🔍 Common Causes of Hyperthyroidism: Graves’ Disease, Toxic Multinodular Goitre, and Thyroiditis

 In the last post, we explored what happens when thyroid hormone levels are too high — and how to reason through the possible causes using the HPT axis. Now, we turn our focus to the three most common conditions that medical students are likely to encounter in practice: Graves’ disease, toxic multinodular goitre (TMNG), and thyroiditis.

These conditions may all present with elevated T3 and T4, but they arise from fundamentally different mechanisms (autoimmune stimulation, nodular autonomy, and inflammatory leakage) and require very different approaches to diagnosis and management.

In this post, we’ll walk through each condition in detail, exploring the pathophysiology, clinical features, investigations, and reasoning that help distinguish them. By the end, you’ll be able to interpret thyroid function tests, understand scan results in context, and explain to patients why their thyroid is misbehaving !

Let’s begin with Graves’ disease.

🔬 Graves’ Disease

Graves’ disease is the most common cause of hyperthyroidism in younger adults, especially women. It’s an autoimmune condition — but unlike many autoimmune diseases that destroy tissue, Graves’ stimulates it. The immune system produces antibodies that mimic TSH, leading to continuous activation of the thyroid gland and systemic thyrotoxicosis.

But how does this happen? Why would the immune system attack the thyroid in the first place?

🧠 How Autoimmunity Develops

In a healthy immune system, T regulatory cells (Tregs) play a crucial role in maintaining tolerance. They suppress autoreactive T cells (the ones that mistakenly target the body’s own tissues ) and prevent them from launching an immune response.

In Graves’ disease, this regulation breaks down.

• Treg dysfunction means autoreactive T cells escape suppression.
• These T cells activate B cells, which then produce autoantibodies — in this case, antibodies that target the TSH receptor on thyroid follicular cells.
• The result is chronic stimulation of the thyroid gland, independent of pituitary control.

This process is influenced by:

• Genetic susceptibility (e.g. HLA-DR3, CTLA-4 variants)
• Environmental triggers (e.g. stress, infection, smoking)
• Hormonal factors — Graves’ is more common in women, suggesting a role for oestrogen in immune modulation

🔬 The Antibodies Involved

The key antibody in Graves’ disease is the thyroid-stimulating immunoglobulin (TSI) — a type of TSH receptor antibody (TRAb). But it’s not the only one.

Other antibodies may be present:

• Thyroid peroxidase antibodies (TPOAb) — more common in Hashimoto’s, but sometimes seen in Graves’
• Thyroglobulin antibodies (TgAb) — also associated with autoimmune thyroid disease
• Blocking or neutral TRAb — rare, but can interfere with TSH binding without stimulating the receptor

Personally, I find this image really helpful to think about the overlap in antibodies in thyroid disease (we will come back to it when we are discussing Hashimoto's thyroiditis). I have drawn this on whiteboards for many cohorts of medical students ! It helps to make it make sense. 

Only stimulating TRAb cause hyperthyroidism — by mimicking TSH and activating the cAMP pathway inside follicular cells. This drives increased iodide uptake, thyroglobulin synthesis, and thyroid hormone production.

🧬 Autoimmune Overlap: Graves Isn’t Always Alone

Graves’ disease is part of a broader family of autoimmune conditions — and patients often have more than one.

Why does this happen?
Autoimmune diseases share common genetic and immunological pathways. If the immune system loses tolerance in one tissue, it’s more likely to misfire elsewhere. Think of it as a breakdown in immune regulation, not just a thyroid-specific problem.

Common associations include:

• Type 1 diabetes
• Coeliac disease
• Pernicious anaemia (B12 deficiency from gastric parietal cell antibodies)
• Vitiligo
• Addison’s disease
• Autoimmune hepatitis or primary biliary cholangitis

💡 Clinical tip:
If a patient with Graves’ has unexplained fatigue, gastrointestinal symptoms, or pigmentation changes — think about autoimmune overlap. A simple screen (B12, glucose, anti-TTG) can reveal important comorbidities.

🩺 Clinical Presentation: What You’ll See and Why

Graves’ disease doesn’t just cause “thyroid symptoms” — it creates a recognisable clinical picture that reflects the systemic effects of excess hormone and the autoimmune process driving it.

