What happens when there’s too much thyroid hormone in the body?
When thyroid hormone levels are elevated, the body doesn’t
just “speed up”, it becomes overstimulated across multiple systems. This isn’t
a random collection of symptoms; it’s a predictable physiological response to
excess T3 and T4.
Thyroid hormones act as metabolic accelerators. They
increase the transcription of genes involved in energy production, oxygen
consumption, and adrenergic sensitivity. The result is a state of heightened
cellular activity that affects everything from heart rate to gut motility to
emotional regulation.
When thyroid hormone levels are elevated, the effects are
not confined to one organ system. Because T3 and T4 act on nuclear receptors in
nearly every tissue, the consequences of excess hormone are systemic and
predictable ... if you understand the physiology.
Let’s reason through what happens when thyroid hormone is
too high.
Systemic effects of hyperthyroidism
Metabolic acceleration
Thyroid hormone increases basal metabolic rate by
stimulating mitochondrial activity and uncoupling oxidative phosphorylation.
This leads to increased oxygen consumption and heat production. Clinically,
patients feel hot, sweat excessively, and lose weight despite eating normally
or even more than usual. The weight loss isn’t just fat, it’s also lean muscle
mass, broken down to meet the body’s heightened energy demands.
Cardiovascular stimulation
T3 upregulates Ξ²-adrenergic receptors in the heart and
peripheral vasculature. This makes the heart more sensitive to circulating
catecholamines, even if adrenaline levels are normal. The result is
tachycardia, palpitations, and sometimes atrial fibrillation. Blood pressure
may be elevated, but with a widened pulse pressure due to reduced systemic
vascular resistance.
Neurological and psychological effects
The central nervous system is also affected. Patients may
feel anxious, restless, or emotionally labile. Sleep becomes difficult, and
fine tremor is common. Reflexes are brisk. These symptoms reflect increased
synaptic activity and heightened adrenergic tone - not a psychological
disorder, but a physiological response to hormone excess.
Gastrointestinal changes
Thyroid hormone increases gut motility. Patients often
report frequent bowel movements or diarrhoea. Appetite may be increased, but
nutrient absorption can be impaired, contributing to weight loss.
Musculoskeletal impact
Muscle protein breakdown leads to proximal muscle weakness,
especially in the thighs and shoulders. Bone turnover is accelerated, which
over time can lead to osteopenia or osteoporosis, particularly in older
patients or those with prolonged disease.
Reproductive effects
Thyroid hormone interacts with the hypothalamic-pituitary-gonadal axis. In women, hyperthyroidism can cause oligomenorrhoea or amenorrhoea. Fertility may be reduced, and pregnancy outcomes can be affected if thyroid dysfunction is not corrected.
𧬠What Causes Hyperthyroidism?
Now that we understand what excess thyroid hormone does, we need to ask:
Why might someone have too much?
To answer that, we start at the top — with the hypothalamic-pituitary-thyroid (HPT) axis — and work our way down. This axis regulates thyroid hormone production through a tightly controlled feedback loop:
- The hypothalamus releases TRH (thyrotropin-releasing hormone)
- TRH stimulates the pituitary to release TSH (thyroid-stimulating hormone)
- TSH stimulates the thyroid gland to produce T3 and T4
- Circulating T3/T4 then inhibit TRH and TSH via negative feedback
Hyperthyroidism can result from dysregulation at any point in this axis - or from factors outside it entirely. Broadly, there are four mechanisms:
- Central Overstimulation
- Primary Overproduction
- Leakage of Stored Hormone
- Exogenous Intake
Lets work through these.
1. Central Overstimulation of the Thyroid Gland
Here, the thyroid is functioning normally, but it’s being overstimulated by excessive signals from the pituitary or hypothalamus.
π§ TSH-Secreting Pituitary Adenoma
This is the most common central cause of hyperthyroidism, though still rare overall. It involves a benign pituitary tumour that secretes TSH autonomously, without regard for negative feedback.
What happens?
Normally, TSH secretion is tightly regulated by circulating T3 and T4 via negative feedback. In a TSH-secreting adenoma, this feedback loop is disrupted. The tumour cells produce TSH continuously, stimulating the thyroid gland to produce excess T3 and T4. Unlike primary hyperthyroidism, TSH is not suppressed — it may be normal or elevated, which is a key diagnostic clue.
