ERS09 Autoimmune Thyroid Disorders And Thyroiditis Flashcards
Normal thyroid gland
Gross appearance: - Weight <20g - Cut section: —> Mahogany-brown colour —> Vague nodularity —> Focal colloid nodules can be identified
Histology:
- Follicles lined by cuboidal / squamous follicular epithelial cells (flat + smooth)
- Variable amount of colloid within different follicles
Thyroiditis
Inflammation of Thyroid gland
Autoimmune
- Graves’ disease
- Hashimoto’s thyroiditis
- Riedel’s thyroiditis
- IgG4 related thyroiditis
Non-autoimmune
- Subacute granulomatous thyroiditis (De Quervain’s)
- Infections
- Iatrogenic
- Drug-induced
Autoimmune thyroid diseases
- Difficult to recognise ∵ may not manifest clinically as “individual, well-defined entities”
- Appear as a continuum with Hyperfunctioning Graves’ —> Hypofunctioning Hashimoto’s disease
- Hyperthyroidism may supervene on pre-existing Hashimoto’s thyroiditis
- Graves’ disease may spontaneously develop thyroid hypofunction
- Frequency of other autoimmune diseases is increased: —> SLE —> pernicious anaemia —> Type I DM —> Addison disease
- Graves’ disease
- Autoimmune thyroiditis
- Commonest cause of ***Hyperthyroidism
- F:M = 8:1
- 20-40 yo
- Male: later in life with more severe symptoms
Causes:
- Genetic + Environmental (infection / stress?)
- Strong familiar predisposition (monozygotic twin concordance: 60%)
- HLA-B8, HLA-DR3 (Caucasians)
- HLA-DR9 (Chinese)
- CTLA-4 (inhibitory T cell receptor), PTPN22 (tyrosine phosphatase) polymorphism —> regulate T cell responses
Hallmark:
Production of AutoAb against TSH receptors (agonistic / antagonistic / neutral effects)
-
**Thyroid-stimulating Ig (TSI) (STIMULATORY)
- almost all patients have
- disease-specific IgG Ab
- bind to TSH receptor
- mimic TSH action
—> stimulation of Adenyl cyclase —> **release of Thyroid hormones -
**Thyroid growth-stimulating Ig (STIMULATORY)
- target TSH receptor
- **proliferation of Thyroid follicular epithelium -
**TSH-binding inhibiting Ig (INHIBITORY)
- prevent TSH from binding to receptor on Thyroid follicular epithelial cells
—> **inhibit thyroid cell function
STIMULATORY / INHIBITORY Ig can co-exist —> May develop hypothyroidism
Clinical presentation:
- ***Diffuse goitre with thyrotoxicosis
- Symptoms: heat intolerance, palpitations, fatigue, weight loss, anxiety, hyperhidrosis
- Signs:
- Infiltrative ophthalmopathy with **exophthalmos
- Infiltrative dermatopathy
- **Wide staring gaze with Lid lag
- **↑ blood flow through hyperactive gland —> audible **bruit
- tachycardia, tremors, warm and moist skin, rare skin lesions in LL
Diagnosis:
- History + P/E
- Blood tests: ***↑ T3, T4, ↓ TSH, Serum AutoAb
- Imaging: Ultrasound / CT —> confirm process ***diffuse rather than solitary
- 123Iodine scan: ***↑ Radioiodine uptake
Treatment:
- Anti-thyroid drugs (Methimazole, Propylthiouracil, Carbimazole)
- β-blocker (cardiac symptom relieve)
- Non-radioactive Iodine —> inhibit Thyroid hormone release + inhibit Peripheral T4 conversion to T3
- Radioactive iodine ablation (refractory cases, lifelong T4 supplements may be required afterwards)
- Thyroidectomy
Gross appearance:
1. **Diffuse symmetric enlargement (may be irregular / nodular), 50-150g
2. Cut surface: homogeneous without well-defined nodules, vague lobulation may present
3. **Prominent vascularity (deep red)
4. ***Soft, spongy consistency