Here’s how it typically presents:

General symptoms

• Weight loss despite normal or increased appetite → Due to increased basal metabolic rate and catabolism of fat and muscle
•  Heat intolerance and excessive sweating → From increased mitochondrial activity and uncoupled oxidative phosphorylation
• Palpitations and tachycardia → T3 upregulates β-adrenergic receptors, making the heart more sensitive to adrenaline
• Anxiety, restlessness, and insomnia → Heightened adrenergic tone and increased synaptic activity
• Frequent bowel movements → Increased gut motility from smooth muscle stimulation
• Menstrual irregularities or reduced fertility → Thyroid hormone interferes with the hypothalamic-pituitary-gonadal axis

On examination

•  Fine tremor and brisk reflexes → Reflect increased neuromuscular excitability
• Diffuse goitre → Smooth, symmetrical enlargement from antibody-driven stimulation
• Eye signs (Graves’ orbitopathy) → Lid lag, proptosis, gritty discomfort, periorbital swelling → Caused by TRAb-mediated inflammation of orbital fibroblasts
• Pretibial myxedema (less common) → Waxy, indurated plaques over the shins from dermal fibroblast activation

Red flags

• Diplopia or vision changes → Suggest extraocular muscle involvement or optic nerve compression
• Atrial fibrillation → May be the first sign in older patient

This constellation of findings — systemic thyrotoxicosis, diffuse goitre, and eye signs — is highly suggestive of Graves’ disease. It’s the only common cause of hyperthyroidism with autoimmune stimulation and extra-thyroidal manifestations.

👁 Why Are the Eyes Affected?

Graves’ orbitopathy (also called thyroid eye disease) is one of the most distinctive features of Graves’ — and it’s not caused by excess thyroid hormone. Instead, it’s an autoimmune reaction in the tissues behind the eyes.

Underlying mechanism:

• Orbital fibroblasts express the TSH receptor — just like thyroid cells.
• TRAb (TSH receptor antibodies) bind to these receptors, triggering inflammation.
• Cytokines and growth factors are released, leading to:
• Fibroblast proliferation
• Glycosaminoglycan (GAG) accumulation → fluid retention and swelling
• Adipogenesis → expansion of orbital fat
• Extraocular muscle enlargement

This leads to:

• Proptosis (bulging eyes)
• Lid retraction
• Periorbital oedema
• Diplopia (double vision)
• Optic nerve compression in severe cases

💡 Clinical insight:
Smoking markedly worsens orbitopathy — likely through increased oxidative stress and impaired immune regulation. Every patient with Graves’ disease should be strongly counselled to stop smoking.

🧪 Investigations 

Thyroid function tests:

• TSH: suppressed
• Free T4 and/or T3: elevated

Thyroid autoantibodies:

•  TRAb or TSI: positive and diagnostic

Radionuclide thyroid scan:

•  Diffuse increased uptake — the entire gland is overactive

Orbital imaging (CT or MRI):

• May be used if eye signs are severe or progressive

🩺 Management of Graves’ Disease: 

Graves’ disease causes hyperthyroidism by stimulating the thyroid gland, not by damaging it. So management has two goals:

1.           Control the symptoms of hormone excess

2.           Remove or suppress the source of stimulation

 

1. Symptom Control

Thyroid hormone overstimulates the heart and nervous system. Even before the diagnosis is confirmed, patients often need relief from symptoms.

 β-blockers (e.g. propranolol)

→ Reduce heart rate, tremor, anxiety, and improve sleep

→ Also slightly inhibit conversion of T4 to T3

Supportive care

→ Hydration, nutrition, and rest

→ Address atrial fibrillation if present

 
2. Disease-Specific Treatment

Graves’ is driven by TSH receptor antibodies. The thyroid is being told to produce hormone — so we need to either block that signal, destroy the tissue, or remove it.

There are three main options:

Antithyroid drugs (e.g. carbimazole, propylthiouracil)

→ Block thyroid peroxidase, reducing hormone synthesis

→ Used short-term or long-term depending on response

→ May induce remission in some patients

💊 How Do Antithyroid Drugs Work?

Antithyroid drugs don’t destroy the thyroid — they block its ability to make hormone. They’re especially useful in Graves’ disease, where the gland is being overstimulated by antibodies.

