Hyperthyroidism specifically refers to the overproduction of thryoid hormones by the thyroid gland. The term thyrotoxicosis is a broader term that refers to elevated thyroid hormone levels occurring due to any cause. This may include hyperthyroidism but there are a multitude of causes of thyrotoxicosis.
Physiology
The thyroid gland is a butterfly-shape gland in the anterior neck and it produces and stores thyroid hormones. At a cellular level, the thyroid gland is made up of follicles, these are multiple epithelial cells which form a ring. In the lumen of these follicle rings there is a protein-rich reservoir of enzymes and substances required to make the thyroid hormones.
The function of the thyroid hormones is vast. They regulate metabolism by acting on nuclear receptors and stimulating metabolic pathways. They essentially increase the metabolism, so high levels increase metabolism while low levels decrease the metabolism.
Some of the processes they increase include:
- Basal metabolic rate
- Gluconeogenesis
- Glyocgenolysis
- Protein synthesis
- Lipogenesis
- Thermogenesis
Let’s take a look at how thyroid hormones are synthesised:
It is a 6 step process (ATE ICE):
- Active transport - iodide is actively transported into the follicular cell by the Sodium-Iodide transporter (NIS).
- Thyroglobulin - is secreted into secretory vesicles. It contains plenty of tyrosine and ribosomes.
- Exocytosis - of thyroglobulin into the lumen of the follicle. Thyroglobulin acts as the scaffolding for thyroid hormone synthesis.
- Iodination - of thyroglobulin by the enzyme thyroperoxidase. The iodide binds to the tyrosine molecules to form either monoiodotyrosine (MIT) or diiodotyrosine (DIT).
- Coupling - of MIT and DIT = triiodothyronine (T3) and coupling of DIT and DIT = tetraiodothyronine (i.e. thyroxine) [T4].
- Endocytosis - of this iodinated thyroglobulin back into the cell. Lysosomes break down the thyroglobulin scaffold to recycle the amino acids while the T3 and T4 are stored for release.
T3 and T4 are fat soluble and are carried by plasma proteins (albumin and thyronine binding globulin). T3 is more potent but has a shorter half-life. T4 is deiodinated into the more active T3 by the enzyme deiodinase.
Lastly, let’s recap the HPT (hypothalamic-pituitary-thyroid) axis:
- The hypothalamus detects low plasma concentrations of T3 and T4. It then releases thyrotropin-releasing hormone (TRH) into the hypophyses portal system.
- TRH binds to receptors on thyrotrophic cells on the anterior pituitary, these thyrotroph cells release thyroid stimulating hormone (TSH) into our systemic circulation.
- TSH binds to the TSH receptor on the basolateral membrane of the follicular cells. This causes the release of thyroid hormones.
Negative feedback on the hypothalamus and pituitary is what normally regulates the amount of thyroid hormone being produced.
🔢 Classification
We will discuss classifications of thyrotoxicosis and hyperthyroidism both:
Thyrotoxicosis may occur with hyperthyroidism and it may also occur without hyperthyroidism.
- Thyrotoxicosis with hyperthyroidism
- Graves’ disease
- Toxic multinodular goitre
- Toxic thyroid nodule/toxic adenoma
- TSH-secreting pituitary adenoma
- Pituitary thyroid hormone resistance syndrome
- hCG mediated thyrotoxicosis
- Iodine-dependent thyrotoxicosis
- Struma ovarii
- Metastatic thyroid cancer
In these instances there is increased production of the thyroid hormone throughout the body.
- Thyrotoxicosis without hyperthyroidism
- Thyroiditis
- Exogenous thyroid administration
In these instances there is an increased availability/release of thyroid hormone that was produced already (regardless of whether that production may be endogenous or exogenous).
We will discuss all of these in further detail below…
Hyperthyroidism may be classified as either:
In primary hyperthyroidism the abnormality lies within the thyroid gland (as seen in Grave’s disease or with thyroid nodules).
- We can sub-classify it further into:
- Overt primary hyperthyroidism - TSH is suppressed and FT4 ± FT3 is elevated.
- Subclinical primary hyperthyroidism - TSH is suppressed, however, FT4 ± FT3 is normal.
In secondary hyperthyroidism his is when the abnormality lies elsewhere in the axis, such as in the hypothalamus or pituitary gland.
⚠️ Risk factors
- Female sex - hyperthyroidism affects women 10x more than men.
