Thyrotoxicosis refers to the clinical, physiological and biochemical findings that are the result of excessive thyroid hormone exposure. Thyrotoxicosis is a syndrome characterised by the physiological effects of excessive thyroid hormones on various organ systems. It can be caused by hyperthyroidism, but it can also result from external sources of thyroid hormone, such as excessive intake of thyroid hormone medication or exposure to high levels of iodine. Hyperthyroidism is a specific condition marked by the increased activity of the thyroid gland, while thyrotoxicosis is a broader term encompassing the signs and symptoms associated with elevated thyroid hormone levels. We will cover hyperthyroidism separately in its own condition (found in endocrinology).
🏃♀️ Physiology
Before we take a look at the pathophysiology, let’s recap our normal thyroid 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.
Pathophysiology
The excessive thyroid hormone levels in thyrotoxicosis result in a hypermetabolic state affecting multiple organ systems:
- Increased metabolism - as T3 increases gene transcription and cellular metabolism. The heightened metabolic rate causes weight loss despite increased appetite, and patients may experience muscle weakness and fatigue.
- Increased sympathetic nervous system activity - due to upregulation of beta-adrenergic receptors. It leads to clinical manifestations such as tachycardia, palpitations, and heat intolerance.
- Cardiovascular manifestations - elevated T3 levels lead to increased cardiac output, heart rate, and contractility, contributing to features like atrial fibrillation and, in severe cases, cardiac failure. Additionally, thyrotoxicosis induces changes in the peripheral vasculature, resulting in decreased systemic vascular resistance. These cardiovascular effects collectively contribute to the characteristic symptoms of thyrotoxicosis, such as palpitations, dyspnoea, and exercise intolerance.
- Skeletal manifestations - thyrotoxicosis extends to the skeletal system, where increased bone resorption occurs, predisposing patients to osteoporosis and an increased risk of fractures. Furthermore, the excess thyroid hormone disrupts the normal feedback inhibition of the hypothalamic-pituitary-thyroid axis, leading to suppressed TSH levels. This feedback disruption can contribute to the enlargement of the thyroid gland (Goitre).
Let’s look at some causes of thyrotoxicosis. Some are related to hyperthyroidism and others are not:
Causes associated with hyperthyroidism:
- Excessive thyroid stimulation, due to:
- ⭐️ Grave's disease
- Hashitoxicosis
- Pituitary thyrotroph adenoma
- Pituitary thyroid hormone resistance syndrome
- Trophoblastic tumours producing hCG with thyrotrophic activity
- Iodinated contrast medium
- Thyroid nodules with autonomous function, such as:
- ⭐️ Toxic multinodular goitre
- Toxic solitary nodule
- Thyroid cancer
Causes not associated with hyperthyroidism:
- Thyroid inflammation, due to:
- Silent/post-partum thyroiditis
- Subacute (de Quervain's) thyroiditis
- Drug-induced thyroiditis - amiodarone, INF-a, TKI's, immunotherapy.
- Exogenous thyroid hormones, due to:
- Overtreatment with thyroid hormone
- Thyrotoxicosis factitia - using thyroxine for non-thyroidal disease.
- Ectopic thyroid tissue, from:
- Metastatic thyroid carcinoma
- Struma ovarii - a teratoma containing functional thyroid tissue.
⭐️ Grave's disease and toxic multinodular goitres account for most cases of thyrotoxicosis.
😷 Presentation
Some of these features may be specific to one underlying diagnosis rather than be seen in all cases of thyrotoxicosis, such as (pre-tibial myxoedema and exophthalmos which indicate Grave's disease).
- General features:
- Weight loss
- Restlessness
- Heat intolerance
- Fatigue
- Skin
- Increased sweating
- Pretibial myxoedema - erythematous, oedematous lesions above the lateral malleoli & on the shins
- Thyroid acropachy
- Gastrointestinal
- Diarrhoea
- Gynaecological
- Oligomenorrhoea
- Neurological
- Anxiety
- Tremor
- Cardiac
- Palpitations
- Tachycardia
- Cardiac failure - specifically high output cardiac failure may occur in elderly patients, a reversible cardiomyopathy can rarely develop
Let’s discuss some of the causes in further detail
More information on Grave’s can be found in the page on hyperthyroidism (link here once completed)
This is the hyperthyroid of Hashimoto’s disease, of which more information may be found here.