The key target?
The enzyme thyroid peroxidase (TPO), which catalyses three critical steps in thyroid hormone synthesis:

1. Oxidation of iodide to iodine
2. Iodination of tyrosine residues on thyroglobulin
3. Coupling of iodotyrosines to form T3 and T4

How do the drugs work?

• Carbimazole (converted to methimazole) and propylthiouracil (PTU) inhibit TPO.
• This prevents new hormone synthesis but doesn’t affect stored hormone already in the gland.
• PTU also inhibits peripheral conversion of T4 to T3, making it useful in thyroid storm.

💡 Clinical tip:
Because stored hormone still exists, it may take weeks for symptoms to improve. That’s why β-blockers are used alongside antithyroid drugs for immediate symptom control.

Side effects to watch for:

• Agranulocytosis (rare but serious) — sudden fever or sore throat warrants urgent full blood count.
• Rash, liver dysfunction, and gastrointestinal upset are more common.

Radioactive iodine therapy

→ Destroys overactive thyroid tissue

→ Often leads to hypothyroidism, requiring thyroxine replacement

→ Contraindicated in pregnancy and orbitopathy

☢️ How Does Radioactive Iodine Work?

Radioactive iodine (RAI) therapy is a targeted treatment for hyperthyroidism — a brilliant example of physiology guiding therapy.

Why iodine?
The thyroid gland is the only tissue in the body that actively concentrates iodine. It uses iodine to make T3 and T4, drawing it in through the sodium-iodide symporter on follicular cells.

How does RAI work?

• RAI uses iodine-131, a radioactive isotope.
• After oral ingestion, it’s absorbed into the bloodstream and taken up by the thyroid — just like normal iodine.
• Once inside follicular cells, iodine-131 emits beta radiation, damaging and destroying the cells from within.
• This causes selective ablation of overactive thyroid tissue, lowering hormone production.

Why is it effective?

• 🎯 Precise: only thyroid cells take it up.
• 🩺 Non-invasive: no surgery required.
• ⏳ Long-lasting: often results in permanent hypothyroidism, which is easier to manage than fluctuating hyperthyroidism.

Surgery (thyroidectomy)

→ Removes the gland entirely

→ Reserved for large goitres, severe orbitopathy, or patient preference

3. Managing the Eyes

Graves’ orbitopathy is not caused by thyroid hormone, so treating the thyroid doesn’t always fix the eyes.

• Smoking cessation is critical as smoking worsens orbitopathy
• Selenium supplementation may help mild cases
• Steroids or immunosuppressants may be needed for active inflammation
• Surgical decompression is reserved for severe or vision-threatening disease

⚠️ Radioactive Iodine and Worsening Eye Symptoms: A Physiological Puzzle

Radioactive iodine (RAI) is a common and effective treatment for Graves’ disease — but in some patients, it can worsen eye symptoms. Understanding why requires thinking physiologically.

Here’s the physiology:

• Graves’ orbitopathy is driven by autoimmune inflammation, not by excess thyroid hormone itself.
• When RAI destroys thyroid tissue, it can cause a transient release of stored antigens — including TSH receptor fragments.
• This antigen release may further stimulate the immune system, triggering a flare in orbital inflammation.
• The risk is highest in patients with active eye disease and in smokers, both of whom have heightened immune reactivity.

Clinical implications:

• Patients with moderate–severe orbitopathy may be given steroids alongside RAI to dampen immune activation.
• In some cases, surgery or antithyroid drugs may be preferred to avoid worsening eye symptoms.
• Smoking cessation is critical — it lowers the risk of orbitopathy progression and improves treatment outcomes.

💡 Clinical reasoning tip:
This illustrates how treating one part of a disease can affect another. It’s a reminder that physiology connects every system — and effective treatment depends on understanding those links.

🔬 Toxic Multinodular Goitre: 

Toxic multinodular goitre (TMNG) is a common cause of hyperthyroidism in older adults, especially in iodine-deficient regions. Unlike Graves’ disease, TMNG is not autoimmune. Instead, it’s caused by patches of thyroid tissue that become autonomous — producing hormone without waiting for TSH.

These nodules arise gradually over years, often in the context of a long-standing goitre. Eventually, one or more nodules begin to produce excess T3 and T4, leading to thyrotoxicosis.