At the cellular level, the thyroid responds to TSH via the cAMP pathway, leading to increased transcription of genes involved in hormone synthesis and iodide uptake. The result is diffuse gland stimulation and systemic thyrotoxicosis
Clinical presentation
Patients present with typical hyperthyroid symptoms — weight loss, tachycardia, tremor — but may also show signs of pituitary mass effect:
- Headaches from increased intracranial pressure
- Visual field defects, especially bitemporal hemianopia, due to compression of the optic chiasm
- Other pituitary hormone disturbances, depending on tumour size and location
Investigations
- Thyroid function tests show elevated T3/T4 with non-suppressed TSH
- MRI of the pituitary reveals the adenoma
- Alpha-subunit testing may help differentiate from other causes of TSH elevation
- Dynamic endocrine testing (e.g. TRH stimulation) may be used in specialist settings
π§ Hypothalamic TRH Overproduction
Extremely rare, but if we are thinking about the axis, its always worth thinking about the possibilities from first principles. In this scenario, excess TRH from hypothalamic dysfunction or tumour leads to increased TSH secretion → increased T3/T4.
What happens?
TRH stimulates the pituitary to release TSH, which then stimulates the thyroid. If TRH is overproduced — due to a hypothalamic tumour or dysregulation — the downstream effect is identical to a TSH-secreting adenoma, but the source is higher up.
Clinical presentation
Similar to pituitary causes, but may include signs of hypothalamic dysfunction:
- Sleep disturbance
- Appetite changes
- Temperature dysregulation
- Behavioural changes in some cases
Investigations
- TFTs show elevated T3/T4 with non-suppressed TSH
- MRI of the brain may reveal hypothalamic pathology
- Diagnosis is often inferred after excluding pituitary and thyroid causes
2. Primary Overproduction by the Thyroid Gland
This is the most common mechanism. The thyroid itself is producing too much hormone, independent of TSH.
π¬ Graves’ Disease
Graves’ disease is the most common cause of hyperthyroidism in younger adults, particularly women. It’s an autoimmune condition in which the immune system produces antibodies that stimulate the thyroid gland — not destroy it. This leads to sustained overproduction of thyroid hormone and systemic thyrotoxicosis. We will discuss in more detail in the next blog post.
What happens?
In Graves’ disease, B cells produce thyroid-stimulating immunoglobulins (TSI) — a subset of TSH receptor antibodies (TRAb). These antibodies bind to the TSH receptor on thyroid follicular cells and mimic the action of TSH, triggering the same intracellular signalling cascade (primarily via cAMP) that normally drives hormone synthesis.
Unlike TSH, which is tightly regulated by negative feedback, these antibodies act continuously and uncontrollably. The result is diffuse stimulation of the entire gland, leading to increased synthesis and release of T3 and T4. Circulating levels of these hormones rise, and TSH is suppressed.
Importantly, TRAb also bind to TSH receptors in extra-thyroidal tissues, particularly:
- Orbital fibroblasts, leading to Graves’ orbitopathy (exophthalmos, lid retraction, periorbital oedema)
- Dermal fibroblasts, causing pretibial myxoedema
These manifestations are not due to excess thyroid hormone, but to autoimmune inflammation driven by antibody cross-reactivity
Clinical presentation
Patients typically present with classic hyperthyroid symptoms — weight loss, heat intolerance, palpitations, anxiety — along with diffuse goitre and eye signs. Lid lag, proptosis, and gritty eye discomfort are common. In severe cases, diplopia or optic nerve compression may occur.
Women may report menstrual irregularities or reduced fertility. In some cases, dermopathy (pretibial myxoedema) is visible as waxy, indurated plaques over the shins.
Investigations
- Thyroid function tests show elevated T3 and/or T4 with suppressed TSH
- Thyroid autoantibodies: TRAb or TSI are positive and diagnostic
- Radionuclide thyroid scan shows diffuse increased uptake — the entire gland is overactive
- Orbital imaging (CT or MRI) may be used if eye signs are severe or progressive
π¬ Toxic Multinodular Goitre (TMNG)
Toxic multinodular goitre is a common cause of hyperthyroidism in older adults, especially in iodine-deficient regions or those with longstanding goitre. It arises when multiple nodules within the thyroid acquire autonomy and begin producing hormone independently of TSH regulation. Again we will discuss in detail in the next post.
What happens?
Over time, chronic TSH stimulation (often due to iodine deficiency) promotes nodule formation. Some of these nodules develop somatic mutations in the TSH receptor or downstream signalling pathways (e.g. Gs-alpha), similar to toxic adenoma — but here, it occurs in multiple foci.