This is when there is a solitary toxic thyroid nodule excessively releases thyroid hormone. The nodule is usually a benign adenoma and warrants surgical removal.
Toxic multinodular goitre (TMG), also known as Plummer's disease, is when a goitre contains many autonomously functioning nodules that are unregulated by the HPT axis. As such, they continuously produce thyroid hormones leading to hyperthyroidism. These nodules are almost always benign though.
⚠️ Risk factors
- Iodine deficiency
- Age >40 years
- Head and neck irradiation
😷 Presentation
Other than the features mentioned above, a specific feature would be:
- Goitre (non-painful) - irregular texture.
🔍 Investigations
- 🥇 TSH - this is the initial test. TSH should be low. If it is not we can rule out TMG.
- Ultrasound - may be the first-line imaging modality of choice to identify any nodules and assess whether they look suspicious for malignancy.
- Nuclear scintigraphy - this is done with technetium-99 pertechnetate or radioiodine (I-123) which identifies variegated (patchy) uptake.
🧰 Management
With TMG, does not remit spontaneously therefore management is indicated. Options for management include:
- Radioactive iodine (I-131) - if there is no suspicion of cancer. Iodine is taken up more readily by the overactive cells and are destroyed by the radiation.
- Antithyroid medication - such as propylthioruacil or thiamazole. These are preferred in pregnancy where iodine therapy is contraindicated.
- Thyroid surgery - this is indicated if malignancy is suspected or if there is a mass effect that causes symptoms such as dyspnoea, choking, Pemberton’s sign.
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
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.
- Amiodarone
- Amiodarone-induced hypothyroidism (AIH):
- Amiodarone-induced thyrotoxicosis (AIT):
- Type 1 AIT - due to the Jod-Basedow effect, where the excessive iodine intake (such as from amiodarone) causes hyperthyroidism. It is a lot more common in those who have nodular disease or Grave's disease, as this excessive iodine easily reactivates the thyroid.
- Type 2 AIT - an immune response to the cytotoxic properties of amiodarone, and it results in a destructive thyroiditis, with leakage of pre-formed thyroid hormone & low uptake of radiolabel on scanning.
Amiodarone has a high concentration of iodine (about 37%), and its half-life is around 65 days. This means that amiodarone administration increases the concentration of iodine in the body over time. Therefore, can disrupt the normal thyroid function resulting in either hypothyroidism or hyperthyroidism.
Let’s look at some of the outcomes that may occur with amiodarone:
The pathophysiology of AIH is thought to be that high iodine content (from amiodarone) inhibits thyroglobulin iodination and thyroid hormone synthesis and release. This is known as the Wolff-Chaikoff effect - an autoregulatory phenomenon where thyroxine formation is inhibited due to high levels of circulating iodide.
Patients with Grave's disease are especially sensitive to this effect, in comparison with euthyroid individuals.
AIT is caused by 2 entirely different mechanisms:
AIT type 1 | AIT type 2 | |
Pathophysiology | Excess iodine-induced thyroid hormone synthesis | Amiodarone-related destructive thyroiditis |
Goitre | Present | Absent |
Management | Thionamides: carbimazole or potassium perchlorate | Glucocorticoids |
AIT is an extremely challenging condition to manage for multiple reasons. These include difficulty in discrimination between type 1 and 2 diseases, each of which have different treatments, and the fact that most patients are taking amiodarone for serious cardiac dysrhythmias and it has a very long tissue half-life. As such, these patients should be under the care of a specialist endocrinology team.
Other drugs that may cause thyrotoxicosis include:
- INF-a
- Tyrosine kinase inhibitors (TKIs)
- Immunotherapy
- Iodine containing contrast agents - patients will develop hyperthyroidism over 2-12 weeks.
🔍 Investigations
- TSH - might be suppressed
- T4 and T3 - might be elevated
- Thyroid autoantibodies - might be positive.
Other investigations are not routinely done but it may include isotope scanning/scintigraphy.
🧰 Management
Managing thyrotoxicosis revolves around treat the underlying cause.