🧠 How Autonomy Develops

In a healthy thyroid, hormone production is tightly regulated by TSH. But in TMNG, some follicular cells acquire mutations that make them independent of TSH.

• Most commonly, these are activating mutations in the TSH receptor or Gs-alpha protein, which drive the cAMP pathway without external stimulation.
• These mutated cells form autonomous nodules — areas of the gland that produce hormone continuously, regardless of pituitary input.
• Over time, multiple nodules may become active, creating a multinodular goitre with focal overproduction.

This process is influenced by:

• Ageing thyroid tissue — more prone to somatic mutations
• iodine deficiency — stimulates chronic TSH elevation, promoting nodule formation
• Environmental factors — smoking, radiation, and dietary influences may play a role

Importantly, there’s no immune attack and no antibody involvement — which helps distinguish TMNG from Graves’.

🩺 Clinical Presentation: What You’ll See and Why

TMNG tends to present more subtly than Graves’, often in older patients with vague symptoms or complications.

General symptoms:

• Weight loss, heat intolerance, and palpitations → Due to excess thyroid hormone, just like in Graves’
• Fatigue and muscle weakness → Common in older adults with chronic thyrotoxicosis
• Atrial fibrillation → May be the first sign — especially in elderly patients
• No eye signs or dermopathy → Because there’s no autoimmune inflammation

On examination:

• Irregular, nodular goitre → Lumpy, asymmetrical enlargement from multiple nodules
•  No orbitopathy → TRAb are absent, and orbital fibroblasts aren’t involved
•  Signs of thyrotoxicosis → Tremor, brisk reflexes, tachycardia — similar to Graves’

Red flags:

• Heart failure or arrhythmia → May occur in older patients with longstanding undiagnosed TMNG
• Compression symptoms → If the goitre is large, it may cause dysphagia, dyspnoea, or hoarseness

🧪 Investigations and Reasoning

 Thyroid function tests:

• TSH: suppressed
•   Free T4 and/or T3: elevated

 Thyroid autoantibodies:

•  TRAb: negative
•  TPOAb: may be present if coexisting Hashimoto’s, but not causative

Radionuclide thyroid scan:

•  Patchy uptake — multiple hot nodules with suppressed surrounding tissue

 Ultrasound:

•  Shows heterogeneous, nodular architecture
• May guide fine-needle aspiration if malignancy is suspected

🩺 Management of TMNG: Targeting the Nodules

TMNG is caused by autonomous nodules, not immune stimulation — so the treatment targets the overactive tissue directly.

1.           Symptom Control

•             β-blockers (e.g. propranolol) 

→ Reduce adrenergic symptoms while definitive treatment is planned

•             Supportive care 

→ Especially important in older patients with cardiac complications

2.           Definitive Treatment

•             Radioactive iodine therapy

→ Preferred in many cases — selectively ablates overactive nodules

→ Less effective if the goitre is large or compressive

•             Surgery (subtotal or total thyroidectomy)

→ Indicated for large goitres, compressive symptoms, or cosmetic concerns

→ Also preferred if malignancy is suspected

3.           Antithyroid drugs

•  May be used short-term to stabilise hormone levels
• Not curative — nodules remain autonomous
• Long-term use is less common than in Graves’

🔬 Thyroiditis: 

Thyroiditis refers to a category of conditions involving inflammation of the thyroid gland, and it can cause hyperthyroidism — but not by stimulating hormone production. Instead, it causes leakage of preformed hormone from damaged follicular cells. The gland isn’t overactive — it’s injured.

This distinction matters. In thyroiditis

, the thyrotoxic phase is transient, and often followed by hypothyroidism before the gland recovers.

🧠 How Thyroiditis Develops

The thyroid stores large amounts of T3 and T4 inside follicles, bound to thyroglobulin. When inflammation disrupts these follicles, hormone spills into the bloodstream — not because the gland is overactive, but because it’s injured.

There’s no increased synthesis. No stimulation. Just passive release of preformed hormone.

