🔍 Common Causes of Hypothyroidism: Hashimoto's thyroiditis

Hashimoto’s thyroiditis is the most common cause of hypothyroidism in iodine-sufficient regions — and a classic example of destructive autoimmunity. Unlike Graves’ disease, which stimulates the thyroid, Hashimoto’s gradually damages and disables it. The immune system mistakes thyroid tissue for a threat, and over time, hormone production declines.

This post will walk you through:

• How the immune system targets the thyroid
• What antibodies and histology reveal
• How to reason through the progression from normal to low hormone states
• What to look for on imaging
• How to manage the condition clinically

🔹 Hashimoto’s Thyroiditis: Understanding Autoimmune Thyroid Destruction

 Hashimoto’s thyroiditis is a slow, deliberate autoimmune attack on the thyroid gland. It doesn’t cause a sudden crisis — it erodes function over time. That’s why patients may feel “off” for months or years before overt hypothyroidism appears. To understand Hashimoto’s, you need to reason through three layers:

1.           What the immune system is targeting

2.           How the thyroid tries to compensate

3.           Why hormone levels eventually fall

🧬 Regulatory T Cells and HLA — The Gatekeepers of Immune Tolerance

The immune system isn’t only about attack — it’s also about restraint. Regulatory T cells (Tregs) are the peacekeepers: they suppress autoreactive T cells, prevent excessive inflammation, and maintain tolerance to self-antigens. In autoimmune thyroid disease, this restraint fails.

🧠 What Tregs Normally Do

• Inhibit activation of autoreactive T cells
• Secrete anti-inflammatory cytokines (IL-10, TGF-β)
• Maintain immune balance in peripheral tissues

In Hashimoto’s thyroiditis:

• Tregs are reduced or dysfunctional
• Autoreactive T cells escape suppression
• Chronic inflammation and tissue destruction follow

💡 Autoimmunity isn’t just about attack — it’s about the failure to suppress inappropriate responses. Tregs are the brakes; without them, the immune system accelerates into self-destruction.

🧬 HLA Associations: Genetic Keys to Autoimmunity

Human leukocyte antigens (HLA) help the immune system present antigens to T cells. Certain HLA types make it easier for the body to present self-antigens in a way that triggers autoimmunity.

• Hashimoto’s thyroiditis: HLA-DR3, DR5
• Graves’ disease: HLA-DR3
• Type 1 diabetes: HLA-DR3, DR4
• Coeliac disease: HLA-DQ2, DQ8

💡 Key concept: HLA types don’t cause disease directly — they shape how antigens are presented. Think of them as the lens through which the immune system sees the world: some lenses make self look like danger.

🧬 What’s Being Attacked — and Why?

The thyroid gland is normally ignored by the immune system. But in Hashimoto’s, immune tolerance breaks down. The body begins to treat thyroid proteins as foreign — particularly:

• Thyroid peroxidase (TPO): an enzyme that helps iodinate tyrosine residues on thyroglobulin
• Thyroglobulin (Tg): the protein scaffold for T3 and T4 synthesis

Remember this image from our post about Graves' disease?

B cells produce autoantibodies against these proteins, and T cells infiltrate the gland. But this isn’t just a passive antibody response — it’s a cell-mediated attack. CD8+ cytotoxic T cells induce apoptosis in follicular cells. CD4+ helper T cells recruit more immune cells. Over time, the gland becomes inflamed, fibrotic, and functionally impaired.

This is primary hypothyroidism with a clear autoimmune cause.

💡Autoantibodies are markers — but the real damage comes from T-cell infiltration and follicular destruction. That’s why antibody titres don’t always correlate with severity.

🧠 Immune Tolerance — Why the Body Turns on Itself

The immune system is trained to distinguish self from non-self. This training occurs in two key stages that keep autoreactive cells in check:

• Central tolerance: In the thymus and bone marrow, autoreactive T and B cells are deleted.
• Peripheral tolerance: In the body, regulatory T cells suppress rogue immune responses that escape central control.

In autoimmune disease, this system fails. Autoreactive cells survive deletion, regulatory mechanisms falter, and the immune system begins attacking its own tissues.

🔬 In Hashimoto’s Thyroiditis

• T cells target thyroid follicular cells.
• B cells produce antibodies against TPO and thyroglobulin (Tg).
• The result is destructive autoimmunity.

🔬 In Graves’ Disease

• B cells produce antibodies that stimulate the TSH receptor.
• The result is stimulating autoimmunity and hormone excess.

💡  Autoimmune diseases reflect a failure of tolerance — but the outcome depends on what’s targeted and how. Hashimoto’s destroys. Graves’ overstimulates. Both begin with the same immunological mistake.

🧠 How the Thyroid Responds — Until It Can’t

Early in the disease, the thyroid tries to keep up. TSH rises, pushing the gland to produce more hormone. This compensatory phase can last for years — patients may be euthyroid despite high antibody levels and subtle symptoms.