- Family history
- Smoking - smoking increases the risk of Graves’ development as well as recurrence. It also greatly increases the risk of Graves’ orbitopathy.
- Insufficient iodine intake
- History of autoimmune disease
- Amiodarone use
- Lithium use - despite being associated with hypothyroidism, if used long-term it may cause painless thyroiditis which leads to hyperthyroidism.
😷 Presentation
Seeing as thyroid hormones control the metabolic rate, the symptoms represent an increase in the metabolic rate. This may include symptoms such as:
- Heat intolerance and sweaty skin
- Fatigue
- Increased hunger
- Tachycardia
- Palpitations
- Weight loss
- Diarrhoea
- Insomnia and disrupted sleep
- Myopathy
- Fine tremor
- Anxiety and/or depression
- Diffuse goitre
- Pretibial myxoedema
- Thyroid acropachy
- Polyuria
- Amenorrhoea/oligomenorrhoea and subfertility in women
- Low libido and gynaecomastia in men
- Hair loss
🔍 Investigations
- Thyroid function tests
- TSH - low in hyperthyroidism.
- Free T3 and free T4 - raised in hyperthyroidism.
- TSH-receptor antibodies (TRAbs) - to assess for Graves’ disease.
- ESR/CRP - to assess for thyroiditis.
- Ultrasound of the neck - if there is palpable thyroid enlargement or any focal modularity.
NICE guidance now advises testing for thyroid dysfunction in individuals with:
- Type 1 diabetes or other autoimmune diseases
OR
- New-onset atrial fibrillation
We shall now discuss the causes of thyrotoxicosis in more detail:
Graves’ disease is an autoimmune condition characterised auto-antibody stimulation of TSH receptor by. TSH-receptor antibodies (TRAbs) can be divided into 2 types:
- Thyroid stimulating antibodies/immunoglobulins (TSAbs/TSIs) - these auto-antibodies bind to the TSH receptor and stimulate it, resulting in thyroid hormone overproduction. It also results in hyperplasia of the thyroid follicular cells (leading to a diffuse goitre).
- Thyrtropin-binding inhibitory immunoglobulins (TBIIs) - these are similar to the TSAbs but also are known to have some inhibitory function on the TSH receptor (hence the name). However, in Graves’ disease it causes overstimulation of the receptor and hypersecretion once again.
There are also TSH receptors present in fibroblasts in the retro-orbital space as well as dermal tissue:
Stimulation of these receptors by autoantibodies (as well as cytokines) leads to production of glycosaminoglycans which accumulate in the retro-orbital space. These glycosaminoglycans trigger tissue expansion and orbital fat deposition. This leads to thyroid-associated ophthalmopathy/orbitopathy.
If these glycosaminoglycans accumulate in the dermal tissue which may lead to pretibial myxoedema. There is associated inflammation which causes damage to the overlying skin.
In thyroid acropachy there is tissue swelling and nail clubbing but there is also a periosteal bone reaction which causes new bone formation too.
😷 Presentation
The symptoms are the same as mentioned above, but it is important to note the triad of Grave’s disease’s extrathyroidal manifestations:
- Thyroid-associated opthalmopathy - this is most common and first to present. It may result in:
- Exophthalmos
- Diplopia
- Lid-retraction
- Pretibial myxoedema - non-pitting oedema and firm plaques on the anterolateral aspects of the legs.
- Thyroid acropachy - the rarest presentation. It appears as clubbing of the the nail and separation of the nail from the nail bed, along with swelling of the fingers.
It may also lead to optic neuropathy and exposure of the cornea which may result in ulceration and perforation.
A diffuse goitre may be present. It should be smooth, symmetrical and painless. A thyroid bruit may be auscultated at the superior poles of the thyroid gland. This is due to increased vascularity of the enlarged thyroid resulting in the superior thyroid artery dividing into anterior and posterior branches and resulting in turbulent blood flow at the superior pole.
🔍 Investigations
- TSH - low/undetectable.
- Free T3/T4 - high (unless subclinical hyperthyroidism).
- TRAbs - detected using assays for TSIs and TBIIs.
- Anti-TPO antibodies - although more commonly associated with Hashimoto’s thyroiditis, it may also be raised in Grave’s disease.
- MRI - may be done for ophthalmopathy.
- Thyroid scintigraphy - if the TRAb’s are low. It is seen as diffuse uptake of iodine.