This explains why:

• TSH is suppressed (due to high circulating T3/T4)
• TPOAb may be positive, but TRAb is negative
• Radionuclide uptake is low — the gland isn’t making new hormone

 Common types include:

🦠 Subacute (de Quervain’s) Thyroiditis

This type usually follows a viral infection - often a cold or flu or even COVID. The immune system responds to the virus, but in the process, it accidentally damages thyroid tissue. The result is granulomatous inflammation, which you can think of as clumps of immune cells forming inside the gland.

Because the inflammation is active and destructive, the thyroid becomes painful and tender. Patients often feel unwell, with fever, fatigue, and neck discomfort. Blood tests show a high ESR or CRP, and thyroid function tests reveal a classic pattern: suppressed TSH, elevated T4/T3, and low uptake on scan.

This is the only common cause of hyperthyroidism that presents with pain, and that’s your diagnostic clue.

🤱 Silent (Painless) Thyroiditis

This form is often autoimmune, but unlike Graves’, it doesn’t stimulate the gland, it damages it. The inflammation is milder and doesn’t cause pain, so patients may not realise anything is wrong until they develop symptoms of hormone imbalance.

It’s especially common after pregnancy, when the immune system rebounds and becomes temporarily overactive. This is called postpartum thyroiditis, and it can look like anxiety, insomnia, or fatigue - symptoms that are easy to miss in new mothers.

TPO antibodies are often positive, and the pattern of hormone change is the same: a brief thyrotoxic phase, followed by hypothyroidism, then recovery. Some patients don’t recover fully and need long-term thyroxine.

💊 Drug-Induced Thyroiditis

Certain medications can damage the thyroid directly. The most important ones are:

• Amiodarone — contains lots of iodine and can be toxic to follicular cells
•  Interferon-α — used in hepatitis and cancer
• Lithium — used in bipolar disorder

These drugs can cause either hyperthyroidism or hypothyroidism, depending on the phase. If a patient on one of these medications develops thyroid symptoms, always check their TFTs — and consider drug-induced thyroiditis in your differential

☢️ Radiation-Induced Thyroiditis

This occurs after radioactive iodine therapy or external beam radiation to the neck. The radiation damages thyroid cells, causing them to release stored hormone. It’s usually mild and self-limiting, but can cause transient thyrotoxicosis.

This type reinforces a key principle: destroying thyroid tissue can cause hormone release before levels fall.

In all cases, the thyrotoxic phase is self-limiting, once the stored hormone is depleted, patients often become hypothyroid before recovering.

🩺 Clinical Presentation: What You’ll See and Why

Thyroiditis can look like hyperthyroidism at first glance - but the underlying mechanism is completely different. Instead of the gland being overstimulated, it’s leaking stored hormone due to inflammation or injury. That changes everything about how the condition behaves, and how it presents.

Here’s how to reason through it:

Early phase: Thyrotoxicosis from leakage

Patients may feel anxious, sweaty, and restless — just like in Graves’ or TMNG. They may have palpitations, tremor, and heat intolerance. But unlike those conditions, the thyroid isn’t working harder — it’s spilling hormone it already made.

The key clue is context:

•  In subacute thyroiditis, patients often report a recent viral illness, followed by neck pain and fatigue. The thyroid is tender to touch, and they may feel generally unwell.
• In silent or postpartum thyroiditis, there’s no pain — just subtle symptoms like insomnia, anxiety, or mood changes. These are easy to miss, especially in new mothers.
• In drug-induced thyroiditis, symptoms may appear gradually, often in patients on amiodarone, lithium, or interferon.

Later phase: Hypothyroidism

Once the stored hormone runs out, the gland may not recover immediately. Patients can swing into hypothyroidism — with fatigue, weight gain, constipation, and low mood. This phase may last weeks to months, and some patients need thyroxine replacement.

What’s missing?

There’s no goitre, no eye signs, and no dermopathy. The thyroid may be slightly enlarged, but it’s not diffusely stimulated like in Graves’, or nodular like in TMNG. That absence of structural change is a clue.

🧪 Investigations: How to Think Through the Results

Thyroiditis follows a biphasic pattern — first hyperthyroid, then hypothyroid. Your investigations need to reflect that timeline.