Eventually:

• Follicular cells are lost
•  Hormone synthesis declines
• TSH rises further
• The gland enlarges (goitre) but becomes less functional

This is the transition from subclinical to overt hypothyroidism.

💡Hashimoto’s is a progressive failure. Always ask: Is the gland still compensating? That’s the difference between a patient with normal T4 and one who needs replacement.

🔬 What You See Under the Microscope 

Histology reveals the immune architecture of the disease:

• Lymphocytic infiltration: T and B cells crowd the interstitium
•  Germinal centres: B cell activation sites form within the gland
• Hurthle cells: follicular cells adapt by increasing mitochondria, appearing eosinophilic
• Follicular dropout: hormone-producing units are lost

This isn’t just inflammation - it’s organ-specific autoimmunity, with structural and functional consequences.

💡Hurthle cells aren’t malignant, they’re a sign the gland is trying to adapt. Their presence reflects chronic stimulation and cellular stress.

⚔️ Hashimoto’s vs Graves’: Opposite Ends of Autoimmune Thyroid Disease

Both Hashimoto’s and Graves’ disease are autoimmune thyroid disorders — but they behave in opposite ways. One stimulates the gland, the other destroys it. Understanding this contrast helps interpret hormone levels, symptoms, and imaging findings.

🔬 What the Immune System Is Doing

• Graves’ disease: TRAb antibodies mimic TSH and overstimulate the receptor → the gland is overactive but not inflamed; follicular cells are intact and hyperfunctioning.
• Hashimoto’s thyroiditis: TPO and Tg antibodies mark the gland for destruction; T-cell infiltration causes apoptosis and fibrosis → the gland is inflamed and failing.

📈 Hormone Levels and Feedback

• Graves’ disease:
  ↑ T4 and T3 | ↓ TSH (negative feedback)
  → Symptoms: weight loss, tachycardia, tremor
• Hashimoto’s thyroiditis:
  Initially normal T4/T3 → later ↓ T4/T3 with ↑ TSH
  → Symptoms: fatigue, weight gain, cold intolerance

💡 In Graves’, the pituitary tries to slow the thyroid. In Hashimoto’s, it tries to speed it up — but the gland can’t respond.

🖥️ Imaging and Histology

• Graves’ disease: Ultrasound → increased vascularity (“thyroid inferno”); histology → hyperplastic follicles, minimal inflammation.
• Hashimoto’s thyroiditis: Ultrasound → heterogeneous, hypoechoic gland; histology → lymphocytic infiltration, germinal centres, Hurthle cells.

💡 Graves’ looks busy and well-perfused. Hashimoto’s looks patchy and inflamed.

📉 Clinical Progression: From Compensation to Collapse

Hashimoto’s thyroiditis doesn’t cause sudden failure. It’s a slow erosion of function and the body tries to compensate every step of the way. That’s why patients may feel “off” long before their blood tests show overt hypothyroidism. To reason through this, students need to understand how the HPT axis responds to gradual gland failure.

 🧪 Phase 1: Euthyroid with Autoantibodies

• The thyroid gland is still functioning
• TPO and Tg antibodies are present, but hormone levels are normal
• TSH may be slightly elevated — the pituitary is nudging the gland to work harder
• Patients may feel well, or have subtle symptoms (fatigue, mood changes)

💡This phase reflects immune activity without overt hormone failure. The gland is under attack, but still compensating. Antibodies are a clue — not a diagnosis.

📈 Phase 2: Subclinical Hypothyroidism

• TSH is elevated
• Free T4 is still within the reference range
• The gland is struggling, but not yet failing
• Symptoms may begin: fatigue, weight gain, cold intolerance

Why is TSH high?

Because the pituitary senses falling T4 , even if it’s still “normal” , and increases TSH to maintain output. This is a classic example of compensatory feedback.

💡Subclinical doesn’t mean asymptomatic. Always ask: Is the patient feeling the strain before the numbers show it?

 📉 Phase 3: Overt Hypothyroidism

•  TSH is high
• Free T4 is low
• The gland can no longer respond
•  Symptoms are more pronounced: bradycardia, constipation, depression, dry skin

Why does this happen?

Because follicular cells have been destroyed. The pituitary keeps shouting (↑TSH), but the gland can’t answer. This is primary hypothyroidism, confirmed biochemically and clinically.

💡The transition from subclinical to overt is gradual. Monitor patients with rising TSH and positive antibodies — they’re on the path, even if they haven’t arrived yet.

🔗 Autoimmune Overlap: Why Hashimoto’s Rarely Stands Alone

Hashimoto’s thyroiditis isn’t just a thyroid problem — it’s part of a broader pattern of immune dysregulation. Many patients with Hashimoto’s have other autoimmune conditions, and that’s not a coincidence. The immune system doesn’t always target one organ in isolation — it follows patterns shaped by genetics, environment, and immune signalling.

