Thyroiditis and Graves Disease

Overview

Mostly NON-infectious. Classification:

• ACUTE: bacterial(Staph/Strep), fungal(Aspergillus/Histoplasma/Pneumocystis), radiation
• SUBACUTE: subacute granulomatous(de Quervain’s/giant cell/viral), subacute lymphocytic(postpartum/silent), tuberculous
• CHRONIC: autoimmune(Hashimoto’s), Riedel’s(invasive fibrous)

Acute infectious=uncommon. Graves’ disease included here — immunologically parallel to Hashimoto’s.

Hashimoto’s (autoimmune/chronic lymphocytic) thyroiditis

= diffuse lymphocytic thyroiditis/struma lymphomatosa. TRIAD: diffuse goitrous enlargement + lymphocytic infiltration + thyroid autoantibodies.

Age 30-50, ~10x FEMALE preponderance. Rare in children but ~half of adolescent goitre. COMMONEST cause of goitrous hypothyroidism where iodine adequate. HIGHER incidence in high-iodine regions(Japan, US) — counterintuitive but true.

Etiopathogenesis (established autoimmune, Hashimoto 1912 = FIRST autoimmune disease described in any organ):

1. Associated autoimmune diseases: Graves’, SLE, Sjögren’s, RA, pernicious anaemia, T1DM
2. Immune destruction: CTLA4 association. CD4+ T-helper activation→CD8+ cytotoxic infiltration→B cells→autoantibodies→destruction
3. Autoantibodies: thyroid microsomal, thyroglobulin, TSH-receptor Abs (± less consistent others)
4. INHIBITORY TSH-receptor Ab→hypothyroidism (CONTRAST: Graves’=STIMULATORY→hyperthyroidism — SAME antibody TYPE, opposite ACTION, explains occasional hypo↔hyper swings in either disease)
5. Genetic: ↑1st-degree relatives, HLA-DR3+DR5

Morphology — 2 varieties: CLASSIC(usual) vs FIBROSING(only ~10%).

Gross: classic=diffuse symmetric firm rubbery(100-300g), fleshy+accentuated lobulation, RETAINED shape. Fibrosing=firm, compresses surrounding tissue.

Micro(classic): lymphocyte/plasma/immunoblast/macrophage infiltrate+germinal centre follicles; decreased atrophic colloid-devoid follicles; HÜRTHLE CELLS(Askanazy/oxyphil, granular mitochondria-rich cytoplasm, bizarre nuclei); slight septal fibrosis. Fibrosing variant=considerable fibrous replacement, LESS lymphoid infiltrate.

Clinical: painless firm moderate goitre, USUALLY hypothyroidism, middle-aged WOMAN. ↓T3/T4, ↓RAIU. Minority→“HASHITOXICOSIS”(hyperthyroid episode, evidences Graves’ overlap). NO ↑thyroid CA risk BUT ↑MALIGNANT LYMPHOMA frequency (key distinguishing risk).

Variant: subacute lymphocytic(postpartum/silent) — 3-6mo post-delivery.

Subacute granulomatous (de Quervain’s) thyroiditis

= giant cell/subacute thyroiditis. Distinctive SELF-LIMITED. Unknown etiology but prodromal+preceding resp infection suggests VIRAL. Young/middle-age WOMEN. Clinical: PAINFUL moderate enlargement+fever (KEY CONTRAST with painless Hashimoto’s), early hyperthyroid features, ±hypothyroidism if extensive. SELF-LIMITING, recovery ~6mo.

Morphology: Gross=moderate, often asymmetric/focal, firm yellowish-white. Micro(staged): initial acute destruction+microabscesses→later GRANULOMAS(central colloid+histiocytes+multinucleate giant cells)→advanced=fibroblastic proliferation. Similar picture from vigorous palpation alone = “palpation thyroiditis.”

Riedel’s thyroiditis

= Riedel’s struma/invasive fibrous thyroiditis. Rare, chronic, STONY-HARD, densely adherent to neck (MIMICS thyroid cancer clinically — classic diagnostic trap, biopsy essential). Compressive symptoms: dysphagia, dyspnoea, RLN paralysis, stridor. Women, 4th-7th decade. Unknown etiology, possibly part of MULTIFOCAL IDIOPATHIC FIBROSCLEROSIS (± retroperitoneal/mediastinal/retro-orbital fibrosis, sclerosing cholangitis co-occurring — worth checking elsewhere).