—> if pre-treated with anti-thyroid drugs —> less vascular, lighter tan colour, firm consistency, hyperplastic changes (cells piling up with overlapping nuclei), nuclear pleomorphism (degenerative change), loss of colloid, cytoplasmic oncocytic metaplasia
—> if pre-treated with radioactive iodine —> follicular destruction, fibrosis, dystrophic calcification, inflammatory cell infiltration
Histology (may be reverted back to normal by drug):
1. **Small follicle size, **Reduced colloid content with scalloping (retraction of colloid from epithelium) (∵ over-excretion, reduced storage)
-
**Hyperplasia of follicular epithelium (Thyroid growth-stimulating Ig)
- non-branching **papillae projecting into colloid (mimic papillary thyroid carcinoma (although darker nucleus in carcinoma))
- becomes ***columnar in shape - ***Prominent / Congested stromal blood vessels
- Lymphocytic infiltrate with / without germinal centres
- Limited fibrosis
Exophthalmos
- Infiltrative ophthalmopathy
- Swelling of **retro-orbital CT + **extraocular muscles (due to T cells)
- **Pathogenesis:
1. Edema with ↑ inflammatory cells (T cells)
2. ECM accumulation (hydrophilic glycosaminoglycans e.g. Hyaluronic acid, Chondroitin sulfate)
3. ↑ Adipocytes (fatty infiltration) - Function of extraocular muscles affected, may be complicated by corneal injury (∵ continuous exposure of eyeball)
- May persist / progress despite successful treatment of underlying thyrotoxicosis
End result: eventually Atrophy + Fibrosis of muscles (with weakness: Ophthalmoplegia)
Pretibial myxedema
- 5-10%
- Thickened skin, pigmented papules / nodules with orange peel texture
- ***Deposits of mucopolysaccharides within dermis (~ Ophthalmopathy)
- Underlying mechanism not understood
Graves’ disease differential diagnosis
Enlarged gland:
1. Adenomatous nodules (**Nodular hyperplasia)
- **Euthyroid
- No AutoAb
- multifactorial (genetic + environmental)
- associated with Cowden syndrome, Carney’s complex, Drugs (amiodarone, lithium, anti-thyroid drugs)
- appearance:
—> **Multinodular asymmetrical goitre (mixture of normal + non-encapsulated hyperplastic nodules)
—>*Abundant colloid
- Toxic multinodular goitre
- Hyperthyroidism
- **No AutoAb
- **Multinodular goitre
- ***Abundant colloid - Hashimoto’s thyroiditis
- early phase: Thyrotoxic (Hashitoxicosis)
Histological similarity:
- Papillary thyroid **carcinoma
- papillary architecture
- **follicular cells with nuclear grooves + pseudonuclear inclusions - Dyshormonogenetic goitre
- microscopically resemble Graves’
- rare condition
- autosomal recessive defects in synthesis + metabolism of thyroid hormone
- ***↓ T3, T4, ↑ TSH
- Hashimoto’s thyroiditis
- Autoimmune thyroiditis
- ***Hypothyroidism —> gradual loss of thyroid function
- F:M = 10-20:1
- 45-65 yo (rare juvenile variant)
Causes:
- Genetic
- monozygotic twin concordance: 40%
- presence of Anti-thyroid Ab in 50% of asymptomatic siblings of affected parents
- association with HLA-DR3, HLA-DR5
- CTLA4 polymorphism (immune regulation-associated genes) - Environmental
- Iodine / Selenium deficiency
3. Association with other autoimmune diseases: —> Type I DM —> Sjogren syndrome —> Pernicious anaemia —> Thrombocytopenic purpura —> SLE
- At risk of developing into primary thyroid lymphoma - diffuse large B cell type of germinal centre type
Hallmark:
Presence of ↑↑ **Anti-thyroglobulin + **Anti-thyroid microsomal Ab (AutoAb)