🧬 Shared Mechanisms

• Genetic predisposition: HLA-DR variants, CTLA-4 polymorphisms
• Loss of immune tolerance: T cells fail to distinguish self from non-self
• Cytokine profiles: Th1 and Th17 dominance promote organ-specific autoimmunity
• Environmental triggers: infections, stress, pregnancy, medications

💡 Key idea: If the immune system has broken tolerance once, it may do so again — in a different tissue, at a different time.

🧠 Common Coexisting Conditions

• Type 1 diabetes: autoimmune destruction of pancreatic β-cells → screen for thyroid disease in diabetic patients
• Coeliac disease: autoimmune reaction to gluten damaging the small intestine → malabsorption may alter thyroxine dosing
• Pernicious anaemia: autoimmune gastritis → B12 deficiency with fatigue and neurological symptoms
• Vitiligo: autoimmune loss of melanocytes → often coexists with thyroid autoimmunity
• Addison’s disease: autoimmune adrenal failure → seen in polyglandular autoimmune syndromes

💡Always think systemically. If a patient has one autoimmune condition, ask: Could there be another? Symptoms such as fatigue, anaemia, or weight loss may reflect overlapping pathology.

🩺 Signs and Symptoms: 

Hashimoto’s thyroiditis unfolds slowly — and so do its symptoms. Patients often describe feeling “off” long before blood tests confirm overt hypothyroidism. Symptoms reflect declining hormone action, not just lab values.

🧠 Common Early Symptoms (Euthyroid or Subclinical Phase)

• Fatigue and low energy
• Mild weight gain despite unchanged diet
• Cold intolerance
• Constipation
• Dry skin
• Low mood or emotional flatness
• Irregular or heavy periods
• Brain fog or slowed thinking
• Puffy face or periorbital swelling

💡 These symptoms may appear before T4 drops - they reflect the body’s struggle to maintain normal function.

📉 Later Symptoms (Overt Hypothyroidism)

• Bradycardia
• Hoarseness
• Depression
• Menorrhagia or amenorrhoea
• Slow reflexes
• Coarse hair, brittle nails
• Goitre (diffuse, firm, non-tender)
• Weight gain, even with reduced appetite

💡 Always ask: Is the patient symptomatic despite “normal” labs? 

A patient before and after treatment with thyroxine replacement. Note the "hypothyroid facies" - dry coarse skin, puffy eyes, apathetic look, ptosis. Patients can also note hair thinning and thinning in the lateral third of their eyebrows.

🦵 Pretibial Myxoedema — Not Just Graves’

Pretibial myxoedema is a form of localised dermopathy — thickened, waxy, non-pitting skin over the shins, often with a peau d’orange texture. It’s caused by TSH receptor antibody stimulation of fibroblasts, leading to mucopolysaccharide deposition.

🧠 Key point:

While pretibial myxoedema is most common in Graves’ disease, it can also occur in Hashimoto’s thyroiditis — particularly in patients who have TSHR antibodies. These antibodies may be present in a subset of Hashimoto’s patients, even without overt hyperthyroidism.

💡 Why does this happen?

TSHR antibodies can stimulate fibroblasts in the skin and orbit, regardless of thyroid function. It’s the presence and activity of the antibody — not the hormone level — that drives the dermopathy.

✅ Graves’ disease:

• Pretibial myxoedema common
• Orbitopathy common
• TSHR-Ab positive

🟡 Hashimoto’s thyroiditis:

• Pretibial myxoedema rare but possible
• Orbitopathy very rare but possible
• TSHR-Ab may be present in a subset of patients

❌ Other causes of hypothyroidism: (iodine deficiency, post-surgical, post-radioiodine)

• No pretibial myxoedema
• No TSHR-Ab

💡 Clinical reasoning tip: Remember the image from the Graves’ disease post (also above) showing the autoimmune thyroid spectrum. TSHR antibodies sit at the interface — linking Graves’ and Hashimoto’s in a shared immunological continuum.

🔍 Investigating Hashimoto’s: 

Hashimoto’s thyroiditis is diagnosed through a combination of clinical suspicion, biochemical testing, and autoimmune markers. But investigations aren’t just about confirming a label — they help you understand where the patient sits on the trajectory from compensation to collapse.