Morphology: Gross=contracted, stony-hard, asymmetric, adherent; hard cut surface, NO lobulation. Micro: extensive fibrocollagenous replacement, marked atrophy, focal lymphocytic infiltrate, muscle invasion.

Graves’ disease (diffuse toxic goitre)

= Basedow’s disease/exophthalmic goitre. TRIAD: hyperthyroidism + diffuse enlargement + ophthalmopathy. Age 30-40, 5x FEMALE preponderance.

Etiopathogenesis — autoimmune, PARALLELS Hashimoto’s:

1. Genetic: familial, HLA-DR3(vs Hashimoto’s DR3+DR5), CTLA-4, PTPN22
2. Autoimmune association: frequently coexists with Hashimoto’s in same families/patients
3. Other: ↑female(7-10x), stress, smoking
4. Autoantibodies target TSH-RECEPTOR:
   • TSI(thyroid-stimulating Ig) — binds receptor, STIMULATES hormone release
   • TGI(growth-stimulating Ig) — stimulates follicular proliferation
   • TBII(TSH-binding inhibitor Ig) — inhibits TSH binding; net stimulatory/inhibitory effect→possible hypo↔hyper swings
   • Trigger for B-cell autoantibody production unclear, likely intrathyroidal CD4+ T cells
5. Ophthalmopathy = ALSO autoimmune: lymphocytic infiltrate around ocular muscles + autoantibodies against muscle antigen cross-reacting with thyroid microsomes

Morphology: Gross=moderate diffuse symmetric(up to 70-90g), homogeneous red-brown meaty, NO translucency. Micro: epithelial hyperplasia/hypertrophy(↑cell height, papillary infoldings, SMALL follicles); markedly ↓DIMINISHED watery vacuolated colloid; ↑stromal vascularity+lymphoid accumulation.

NOTE: preoperative meds alter morphology — iodine→colloid accumulation+↓vascularity/height; antithyroid drugs(thiouracil)→marked hyperplasia.

Clinical: slow insidious, YOUNG WOMEN. Symmetric moderate goitre+thyrotoxicosis+ophthalmopathy+dermatopathy. Ocular: lid lag, upper lid retraction, stare, EOM weakness, proptosis; extreme=corneal injury. Dermatopathy: PRETIBIAL MYXOEDEMA(firm plaques). NO ↑thyroid CA risk (parallels Hashimoto’s).

Clinical relevance

Hashimoto’s+Graves’ = parallel autoimmune architecture (genetic HLA, TSH-receptor-directed Abs, familial co-occurrence) but OPPOSITE outcomes purely from inhibitory vs stimulatory antibody action at SAME receptor — organising fact for comparison. Hashitoxicosis+Graves’ hypothyroid episodes = same principle: TSH-receptor Ab action isn’t fixed, clinical picture can shift as balance changes. De Quervain’s PAINFUL+self-limiting = key discriminator from Hashimoto’s PAINLESS — pain+preceding resp infection points viral/granulomatous not autoimmune. Riedel’s mimicking cancer despite being benign = classic diagnostic trap, biopsy essential, check for multifocal idiopathic fibrosclerosis elsewhere.

Overview

Thyroiditis (thyroid inflammation) is more often non-infectious and is classified by onset/duration:

• Acute: bacterial (Staphylococcus, Streptococcus), fungal (Aspergillus, Histoplasma, Pneumocystis), radiation injury.
• Subacute: subacute granulomatous (de Quervain’s/giant cell/viral thyroiditis), subacute lymphocytic (postpartum/silent), tuberculous.
• Chronic: autoimmune (Hashimoto’s/chronic lymphocytic), Riedel’s (invasive fibrous).

Acute infectious thyroiditis is uncommon; the morphologically important forms are discussed below, alongside Graves’ disease — an autoimmune thyroid disease closely related to Hashimoto’s thyroiditis immunologically.

Hashimoto’s (Autoimmune, Chronic Lymphocytic) Thyroiditis

Also called diffuse lymphocytic thyroiditis, struma lymphomatosa, or goitrous autoimmune thyroiditis. Three principal features: diffuse goitrous enlargement, lymphocytic infiltration, thyroid autoantibodies.