Each autonomous nodule activates the cAMP pathway without TSH, leading to patchy overproduction of T3 and T4. Circulating hormone levels rise, and TSH is suppressed. The remaining thyroid tissue becomes inactive due to negative feedback.
Unlike Graves’, this is not an autoimmune process. There are no antibodies, and the gland is structurally abnormal rather than diffusely hyperplastic
Clinical presentation
Symptoms of thyrotoxicosis may be subtle or gradual, especially in older patients. Atrial fibrillation and weight loss may be the first signs. On examination, the goitre is nodular, often asymmetrical, and may be longstanding. There are no eye signs.
Investigations
- Thyroid function tests show elevated T3/T4 with suppressed TSH
- Thyroid autoantibodies are absent
- Radionuclide thyroid scan shows patchy uptake: hot nodules interspersed with cold areas
- Ultrasound may reveal heterogeneous echotexture and multiple nodules
π¬ Toxic Adenoma
A toxic adenoma is a solitary, autonomously functioning thyroid nodule that produces thyroid hormone without input from the pituitary. It’s most often seen in younger adults and is caused by a somatic mutation in the nodule itself.
What happens?
Normally, thyroid follicular cells respond to TSH by activating intracellular signalling pathways - primarily the cAMP pathway via the TSH receptor. In a toxic adenoma, a gain-of-function mutation in the TSH receptor or downstream signalling components (such as Gs-alpha protein) allows the nodule to activate this pathway without TSH. The result is constitutive activation of thyroid hormone synthesis and secretion, independent of physiological regulation.
Because the rest of the thyroid gland is exposed to high circulating T3 and T4, TSH is suppressed via negative feedback. This leads to functional suppression of the surrounding thyroid tissue, which becomes inactive on imaging.
Clinical presentation
Patients typically present with signs of thyrotoxicosis — weight loss, heat intolerance, palpitations — but without eye signs or diffuse goitre. On examination, a palpable nodule may be present, and symptoms are often milder than in Graves’ disease.
Investigations
- Thyroid function tests show elevated T3 and/or T4 with suppressed TSH.
- Thyroid autoantibodies are absent.
- Radionuclide thyroid scan shows focal increased uptake in the autonomous nodule, with suppressed uptake in the rest of the gland.
3. Leakage of Stored Hormone
The thyroid isn’t overproducing — it’s leaking preformed hormone due to inflammation or damage.
π₯ Thyroiditis
Thyroiditis refers to inflammation of the thyroid gland that leads to the release of preformed thyroid hormone into the circulation. Unlike other causes of hyperthyroidism, the gland is not overproducing hormone, it’s leaking it. This distinction is crucial for diagnosis and management.
What happens?
Thyroid follicles store large amounts of T3 and T4 bound to thyroglobulin within the colloid. In thyroiditis, inflammatory damage disrupts follicular integrity, allowing stored hormone to spill into the bloodstream. Because this hormone was already synthesised, there is no new production — and no stimulation of the synthetic machinery.
As circulating T3 and T4 rise, TSH is suppressed via negative feedback. However, because the gland is not actively producing hormone, radionuclide uptake is low. Once the stored hormone is depleted, patients often enter a hypothyroid phase, as the damaged gland struggles to resume normal function.
There are several subtypes:
- Subacute (de Quervain’s) thyroiditis: Often viral, typically painful, with elevated inflammatory markers.
- Postpartum thyroiditis: Occurs within 12 months of delivery, usually painless.
- Drug-induced thyroiditis: Commonly triggered by amiodarone or immune checkpoint inhibitors.
Clinical presentation
Patients may present with transient thyrotoxic symptoms — anxiety, palpitations, heat intolerance — but without goitre, eye signs, or nodules. In subacute thyroiditis, the gland is often tender to palpation. Symptoms typically resolve over weeks, but some patients progress to hypothyroidism before recovery.
Investigations
- Thyroid function tests show elevated T3/T4 with suppressed TSH during the thyrotoxic phase.
- Inflammatory markers (ESR, CRP) are often elevated, especially in subacute thyroiditis.
- Thyroid autoantibodies may be present in postpartum or autoimmune thyroiditis.
- Radionuclide thyroid scan shows low uptake, confirming that the gland is not actively producing hormone.
4. Exogenous Intake of Thyroid Hormone
This occurs when a person takes excess thyroid hormone — either accidentally (e.g. overtreatment of hypothyroidism) or deliberately (e.g. for weight loss or in factitious disorder).
π Iatrogenic or Factitious Thyrotoxicosis
What happens?