🧪 Core Tests in Hashimoto’s Thyroiditis

TSH

• What it tells you: Pituitary response to circulating T4
• How to interpret: Elevated = gland is struggling; normal = may still be compensating

Free T4

• What it tells you: Available thyroid hormone
• How to interpret: Low = overt hypothyroidism; normal = may still be subclinical

Free T3

• What it tells you: Active hormone (less useful in hypothyroidism)
• How to interpret: Often normal or low; not essential unless symptoms are discordant

TPO antibodies

• What it tells you: Marker of autoimmune thyroiditis
• How to interpret: Positive = confirms autoimmune cause; titres don’t track severity

Thyroglobulin antibodies

• What it t ells you: Additional autoimmune marker
• How to interpret: Often positive in Hashimoto’s; useful if TPOAb negative

Thyroid ultrasound

• What it tells you: Structural assessment
• How to interpret: Heterogeneous echotexture, hypoechoic areas, pseudonodules, or goitre suggest chronic inflammation

💡 Always interpret TSH in context. A “normal” TSH doesn’t rule out Hashimoto’s — it may reflect early compensation or central dysfunction.

🧠 When to Order Antibodies

• Suspected autoimmune cause: unexplained hypothyroidism, goitre, or family history
• Subclinical hypothyroidism: helps predict progression
• Pregnancy or fertility concerns: even mild dysfunction matters
• Other autoimmune conditions: screen for thyroid involvement

💡 Antibodies confirm the cause — not the need for treatment. A patient with positive TPOAb and normal TFTs doesn’t need thyroxine, but they do need monitoring.

🖼️ What Imaging Adds

Thyroid ultrasound isn’t always necessary, but it’s helpful when:

• The gland is enlarged or nodular
• There’s diagnostic uncertainty
• You’re assessing for compressive symptoms or malignancy risk

Typical findings in Hashimoto’s:

• Diffuse heterogeneity
• Hypoechoic areas
• Pseudonodules
• Reduced vascularity (in contrast to Graves’)

💡 Ultrasound shows structure, not function. It complements — but doesn’t replace — biochemical testing.

🩺 Management Principles: 

Hashimoto’s thyroiditis is a progressive autoimmune condition. We don’t treat the antibodies, we treat the hormonal consequences. That means recognising when the gland is failing, replacing what’s missing, and monitoring the system’s response over time.

 💊 When and Why to Start Treatment

Treat hypothyroidism when:

•  Free T4 is low and TSH is high → overt hypothyroidism
• TSH is persistently elevated with symptoms → subclinical but clinically significant
• Pregnancy or fertility is affected → even mild hypothyroidism can impair outcomes
•  Goitre is present and causing pressure or cosmetic concerns

💡We don’t treat antibodies alone. A patient with positive TPOAb but normal TSH and T4 doesn’t need thyroxine, they need monitoring. Treatment begins when the gland can’t keep up.

📈 How to Monitor and Adjust

• Start with levothyroxine (T4) — usually 1.6 mcg/kg/day in healthy adults
• Recheck TSH and free T4 after 6–8 weeks
• Adjust dose based on TSH (in primary hypothyroidism) or T4 (in central hypothyroidism)
• Once stable, monitor every 6–12 months

Special cases:

•  Pregnancy: increase dose by ~30% early in gestation
• Elderly or cardiac patients: start low and go slow
•  Malabsorption or drug interactions: may require higher doses

💡Thyroxine has a long half-life (~7 days), so changes take time. Always wait 6 weeks before rechecking, and interpret results in context.

🧠 What to Consider in Borderline or Evolving Cases

• Subclinical hypothyroidism: TSH elevated, T4 normal
• → Treat if symptomatic, pregnant, or TSH >10
• → Monitor if asymptomatic and TSH <10

• Positive antibodies, normal TFTs:
• → No treatment needed
• → Annual monitoring is reasonable

•  Fluctuating TSH:
• → May reflect early gland failure or lab variation
• → Repeat testing before starting treatment

💡Hashimoto’s is a trajectory, not a snapshot. 

 

🧠 Wrapping Up: What Hashimoto’s Teaches Us About Autoimmunity and Clinical Reasoning

Hashimoto’s thyroiditis isn’t just a thyroid disease — it’s a window into how the immune system can quietly reshape physiology over time. It teaches us that:

 Autoimmunity can be slow and silent → Patients may feel unwell long before blood tests confirm it

Compensation precedes collapse → The HPT axis works hard to maintain balance — until it can’t

Symptoms reflect hormone action, not just hormone levels → Fatigue, weight gain, and mood changes often appear before overt hypothyroidism

Diagnosis is a trajectory, not a snapshot → Antibodies, TSH, and T4 must be interpreted in context

Management is about restoring physiological function → We replace what’s missing, monitor the system, and support the patient

Above all, Hashimoto’s reminds us that medicine isn’t just about identifying disease — it’s about understanding how systems adapt, fail, and recover. That’s the heart of clinical reasoning.

📚 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 →
• ❄️ Pathophysiology of HYPOthyroidism →
• 🩶 Common Causes of Hypothyroidism: Hashimoto’s Thyroiditis →
• 🧩 Clinical Cases in Endocrinology: The Thyroid Axis →