Occurs mainly ages 30–50, ~10-fold female preponderance; rare in children, but accounts for about half of adolescent goitre cases. The commonest cause of goitrous hypothyroidism where iodine supply is adequate; incidence is actually higher in high-iodine-intake regions (Japan, US).

Etiopathogenesis — well-established autoimmune disease (first described by Hashimoto, a Japanese surgeon, in 1912 — historically the first autoimmune disease described in any organ):

1. Associated with other autoimmune diseases: Graves’ disease, SLE, Sjögren’s syndrome, rheumatoid arthritis, pernicious anaemia, Type 1 diabetes mellitus.
2. Immune destruction: CTLA4 (T-cell regulatory gene) association; initial CD4+ T-helper activation induces CD8+ cytotoxic T-cell infiltration; B cells activate to form autoantibodies, together destroying thyroid parenchyma.
3. Autoantibodies detectable in most patients: thyroid microsomal antibodies, thyroglobulin antibodies, TSH-receptor antibodies; less consistently, antibodies against follicular cell membranes, thyroid hormones, and other colloid components.
4. Inhibitory TSH-receptor antibodies — cause hypothyroidism (contrast: the stimulatory TSH-receptor antibody in Graves’ causes hyperthyroidism); the same antibody type can act either way, explaining alternating hypo-/hyperthyroid episodes in some patients.
5. Genetic basis: higher incidence in first-degree relatives; associated with HLA-DR3 and HLA-DR5.

Morphology — two varieties: classic form (usual, common) and fibrosing variant (only ~10% of cases).

Gross: classic form — diffuse, symmetric, firm, rubbery enlargement (100–300 g), fleshy cut surface with accentuated lobulation but retained gland shape. Fibrosing variant — firm, enlarged, compressing surrounding tissue.

Micro (classic form):

1. Extensive lymphocyte/plasma cell/immunoblast/macrophage infiltration with lymphoid follicles bearing germinal centres.
2. Decreased, atrophic, often colloid-devoid follicles.
3. Follicular epithelial cells transformed into Hürthle cells (Askanazy/oxyphil cells/oncocytes) — abundant oxyphilic granular cytoplasm (mitochondria-rich), large bizarre nuclei.
4. Slight fibrous thickening of interlobular septa.

The fibrosing variant shows considerable fibrous parenchymal replacement with a less prominent lymphoid infiltrate.

Clinical features: painless, firm, moderate goitrous enlargement, usually with hypothyroidism, typically a middle-aged woman. T3/T4 decreased, RAIU reduced. A minority develop hyperthyroidism (“hashitoxicosis”), further evidencing the autoimmune overlap with Graves’. No increased thyroid carcinoma risk, but increased malignant lymphoma frequency.

A variant — subacute lymphocytic (postpartum/silent) thyroiditis — appears 3–6 months post-delivery.

Subacute Granulomatous (de Quervain’s) Thyroiditis

Also called giant cell or subacute thyroiditis — a distinctive, self-limited inflammation. Etiology unknown, but a prodromal phase and preceding respiratory infection suggest a viral cause. More common in young/middle-aged women. Clinical: painful moderate thyroid enlargement with fever, early hyperthyroid features, hypothyroidism if damage is extensive. Self-limiting — complete functional recovery in ~6 months.

Morphology: Gross — moderate, often asymmetric/focal enlargement; firm, yellowish-white cut surface. Micro (stage-dependent): initially acute inflammatory destruction with microabscesses; later, characteristic granulomas (central colloid surrounded by histiocytes and scattered multinucleate giant cells); advanced cases show fibroblastic proliferation. A similar appearance (“palpation thyroiditis”) can result from vigorous mechanical thyroid palpation alone.

Riedel’s Thyroiditis

Also called Riedel’s struma or invasive fibrous thyroiditis — rare, chronic, stony-hard thyroid densely adherent to neck structures. Clinically significant for compressive symptoms (dysphagia, dyspnoea, recurrent laryngeal nerve paralysis, stridor) and its resemblance to thyroid cancer. More common in women, 4th–7th decades. Etiology unknown, but possibly part of multifocal idiopathic fibrosclerosis (alongside idiopathic retroperitoneal/mediastinal/retro-orbital fibrosis and sclerosing cholangitis, which may co-occur).

