxicosis due to 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 increases iodine levels and so increases follicular thyroid hormone production. Levothyroxine is used in the management of hypothyroidism to increase thyroid hormone production where there is a deficit. Overuse of this drug can cause an inappropriately 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 inflammation of the thyroid gland and subsequent excessive excretion of thyroid 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 inflammation.

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
  • 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
  • Loss of the outer third of the eyebrow
  • Warm and moist skin
  • Irregular or fast heart rate
  • Fine tremor
  • Brisk reflexes
  • Palmar erythema
  • Lid lag and lid retraction
  • Goitre (enlargement of the neck due to an enlarged thyroid gland)

Graves’ disease

There are some clinical features of thyrotoxicosis which are specific to Graves’ disease, due to the presence of the anti-TSHR autoantibodies.

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)
What are the two commonest causes of hyperthyroidism?

Figure 2. Thyroid eye disease
What are the two commonest causes of hyperthyroidism?

Figure 3. Thyroid acropachy
What are the two commonest causes of hyperthyroidism?

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, T3 and T4.

In most cases of thyrotoxicosis, the pattern of TFTs will reflect an increased production of thyroid hormones from the 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 T3 and T4
  • Decreased TSH

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 T3 and T4
  • 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-specific and can be present in autoimmune causes of both hyperthyroidism (Graves’ disease) and hypothyroidism (Hashimotos’ disease).4

Imaging

Doppler ultrasound may be used to image the thyroid gland, to confirm the presence of goitre and identify nodules.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 first-line management option for hyperthyroidism in children.

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 definitive management option for Graves’ disease and toxic multinodular goitre.

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.

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:13 

  • 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 fibrillation: can be seen in up to 10-25% of patients. These patients require management of their hyperthyroidism as 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 affected.14

Key points

  • 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 specifically to excess thyroid hormone synthesis and secretion by the thyroid gland
  • Thyroid hormone production is regulated via the hypothalamic-pituitary-thyroid (HPT) axis.
  • Common causes of thyrotoxicosis include Graves’ disease and toxic multinodular goitre.
  • Clinical features of thyrotoxicosis occur due to an abnormally increased basal metabolic rate.
  • Clinical features specific to Graves’ disease include thyroid eye disease, thyroid acropachy and pretibial myxoedema.
  • Thyroid function tests and autoantibody status can allow the underlying cause of thyrotoxicosis to be established.
  • Beta-blockers (e.g. propranolol) are used to manage the adrenergic clinical features of thyrotoxicosis (e.g. tachycardia, tremor).
  • First-line pharmacological management of thyrotoxicosis involves the use of a block (carbimazole) and replace (levothyroxine) regime.
  • Other management options include radioiodine and thyroidectomy.

Reviewer

Dr Peter King

Reader in Molecular Endocrinology

Editor

Dr Chris Jefferies

References

Text references

  1. Parveen K, Michael C. Kumar and Clark’s Clinical Medicine. 9 ed. London: Elsevier; 2017.
  2. Moore K, Dalley A, Agur A. Clinically Oriented Anatomy. 7 ed: Lippincott Williams and Wilkins 2013. 1168 p.
  3. Rhoades R, Bell D. Medical Physiology. 4 ed. Philadelphia: Lippincott Williams & Wilkins 2013. p. 621-8.
  4. Wilkinson I, Raine T, Wiles K, Goodhart A, Hall C, O’Neil H. Oxford Handbook of Clinical Medicine. 10 ed. Oxford: Oxford University Press; 2017.
  5. Kim HY, Mohan S. Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development. Bone Res. 2013;1(2):146-61.
  6. BMJ Best Practice. Toxic multinodular goitre. 2019. Available from: [LINK].
  7. NICE CKS. Hyperthyroidism. 2020. Available from: [LINK].
  8. Jadidi J, Sigari M, Efendizade A, Grigorian A, Lehto SA, Kolla S. Thyroid acropachy: A rare skeletal manifestation of autoimmune thyroid disease. Radiol Case Rep. 2019;14(8):917-9.
  9. Starr O, Tidy C. Thyroid Function Tests. 2020. Available from: [LINK].
  10. BMJ Best Practice. Graves’ disease. 2020. Available from: [LINK].
  11. NICE. Hyperthyroidism: Diagnosis. 2020. Available from: [LINK].
  12. NICE. Hyperthyroidism: Management. 2020. Available from: [LINK].
  13. Newson L, Bonsall A. Hyperthyroid Crisis (Thyrotoxic storm). 2015. Available from: [LINK].
  14. Foundation BT. Thyroid Eye Disease. 2019. Available from: [LINK].

Image references

  • Figure 1. Geeky Medics. The hypothalamic-pituitary-thyroid (HPT) axis.
  • Figure 2. Jonathan Trobe, M.D. Thyroid eye disease. License: [CC-BY]. Available from: [LINK]
  • Figure 3. Herbert L. Fred, MD and Hendrik A. van Dijk. Thyroid acropachy. License: [CC-BY]. Available from: [LINK]
  • Figure 4. Herbert L. Fred, MD and Hendrik A. van Dijk. Pretibial myxoedema. License: [CC-BY]. Available from: [LINK]

What are the two commonest causes of hyperthyroidism?