- Thyroid ultrasound - may be done if TRAb’s are low and the patient is unable to undergo nuclear medicine tests (such as scintigraphy). It would show an enlarged thyroid gland as well as increased vascularity.
Sometimes referred to as Plummer’s disease, MNG occurs when there is a presence of a goitre with multiple palpable nodules (≥2) that are hormonally and autonomous. These nodules synthesise and secrete thyroid hormones without the need for TSH stimulation → hyperthyroidism. The nodules are histologically benign follicular adenomas.
It is the second most common cause of hyperthyroidism.
⚠️ Risk factors
- >50 years old
- Female sex
- Iodine-deficient area - this is because autonomous follicular cells begin to activate after periods of low iodine intake.
🔍 Investigations
- Thyroid scintigraphy - it will show “patchy” uptake with multiple hot nodules (hyper-functioning nodules). There may be suppression of the rest of the gland as well.
🧰 Management
🥇 Pharmacological management
- Beta blockers - for symptomatic management.
- Anti thyroid medication - such as carbimazole or propylthiouracil to regulate the thyroid function.
Definitive management
- 🏆 Radioactive iodine ablation (RAIA) - this is the treatment of choice for MNG.
- Thyroidectomy (total/near-total)
Toxic adenoma is a solitary toxic thyroid nodule that produces sufficient thyroid hormone to suppress TSH secretion from the pituitary as well as thyroid hormone suppression from the opposite lobe of the thyroid gland. It too is a benign follicular adenoma.
Pathophysiology
Follicular cells within the thyroid gland undergo gain of function mutations affected the TSH receptor. This occurs due to genetic factors as well as iodine deficiency. These mutations result in increased cAMP levels internally which increases follicular cell function (causing hyperthyroidism and growth of the cell).
🔍 Investigations
- TSH - low.
- T3/T4 - high.
- Thyroid scintigraphy - a solitary hot nodule and suppression of the rest of the thyroid gland.
🧰 Management
🥇 Pharmacological management
- Beta blockers - for symptomatic management.
- Anti thyroid medication - such as carbimazole or propylthiouracil to regulate the thyroid function.
🏆 Definitive management
- Nodule removal/hemithyroidectomy
- Radioactive iodine ablation (RAIA) - this is the treatment of choice for MNG.
Pituitary tumoursThyroid hormone resistance (TRH) is a syndrome with varying phenotypes based on the receptors that are affected. It may be generalised, there may be predominant pituitary resistance or there may be peripheral thyroid resistance.
It occurs due to missense mutations that inactivate the thyroid hormone receptor beta-1 gene.
If there is predominant pituitary resistance, the pituitary’s thyrotroph cells are resistant to negative feedback from the thyroid hormones. As such the TSH-level is normal/elevated while there is overt hyperthyroidism seen (elevated T3/T4).
It may be diagnosed with a positive family history or DNA analysis of the TRß1 gene.
hCG is a dimer made up of an alpha-subunit and beta-subunit. The alpha-subunit has the same structure as TSH (as well as luteinising hormone and follicle stimulating hormone). As such it may stimulate TSH receptors
High levels of hCG may be seen in:
- Gestational thyrotoxicosis - this is a benign and transient disorder seen most commonly in the first trimester of pregnancy. Placental beta-hCG stimulates the thyroid receptors and as such thyrotoxicosis is seen. It does not require any specialist treatment.
- Chorionic gonadotropin-secreting tumours (such as choriocarcinoma or a hydatidiform mole) - these tumours produce beta-hCG which stimulates the thyroid receptors as well and may cause thyrotoxicosis.
In iodine-deficient countries low iodine intake may result in hyperthyroidism. This is because compensatory mechanisms of the thyroid are put in place to maintain euthyroid levels when iodine intake is low. However, when there is an increase in iodine intake, hyperthyroidism may be observed due to hyperstimulation of an already overactive thyroid gland.
Elevated iodine intake may result in thyroiditis and hyperthyroidism too.
We can find iodine in:
- Seafood, dairy products and iodised salt
- Amiodarone
- Kelp supplementation
- Iodine contrast
To investigate, we may perform a 24-hour urinary iodine excretion measurement to assess any excessive iodine intake.
Struma ovarii is a rare variant of an ovarian teratoma that contains >50% thyroid tissue. It secretes ectopic thyroid hormone and can often lead to thyrotoxicosis.
