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PA31.1-3 | Thyroid: Goiter, Thyroiditis & Thyroid Function Disorders — SDL Guide (Part 3)

Graves Disease — Pathogenesis and Morphology (PA31.2)

Graves disease (diffuse toxic goiter) is the most common cause of hyperthyroidism and a prototypical organ-specific autoimmune disease.

Epidemiology: F:M = 7–10:1; peak 20–40 years; HLA-DR3, HLA-B8 association.

Autoimmune pathogenesis — the TSI antibody:
• CD4+ Th2 cells stimulate autoreactive B cells to produce thyroid-stimulating immunoglobulins (TSI) — IgG antibodies that bind the TSH receptor (TSHR) on follicular cells
• TSI mimics TSH → persistent receptor activation → cAMP pathway → unregulated T3/T4 synthesis and secretion
• Unlike TSH, TSI is NOT subject to negative feedback → sustained hyperthyroidism
• Also: TSH-receptor blocking antibodies (in some patients, same antigen, different epitope → hypothyroidism)

Gross morphology:
• Diffusely enlarged, symmetric, firm, red-brown (hyperemic) gland — 35–60 g
• Markedly increased vascularity → bruit on auscultation (thyroid bruit = clinical sign of Graves)

Microscopic hallmarks:
1. Tall, crowded columnar follicular cells — marked cellular hypertrophy
2. Papillary infoldings into follicular lumen (without fibrovascular cores — NOT true papillae of carcinoma)
3. Scalloped/pale colloid — peripheral resorption vacuoles at cell-colloid interface (colloid being actively endocytosed)
4. Lymphocytic infiltrate in interstitium (autoimmune component)
5. May have germinal centres (overlap with Hashimoto in long-standing cases)

Pre-treatment hallmark: After antithyroid drug treatment (PTU/carbimazole), colloid reaccumulates and cells flatten — gland "involutes" before surgery.

Two-panel H&E histology diagram of Graves disease thyroid showing medium-power view of hyperplastic follicles with tall columnar epithelium, papillary infoldings, scalloped pale colloid with resorption vacuoles, and interstitial lymphocytic infiltrate, alongside a high-power detail of a single follicle. — **Panel A:** Tall columnar follicular cells, papillary infolding into lumen, scalloped pale colloid, peripheral resorption vacuoles (Sanderson's polsters), interstitial lymphocytic infiltrate. **Panel B:** Tall columnar epithelium with basal nuclei and prominent apical cytoplasm, papillary infolding with fibrovascular core, pale eosinophilic scalloped colloid, peripheral resorption vacuole.

Graves Disease — Extrathyroidal Manifestations

Graves disease is a systemic autoimmune condition with three classic extrathyroidal features:

1. Graves ophthalmopathy (thyroid eye disease):
• Autoantibodies cross-react with TSHR on orbital fibroblasts → fibroblast activation → glycosaminoglycan (hyaluronate) deposition in retroorbital fat and extraocular muscles → proptosis (exophthalmos), periorbital oedema, diplopia
• Occurs in ~50% of Graves patients; can worsen AFTER thyroid treatment (immune rebound)
• May persist/progress even when thyrotoxicosis is controlled
• Corneal exposure → keratitis if severe

2. Graves dermopathy (pretibial myxedema):
• TSI stimulates dermal fibroblasts → mucin (glycosaminoglycan) deposition in dermis
• Thickened, indurated orange-peel texture skin over pretibial area
• Present in <5%; associated with severe ophthalmopathy

3. Thyroid acropachy:
• Rare; clubbing of fingers + soft tissue swelling of hands/feet + periosteal new bone formation
• Triplet of acropachy + dermopathy + ophthalmopathy = highly specific for Graves

TSI detection: Detected as TRAb (TSH receptor antibodies) by competition assay or as TSI by bioassay. Positive in >95% of untreated Graves.

Two-panel diagram: Panel A shows a frontal facial illustration of bilateral proptosis in Graves disease with labels for lid retraction, scleral show, and periorbital oedema; Panel B shows an axial orbital cross-section with enlarged extraocular muscles, expanded retroorbital fat, and glycosaminoglycan deposition pushing the globe anteriorly. — **Panel A:** Proptosis (exophthalmos) — bilateral anterior globe displacement; Lid retraction — elevated upper eyelid margin; Scleral show — exposed inferior sclera below limbus; Periorbital oedema — swelling of periorbital soft tissue. **Panel B:** Enlarged extraocular muscles (cross-section, most marked in inferior and medial recti); Retroorbital fat expansion; Glycosaminoglycan (GAG) deposition — callout inset; Optic nerve at orbital apex; Anterior globe displacement arrow (proptosis mechanism).

Thyrotoxicosis — Causes, Clinical Features & Pathophysiology (PA31.2)

Thyrotoxicosis is the clinical state caused by excess thyroid hormones in tissues, regardless of source.

Causes (memorise the RAIU pattern — it's the diagnostic key):

Cause	TSH	Free T4	RAIU	Mechanism
Graves disease	↓↓	↑↑	↑↑ diffuse	TSI-driven overproduction
Toxic MNG	↓↓	↑↑	↑ patchy	Autonomous nodules
Toxic adenoma	↓↓	↑↑	↑ focal "hot" nodule	Autonomous adenoma
De Quervain thyroiditis	↓↓	↑↑	↓↓ suppressed	Passive leakage from damaged follicles
Factitious thyrotoxicosis	↓↓	↑↑	↓↓ suppressed	Exogenous T4 (thyroglobulin ↓)
TSH-secreting pituitary adenoma	↑	↑↑	↑	Secondary (very rare)

Clinical manifestations — "sympathetic storm" + hypermetabolism:
• Cardiovascular: tachycardia, wide pulse pressure, high-output cardiac failure, atrial fibrillation (T3 directly shortens action potential in atrial myocytes)
• Neurological/psychiatric: anxiety, tremor, emotional lability, hyperreflexia, insomnia
• Metabolic: weight loss despite increased appetite (↑ basal metabolic rate), heat intolerance, excessive sweating
• Musculoskeletal: proximal myopathy, thyrotoxic periodic paralysis (hypokalemia, more common in Asian males)
• Skin/hair: fine hair, moist skin, onycholysis (Plummer nails)
• Reproductive: oligomenorrhea, reduced fertility; gynaecomastia in males
• Ocular (Graves-specific): proptosis, lid lag, lid retraction, Stellwag sign (infrequent blinking)

Thyroid storm (thyrotoxic crisis): Acute exacerbation — hyperpyrexia, delirium, cardiovascular collapse; mortality ~20% with treatment, >90% untreated.