- mediate **ADCC
- activation of **CD4 Th cells (targeted at thyroid antigens)
End result: Progressive **depletion of thyroid epithelial cells + **Fibrosis
Clinical presentations:
- Asymptomatic
- Initial transient phase of hyperthyroidism (***Hashitoxicosis) (∵ destruction and release of thyroid hormone from gland)
- Non-specific symptoms: fatigue, apathy, mental sluggishness (~ depression), constipation, ↓ sweating)
- Signs: painless, symmetrical + ***diffusely enlarged thyroid (esp. in fibrous variant), cold hands and feet, cool + pale + dry skin, weight gain, hair loss, slow heart beat
Diagnosis:
- History + P/E
- Blood tests: ***↓ T3, T4, ↑ TSH, Anti-thyroglobulin Ab, Anti-thyroid microsomal Ab
- Imaging: 123Iodine scan: ***↓ uptake
- CT: ***Diffusely enlarged thyroid
Gross appearance:
- ***Diffuse, symmetrical enlargement 2-3x, 200g
- Bosselated / Irregular surface
- Cut surface:
- Prominent lobulation + Fibrosis / Prominent nodules
- light-tan colour (∵ ***Fibrosis + Lymphoid cell infiltration)
Histology:
- **Atrophic follicles separated by large areas of **Fibrosis (confined)
- Follicular cell: ***Hurthle cell change (eosinophilic, granular cytoplasm, enlarged cells - contain abundant mitochondria) (Oxyphilic / Oncocytic metaplasia)
- ***Plasma cell + Lymphocyte infiltration + Prominent lymphoid follicles with germinal centres (active lymphoid activity in gland)
- Limited colloid
- ***Firm + Lobular
Treatment:
- Levothyroxine (lifelong)
- Immunosuppressants (e.g. Corticosteroid) (cannot given long-term)
- Surgery (for large gland that causes compressive symptoms / clinical suspicion of malignancy / did not respond to drug)
Fibrous variant of Hashimoto’s thyroiditis
- 10% cases in older patients
- end-stage?
- Small thyroid gland
- Chronic inflammatory cell infiltrate
- Marked follicle atrophy
- Oxyphilic, squamous metaplasia
- Prominent acellular, thick **keloid-like fibrosis —> **NOT extend beyond gland (confined within gland)
Hashimoto’s thyroiditis differential diagnosis
- Lymphocytic thyroiditis, Post-partum thyroiditis
- subclinical hypothyroidism
- initial thyrotoxicosis (4-8 weeks) (but no exophthalmos)
—> depleted of colloid
—> Hypothyroid phase (2 months)
- ***No AutoAb
- incidental finding in glands during resection
- no therapy needed
- Juvenile lymphocytic thyroiditis: ↑ Anti-thyroglobulin Ab but only focal / absent Follicular atrophy / Oxyphilic metaplasia - ***Riedel thyroiditis / IgG4-related thyroiditis
- morphologic overlap - Papillary thyroid carcinoma
- ***distinctive nuclear features - Lymphoma
- may develop into primary thyroid lymphoma - diffuse large B cell type of germinal centre type
- Riedel’s thyroiditis
- Rare disease
- Adult
- Female more common
- **Euthyroid —> eventually **Hypothyroidism ∵ destruction of gland
- historically considered autoimmune (∵ close clinical, histological association with Hashimoto’s)
- Anti-thyroid Ab / Co-existing SLE / Scleroderma
Clinical presentation:
- Symptoms: ***sudden onset of enlarged, painless neck mass —> dysphagia, dyspnea, stridor
- Signs: **non-tender + **hard gland, ***vocal cord paralysis (involvement of fibrous neck structures —> compression and encasement of recurrent laryngeal nerve)
- Rare cases: associated with other ***systemic fibrosclerosing diseases (multiple organ: retroperitoneum, retro-orbital, lung, mediastinum etc.)