Exogenous thyroxine bypasses the HPT axis entirely. Circulating T4 (and sometimes T3) rises, leading to suppression of TSH. The thyroid gland itself becomes inactive due to lack of stimulation.
Clinical presentation
Symptoms mirror other forms of thyrotoxicosis — weight loss, anxiety, tremor — but there is no goitre, no eye signs, and often no palpable thyroid abnormality. In factitious cases, patients may deny taking medication, making diagnosis challenging.
Investigations
- TFTs show elevated T4 (and/or T3) with suppressed TSH
- Thyroid autoantibodies are absent
- Radionuclide thyroid scan shows low uptake, confirming that the gland is not producing hormone
- Serum thyroglobulin may be low in factitious cases (since exogenous hormone doesn’t contain it)
π§ Iodine-Induced Hyperthyroidism
Known as the Jod-Basedow phenomenon, this occurs when excess iodine triggers hormone overproduction in a susceptible thyroid — usually one with autonomous nodules.
What happens?
Iodine is a substrate for thyroid hormone synthesis. In normal physiology, excess iodine suppresses hormone production (Wolff-Chaikoff effect). But in autonomous tissue, this suppression fails — and iodine acts as fuel, driving increased hormone synthesis.
Clinical presentation
Often subtle, especially in older adults. May occur after exposure to:
- Amiodarone (a highly iodinated antiarrhythmic)
- Iodinated contrast media
- Dietary supplements
Investigations
- TFTs show elevated T3/T4 with suppressed TSH
- Thyroid scan may show patchy uptake if nodules are present
- History of iodine exposure is key to diagnosis
π©Ί Principles of Hyperthyroidism Management
1. Control the Symptoms First
Thyroid hormone excess overstimulates multiple systems — especially the cardiovascular and nervous systems. Symptom control is often urgent, even before the cause is confirmed.
Why do symptoms occur?
T3 increases the number and sensitivity of Ξ²-adrenergic receptors. This means the body reacts as if it’s flooded with adrenaline — even when catecholamine levels are normal. The result? Palpitations, tremor, anxiety, heat intolerance, and insomnia.
Key strategy: Ξ²-blockers
- Ξ²-blockers (e.g. propranolol) are first line - they reduce heart rate, tremor, anxiety, and improve sleep.
- Bonus effect: Propranolol also slightly inhibits peripheral conversion of T4 to T3.
Other symptomatic supports:
- Hydration and nutrition — to counter weight loss and catabolism
- Calcium and bone protection — in prolonged or severe cases
- Addressing atrial fibrillation — rate control, anticoagulation if indicated
2. Remove or Suppress the Source of Excess Hormone
- Treat the tumour — usually surgical resection
- May require adjunct medical therapy or radiotherapy
- Antithyroid drugs (carbimazole, PTU) block thyroid peroxidase, reducing hormone synthesis
- Radioactive iodine ablates overactive tissue
- Surgery removes the gland or nodules
- No role for antithyroid drugs — the gland isn’t producing, it’s leaking
- Management is supportive: Ξ²-blockers, NSAIDs, monitoring
- Stop the source — adjust dose, cease supplements, address factitious behaviour
- Educate and monitor for rebound hypothyroidism
3. Monitor and Support Recovery
- Regular TFTs — to track response and detect hypothyroidism
- Patient education — about symptoms, medication adherence, and long-term risks
- Specialist referral — for eye disease, pregnancy, or complex cases
- Thyroxine replacement if hypothyroidism develops after definitive treatment
Clinical cases
Explanation
This is subacute (de Quervain’s) thyroiditis, triggered by viral inflammation. Follicular damage causes leakage of stored hormone, not increased synthesis. The gland is not being stimulated — it’s spilling what it already made. That’s why TSH is suppressed, but uptake is low.
The elevated ESR supports an inflammatory process. Symptoms are transient, and many patients progress to a hypothyroid phase before recovery. Antithyroid drugs are ineffective here — management is supportive
In closing
We’ve now built a framework for understanding hyperthyroidism: what excess thyroid hormone does, how it arises, and how to manage it. In the next post, we’ll take a closer look at three of the most common causes of hyperthyroidism - Graves’ disease, toxic multinodular goitre, and thyroiditis -exploring their pathophysiology, clinical features, and diagnostic reasoning in detail. By comparing these mechanisms side by side, we’ll strengthen your ability to interpret thyroid function tests, recognise patterns, and think clinically from first principles.
No comments:
Post a Comment