Hyperfunctioning metastatic tumours as well as leakage of thyroid hormones into the bloodstream through thyrocyte destruction are 2 mechanisms by which thyroid cancer may cause thyrotoxicosis.
Thyroiditis, inflammation of the thyroid gland, results in a release of pre-formed thyroid hormones due to follicular cell destruction and inflammation.
We will discuss 2 types:
- Subacute thyroiditis (de Quervain’s thyroiditis)
- Postpartum thyroiditis (silent lymphocytic thyroiditis)
- Subacute thyroiditis (de Quervain’s thyroiditis)
Also known as subacute granulomatous thyroiditis. It is believed to follow a viral infection (such as mumps or flu) and typically presents with hyperthyroidism in its acute phase but cases hypothyroidism in its chronic phase.
It has 4 typical phases:
- ⭐️ Hyperthyroid phase - presents with a painful goitre and raised ESR. Lasts 3-6 weeks.
- Euthyroid phase - normal thyroid levels. Lasts 1-3 weeks.
- Hypothyroidism phase - lasts weeks-months.
- Euthyroid recovery - a return to normal function and structure of the thyroid.
🔍 Investigations
- Thyroid scintigraphy - it shows globally reduced uptake of iodine-131.
- ESR
🧰 Management
Most patients require no treatment.
The thyroid pain may respond to NSAIDs.
Steroids may be used in severe cases, especially if hypothyroidism develops.
- Postpartum thyroiditis (silent lymphocytic thyroiditis)
This affects about 3 in 100 women after pregnancy. It is a sort of transient Hashimoto’s thyroiditis in that it has an initial thyrotoxicosis phase and anti-TPO antibodies are present in about 90% of patients.
There are 3 stages in postpartum thyroiditis:
- Thyrotoxicosis phase - may be treated using propranolol for symptom control but not usually treated with anti-thyroid medications.
- Hypothyroidism - treated with levothyroxine.
- Normal thyroid function
🔍 Investigations
- Anti-TPO antibodies - found in 90% of patients.
- Levothyroxine and liothyronine intake may lead to thyrotoxicosis. It is the most common cause of a serum TSH <0.1mU/L in the UK. It may be done through intentional over-ingestion of the medication (often to help with weight loss or to induce symptoms of hyperthyroidism, as seen in Münchausen syndrome). This is known as factitious hyperthyroidism. Other times it may be done unintentionally through improper dosing of the medication (iatrogenic hyperthyroidism).
- INF-alpha
- Tyrosine kinase inhibitors
- Immunotherapy agents
- Contrast agents containing iodine - patients may develop hyperthyroidism over the subsequent 2-12 weeks.
- Amiodarone
- Amiodarone-induced hypothyroidism (AIH)
- Amiodarone-induced thyrotoxicosis (AIT)
- Type 1 AIT - this occurs due to the Jod-Basedow effect. The Jod-Basedow effect is when the excess iodine intake results in excessive thyroid hormone synthesis. It is more common in individuals with Graves’ disease or any hot nodules as the hyperfunctioning thyroid is ready to use the available iodine. It may also result in goitre formation.
- Type 2 AIT - this is rarer. It occurs as an immune response to amiodarone which has cytotoxic properties. As such there is resultant destructive thyroiditis which, as discussed previously with thyroiditis, causes leakage of pre-formed thyroid hormone into the bloodstream. Goitre is typically absent.
Let’s discuss amiodarone in more detail…
Amiodarone has a high concentration of iodine as well as a long half-life (65 days). As such anyone who takes amiodarone will have high concentrations of iodine circulating for a prolonged time. This may disrupt the thyroid to produce either hypothyroidism or thyrotoxicosis.
High iodine content within amiodarone inhibits thyroglobulin iodisation and thyroid hormone synthesis/release (as an autoregulatory mechanism). It is especially common in patients with Graves’ disease.
AIT may occur due to 2 mechanisms:
It may be treated with potassium perchlorate (especially good for type 1 AIT) or carbimazole.
It may be treated with steroids to prevent the inflammatory response.
It may be difficult to discriminate between type 1 and type 2 AIT as well as treat them appropriately.
🧰 Management
- Antithyroid medications
Antithyroid medications are competitive thyroperoxidase inhibitors. They are used in the short-term to achieve euthyroidism prior to surgery or RAIA. They may be used in the medium-term (1-1.5 years) to induce remission of Graves’ disease. They are only used in the long-term if surgery or RAIA is contraindicated/declined.