Morphology: Gross — contracted, stony-hard, asymmetric, firmly adherent gland; hard cut surface, no lobulation. Micro — extensive fibrocollagenous replacement, marked parenchymal atrophy, focal lymphocytic infiltrate, invasion of adjacent muscle.

Graves’ Disease (Diffuse Toxic Goitre)

Also called Basedow’s disease, primary hyperplasia, or exophthalmic goitre. Triad: hyperthyroidism, diffuse thyroid enlargement, ophthalmopathy. Ages 30–40, 5-fold female preponderance.

Etiopathogenesis — autoimmune, with many immunologic parallels to Hashimoto’s thyroiditis:

1. Genetic factors: familial occurrence; associated with HLA-DR3 (vs Hashimoto’s HLA-DR3/DR5), CTLA-4, PTPN22.
2. Autoimmune disease association: frequently coexists with Hashimoto’s in the same families/patients.
3. Other factors: higher female prevalence (7–10×), emotional stress, smoking.
4. Autoantibodies — the target is the TSH-receptor:
   • Thyroid-stimulating immunoglobulin (TSI) — binds TSH receptor, stimulates hormone release.
   • Thyroid growth-stimulating immunoglobulin (TGI) — stimulates follicular epithelium proliferation.
   • TSH-binding inhibitor immunoglobulin (TBII) — inhibits TSH binding; depending on its stimulatory/inhibitory net effect, can cause alternating hypo-/hyperthyroid episodes.
   • The trigger for B-cell autoantibody production is unclear, but likely intrathyroidal CD4+ helper T cells.
5. Ophthalmopathy pathogenesis — also autoimmune: intense lymphocytic infiltrate around ocular muscles and circulating autoantibodies against muscle antigen cross-reacting with thyroid microsomes.

Morphology: Gross — moderate, diffuse, symmetric enlargement (up to 70–90 g); homogeneous, red-brown, meaty cut surface, lacking normal translucency. Micro:

1. Epithelial hyperplasia/hypertrophy — increased follicular cell height, papillary infoldings into small follicular lumina.
2. Markedly diminished, lightly-staining, watery, finely-vacuolated colloid.
3. Increased stromal vascularity with lymphoid cell accumulation.

Note: preoperative medication alters morphology — iodine causes colloid accumulation and decreased vascularity/cell height; antithyroid drugs (thiouracil) cause marked hyperplasia.

Clinical features: slow, insidious onset, typically young women — symmetric moderate goitre with thyrotoxicosis, ophthalmopathy, and dermatopathy. Ocular: lid lag, upper lid retraction, stare, extraocular muscle weakness, proptosis; extreme cases risk corneal injury from incomplete lid closure. Dermatopathy: pretibial (localised) myxoedema — firm plaques. No increased thyroid cancer risk (parallel to Hashimoto’s).

Clinical Relevance

• Hashimoto’s and Graves’ disease share a remarkably parallel autoimmune architecture (genetic HLA associations, TSH-receptor-directed antibodies, familial co-occurrence) but produce opposite functional outcomes (hypo- vs hyperthyroidism) purely because their antibodies act as inhibitory versus stimulatory at the same receptor — this single mechanistic distinction is the organising fact for comparing the two diseases.
• “Hashitoxicosis” and Graves’-associated hypothyroid episodes both stem from the same underlying principle: TSH-receptor antibodies aren’t fixed in their action, and a given patient’s clinical picture can shift between hyper- and hypothyroid states as the antibody balance changes.
• De Quervain’s thyroiditis’s self-limiting course with painful presentation is the key discriminator from Hashimoto’s (painless) — pain plus a preceding respiratory infection should point toward a viral/granulomatous process rather than autoimmune disease.
• Riedel’s thyroiditis mimicking thyroid cancer clinically (stony-hard, fixed, compressive) despite being a benign fibrosing process is a classic diagnostic trap — biopsy is essential to avoid unnecessary aggressive cancer treatment, and its association with multifocal idiopathic fibrosclerosis is worth checking for elsewhere in the body.

• Hashimoto’s vs Graves’ disease side-by-side comparison, with the same TSH-receptor antibody target but opposite (inhibitory vs stimulatory) action highlighted
• Thyroiditis classification tree by onset/duration (acute/subacute/chronic) with each type’s hallmark feature
• De Quervain’s thyroiditis staged progression (acute destruction → granuloma formation → fibroblastic proliferation)

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