Thyroid function tests

•  TSH: suppressed during the thyrotoxic phase, then rises as hormone levels fall
• Free T4 and T3: elevated early, then drop below normal
•  This pattern helps distinguish thyroiditis from conditions with persistent stimulation

Autoantibodies

• TRAb: negative — this rules out Graves’
•  TPOAb: may be positive in autoimmune thyroiditis, especially postpartum or silent types
• A positive TPOAb suggests a higher risk of long-term hypothyroidism

Inflammatory markers

•  ESR and CRP: often elevated in subacute thyroiditis
• These support the diagnosis of active inflammation, especially when pain is present

Radionuclide thyroid scan

• Shows low uptake — because the gland isn’t making new hormone
•  This is the key test to distinguish thyroiditis from Graves’ or TMNG, which show high uptake

Ultrasound

•  May show hypoechoic areas or reduced vascularity
•  Useful for confirming inflammation or ruling out nodules

🩺 Management of Thyroiditis: 

Thyroiditis causes hyperthyroidism — but not because the gland is working harder. It’s leaking. That means the usual treatments for Graves’ or TMNG, which aim to suppress hormone production, won’t work here. There’s no overproduction to suppress.

Instead, management focuses on:

1. Relieving symptoms during the thyrotoxic phase
2. Reducing inflammation if present
3. Monitoring for hypothyroidism and supporting recovery

 

1. Symptom Relief

During the thyrotoxic phase, patients may feel anxious, sweaty, and tachycardic. Even though the hormone excess is temporary, it can be distressing.

•             β-blockers (e.g. propranolol)

→ Reduce heart rate, tremor, and adrenergic symptoms

→ Often used for a few weeks until hormone levels settle

Importantly: antithyroid drugs are not used. They block hormone synthesis, but in thyroiditis, the gland isn’t making new hormone - it’s releasing what’s already stored.

 

2. Reducing Inflammation

This applies mainly to subacute thyroiditis, where the gland is actively inflamed and painful.

•             NSAIDs (e.g. ibuprofen)

→ First-line for pain and inflammation

•             Corticosteroids (e.g. prednisolone)

→ Used if NSAIDs aren’t effective or symptoms are severe

→ Help reduce immune-mediated damage and shorten the course

Silent, postpartum, and drug-induced thyroiditis usually don’t require anti-inflammatory treatment - they’re not painful, and the inflammation is less aggressive.

 

3. Monitoring and Recovery

After the thyrotoxic phase, many patients enter a period of hypothyroidism. This happens because the gland is depleted and temporarily unable to make new hormone.

•             Monitor TFTs every 4–6 weeks

→ Watch for rising TSH and falling T4/T3

•             Thyroxine replacement

→ May be needed if hypothyroidism is symptomatic or prolonged

→ Some patients recover fully, others need long-term replacement

Patients with positive TPO antibodies (especially in postpartum thyroiditis) are more likely to develop permanent hypothyroidism. These patients should be followed long-term.

Patient Education

This is one of the most important parts of management. Patients need to understand:

• That their symptoms are caused by leakage, not overstimulation
• That the condition often follows a biphasic course - hyperthyroid, then hypothyroid
• That most cases resolve spontaneously, but some require thyroxine
• That antithyroid drugs won’t help, and may even delay recovery

In closing:

Although Graves’ disease, toxic multinodular goitre, and thyroiditis all cause hyperthyroidism, they do so in fundamentally different ways, and understanding those mechanisms is the key to clinical reasoning. Graves’ is driven by autoimmune stimulation, with antibodies mimicking TSH and activating the entire gland. TMNG arises from patches of autonomy, where mutated nodules produce hormone independently of pituitary control. Thyroiditis, by contrast, reflects inflammation and injury, causing passive leakage of stored hormone without increased synthesis. These differences shape everything: the scan results, the antibody profile, the clinical presentation, and the treatment approach. When you see a patient with suppressed TSH and elevated T4/T3, don’t just name the condition, ask why the gland is misbehaving. That’s the heart of endocrine reasoning.

This chart provides an interesting decision making tree. Don't rote learn it, but can you follow its logic now? 

In the next post we will look at the pathophysiology of hypothyroidism

📚 Want to learn more?

• 🧠 All endocrine system posts →
• 🧬 The HPA axis →
• 🦋 The thyroid axis →
• 🔥 Pathophysiology of Hyperthyroidism →
• 🌡 Common Causes of Hyperthyroidism: Graves, TMNG and Thyroiditis →