- 🥇 Carbimazole - it is the preferred first-line option (but not used in pregnancy). Side effects include: agranulocytosis, acute pancreatitis, teratogenicity (especially in the first trimester).
- 🥈 Propylthiouracil - preferred in the first-trimester of pregnancy and pre-pregnancy. It may also be used for specialist treatment of a thyrotoxic crisis. Side effects include: agranulocytosis, severe liver injury.
⚠️ Agranulocytosis is a severe adverse effect of both antithyroid medications. It may then cause the patient to have sepsis. Therefore any signs of infection (such as sore throat, fever, oral ulcers) need appropriate investigation and require temporary cessation of the medication.
Once euthyroidism is achieved, the patient will be placed on one of 2 regimes to maintain remission after 6-18 months (of which the success rate is 50% for both):
- Titration-block regime - the antithyroid medication is dose adjusted regularly depending on the FT4 measurements.
- Block and replace regime - high doses of the antithyroid medication are given to completely block synthesis of thyroid hormones. Then levothyroxine may be added in to replace the missing thyroid horomones. The levothyroxine dose would then be adjusted based on the FT4 measurements.
- Definitive management
- Radioactive iodine ablation (RAIA) - radioactive iodine is taken up by the follicular cells and causes DNA damage and cell death. This reduces the thyroid function as well as size.
It is a first-line definitive management option in Graves’ disease as well as toxic MNG. Most patients with Graves’ become euthyroid and subsequently hypothyroid within 6 weeks to 6 months after treatment.
It may exacerbate existing orbitopathy or precipitate de novo development of it.
It is also to be avoided in pregnancy, breastfeeding or women planning to be pregnant within the next 6 months. The radioactive iodine is able to cross the placenta → severe hypothyroidism in the fetus. Men are advised not to father children for 4 months after treatment.
- Thyroidectomy/hemithyroidectomy - post-operative complications include hypothyroidism, hypocalcaemia (due to hypoparathyroidism, although this is often transient). There is also risk of vocal cord paresis if there is damage to the
Subclinical hyperthyroidism occurs when the TSH levels are low but the FT3 and FT4 values remain in range. NICE does not recommend routinely treating subclinical hyperthyroidism unless it is persistent and the patient shows symptoms. Monitoring is also not necessary but can also be considered by measuring TSH levels every 6 months (or every 3 months in children).
- Pre-conception
Arrange referral to endocrinology for all women with overt/subclinical hyperthyroidism who are planning pregnancy.
If the woman has had RAIA, remind them to wait 6 months after RAIA before conceiving.
- During pregnancy
- Known hyperthyroidism - if on block and replace regime, switch the patient titration-block regime. Propylthiouracil to be used in the 1st trimester and then switch to carbamazepine afterwards.
- New diagnosis of hyperthyroidism - propylthiouracil in the 1st trimester and then switch to carbamazepine afterwards.
TFTs should be checked every 4 weeks.
- Post-partum
Ensure all women with a diagnosis of hyperthyroidism have their TFTs checked after delivery.
Arrange annual monitoring of TFTs for all women with a history of postpartum thyroiditis.
🚨 Complications
- Thyroid storm/thyrotoxic crisis
- Graves’ orbitopathy
- Atrial fibrillation
- Cardiac failure
- Osteoporosis
- Anxiety and depression
- Goitre compression leading to dysphagia or breathlessness
- Pregnancy risks
- Miscarriage
- Preterm birth
- Intrauterine growth restriction
- Fetal death
- Fetal hydrops
- Fetal goitre
- Neonatal thyrotoxicosis
Thyroid storm is an exacerbation of hyperthyroidism that may be precipitated by:
- Trauma
- Surgery
- Infection
- Acute iodine load (e.g. CT contrast)
😷 Presentation
- Fever >38.5ºC
- Tachycardia
- Confusion and agitation
- Nausea and vomiting
- Hypertension
- Cardiac failure
- Jaundice/abnormal liver function
🧰 Management
- Treat underlying infection/manage precipitating event
- IV propranolol
- Dexamethasone
- Lugol’s ioodine - reduces the thyroid hormones, T4 and T3 by increasing iodine uptake and inhibiting TPO enzymatic activity.
- Antithyroid medication - propylthiouracil or methimazole
- Fluid rescuscitation