Diagnosis:
- Euthyroid, 30-40% develop Hypothyroidism
- ↑ ***Anti-thyroglobulin Ab, Anti-microsomal Ab
- ***Extra-thyroidal extension of disease: neck structure —> Hypoparathyroidism, Venous thrombosis, Nerve involvement
Gross appearance:
- Enlarged gland ***densely adhered to surrounding soft tissues —> difficulty to remove from surrounding neck structure ∵ extensive extra-thyroidal fibrosis
- Cut surface: Without normal lobulation, Tan-gray, Avascular, woody
Histology:
1. Gland replaced by **dense, sclerotic, keloid-like fibrous tissue
—> extend to **Extrathyroidal soft tissue (muscle, nerve, adipose tissue) + Parathyroid gland
—> entrap adjacent adipose tissue, striated muscles, Parathyroid gland
—> islands of residual thyroid follicles —> simulate thyroid carcinoma
—> ***NOT seen in Hashimoto’s / IgG4-associated thyroiditis
- ***NO Hurthle cell change
- Other features identical to Hashimoto’s
- ***Plasma cell + Lymphocyte infiltration
- Destruction of follicles
- Limited colloid
Treatment:
- Corticosteroid, Tamoxifen
- Levothyroxine for Hypothyroidism
- ***Mycophenolate mofetil (for systemic fibrosis)
- Surgery (necessary to relief compressive symptoms + preserve tracheal / esophageal functions)
Riedel’s thyroiditis differential diagnosis
- Hashimoto’s thyroiditis (Fibrous variant)
- Fibrosis **confined in gland
- **Hurthle cell change prominent - IgG4-related thyroiditis
- overlap morphological features (if not identical)
- but ***↑ IgG4 plasma levels - Undifferentiated thyroid carcinoma
- extrathyroid extension in common
- but have other ***cytological features indicate malignancy
- IgG4 related thyroiditis
- Historically closely related to Riedel’s thyroiditis
- within IgG4-related disease group —> ***multi-organ disorder
- ***↑ IgG4 plasma levels
- Fibrosclerosing changes ***limited to thyroid ~ Hashimoto’s thyroiditis
- Riedel’s thyroiditis may also present with ↑ IgG4 plasma levels
—> overlapping clinical and pathological entity between IgG4 related thyroiditis and Riedel’s thyroiditis
Gross appearance:
- Cut surface: Pale white with Lobulations (∵ fibrosis, but confined to gland only)
Histology:
- Stromal fibrosis (~ Fibrous variant Hashimoto’s)
- Follicle atrophy (~ Fibrous variant Hashimoto’s)
- Plasma cell + Lymphocyte + ***Eosinophils infiltration (confined to gland)
Diagnosis:
1. ↑ IgG+, ↑ IgG4+ plasma cells per high-powered field under microscope
2. **↑ IgG4+ / IgG+ plasma cells ratio > 40% (Definitive)
—> 2 separate **Immunohistochemical stains to demonstrate plasma cells
- Subacute granulomatous thyroiditis (De Quervain’s)
- Non-autoimmune thyroiditis
- a type of ***Granulomatous thyroiditis
- 30-50 yo
- Female more common
- Most have **preceding history of upper-respiratory infection
—> usually **viral (e.g. measles, influenza, adenovirus, EBV, Coxsackie, mumps, HIV, H1N1)
—> rare cases develop after anti-viral therapy (e.g. IFN)
Clinical presentation:
1. Symptoms:
- neck pain, sore throat, difficulty swallowing, low-grade fever, malaise
- Initial “thyroid storm” —> disruption of follicles, release of hormones into blood stream followed by brief episode of Hypothyroidism —> complete resolution within 6-8 weeks
2. Signs: enlarged gland, ***tender
—> not definitive, may have gland removed surgically
Investigations:
- Blood test:
- Initial-phase: ↑T3, T4, ↓TSH
- Mid-phase: Hypothyroidism
- Late-phase: Euthyroid (when inflammation subsided)
Gross appearance:
- ***Firm, intact capsule
- Unilaterally / Bilaterally enlarged
Histology:
1. Disruption of follicles, **Extravasation of colloid, Neutrophil infiltration
—> replaced over time by lymphocytes, plasma cells, macrophages
2. **Granulomas (multi-nucleated giant cells, epitheloid histiocytes surrounding colloid, granulomatous inflammation —> ***“foreign body” type —> a secondary reaction to extravasation of colloid fragments)
—> healing by inflammation resolution / fibrosis
Subacute granulomatous thyroiditis differential diagnosis
Any granulomatous inflammation:
- Mycobacterium (Ziehl-Neelsen stain)
- Fungus
- Sarcoidosis
