Pathogenesis of Hashimoto Thyroiditis

Core Mechanism: Breakdown of Self-Tolerance

• Abnormalities in regulatory T cells (Tregs) that normally suppress autoreactive clones
• Exposure of normally sequestered thyroid antigens to the immune system

Pathogenesis Diagram

Four Major Immunologic Mechanisms of Thyrocyte Destruction

1. CD8+ Cytotoxic T Cell-Mediated Killing

• Activated CD4+ T (helper) cells recognize thyroid antigens and recruit CD8+ cytotoxic T cells to the gland
• These cytotoxic T cells directly kill thyroid follicular epithelial cells via MHC-I-restricted antigen recognition
• This is considered the primary effector mechanism

2. Cytokine-Mediated Cell Death (Th1 Pathway)

• Activated CD4+ Th1 cells secrete IFN-γ in the thyroid microenvironment
• IFN-γ recruits and activates macrophages
• Activated macrophages cause bystander damage to thyroid follicles
• This inflammatory milieu sustains progressive follicular destruction

3. Antibody-Mediated Mechanisms

• Anti-thyroid peroxidase (anti-TPO) antibodies - present in ~95% of patients
• Anti-thyroglobulin (anti-Tg) antibodies - present in ~60% of patients
• Anti-TSH receptor (anti-TSH-R) antibodies - present in ~60% (blocking type, contributing to hypothyroidism)
• Less commonly: anti-sodium/iodine symporter antibodies (~25%)

• Antibody-dependent cell-mediated cytotoxicity (ADCC) - NK cells kill antibody-coated thyrocytes
• Complement-dependent cytotoxicity - complement fixation leads to membrane attack
• TSH receptor blockade - blocking antibodies impair TSH signaling, reducing thyroid function

4. Apoptosis (Programmed Cell Death)

• Fas-FasL interactions have been implicated as an additional mechanism of thyrocyte destruction
• Apoptosis of thyroid epithelial cells contributes to the progressive loss of functional parenchyma - Schwartz's Principles of Surgery, 11th Edition

Genetic Susceptibility

• ~40% concordance in monozygotic twins
• ~50% of asymptomatic siblings of affected patients have circulating antithyroid antibodies

Environmental Triggers and Associations

• Excess iodine intake - associated with increased incidence of chronic thyroiditis
• Medications: interferon-α, lithium, amiodarone can precipitate or worsen thyroiditis
• Postpartum state - postpartum thyroiditis shares mechanistic parallels (TPOAb positive, preceded by thyrotoxic phase)
• Familial clustering and co-occurrence with Graves' disease and other autoimmune diseases (type 1 diabetes, pernicious anemia, Addison's disease)

Morphological Consequences of the Pathogenesis

1. Diffuse lymphocytic infiltration - lymphocytes, plasma cells, macrophages with germinal center formation
2. Hurthle (Oxyphil/Oncocytic) cell metaplasia - follicular epithelial cells develop abundant eosinophilic cytoplasm packed with mitochondria; a metaplastic response to chronic injury
3. Follicular atrophy - destruction of normal follicular architecture
4. Interstitial fibrosis - connective tissue replacement of destroyed parenchyma (especially in the fibrosing variant)

Summary Flow

Genetic predisposition (CTLA4/PTPN22/IL2RA polymorphisms)
         +
Environmental trigger (iodine, drugs, viral?)
         ↓
Breakdown of Treg-mediated self-tolerance
         ↓
Autoreactive CD4+ T helper cell activation against thyroid antigens
     ↙                          ↘
CD8+ CTL recruitment         Th1 cytokines (IFN-γ)
(direct killing)              → macrophage activation
         +
Autoantibodies (anti-TPO, anti-Tg, anti-TSHR)
→ ADCC, complement, TSH-R blockade
         +
Apoptosis (Fas-FasL)
         ↓
Progressive thyrocyte destruction → Hurthle cell metaplasia + fibrosis
         ↓
Hypothyroidism (in ~20-85% depending on population)

• Robbins & Kumar Basic Pathology (p. 731) - Primary reference
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Detailed molecular mechanisms
• Schwartz's Principles of Surgery, 11th Edition - Apoptosis and antibody targets
• Current Surgical Therapy, 14th Edition - Clinical correlations

Types of Thyroiditis

Classification Overview

• Harrison's Principles of Internal Medicine, 22nd Edition; Current Surgical Therapy, 14th Edition

1. Acute (Suppurative) Thyroiditis

• Children/young adults: piriform sinus fistula (remnant of 4th branchial pouch, predominantly left-sided)
• Elderly: pre-existing goiter, degenerating thyroid malignancy

• Acute onset with fever, severe thyroid pain referred to the throat or ears
• Tender, asymmetric goiter; erythema over the gland
• Dysphagia, lymphadenopathy, systemic illness
• ESR and WBC elevated; thyroid function usually normal

2. Subacute Granulomatous Thyroiditis (de Quervain / Viral / Giant Cell Thyroiditis)

1. Early: disrupted follicles, neutrophilic microabscesses
2. Later: lymphocytes, activated histiocytes/macrophages, multinucleated giant cells engulfing colloid (characteristic)
3. Resolution: fibrosis, then restoration of normal architecture

• Exquisitely tender goiter; pain referred to jaw or ear
• Malaise, fever, sore throat; preceded by URTI
• T4:T3 ratio lower than in Graves' disease
• Antithyroid antibodies usually negative
• ESR typically >50 mm/h (often >100)

• NSAIDs/aspirin for pain relief
• Corticosteroids for severe cases
• Beta-blockers for symptomatic thyrotoxicosis
• Thyroid hormone replacement if symptomatic hypothyroidism
• Self-limited in >90%; ~15% develop permanent hypothyroidism

3. Hashimoto Thyroiditis (Chronic Autoimmune / Chronic Lymphocytic Thyroiditis)

• Genetic predisposition: CTLA4, PTPN22, IL2RA polymorphisms
• Treg dysfunction → autoreactive CD4+ and CD8+ T-cell activation
• CD8+ cytotoxic T cells directly kill thyrocytes
• CD4+ Th1 cells → IFN-γ → macrophage activation and follicular damage
• Autoantibodies (anti-TPO ~95%, anti-Tg ~60%) → ADCC and complement-dependent killing
• Apoptosis (Fas-FasL pathway) contributes additionally

• Diffuse lymphoplasmacytic infiltration with germinal center formation
• Hürthle (oxyphil/oncocytic) cell metaplasia of follicular epithelium
• Follicular atrophy
• Variable interstitial fibrosis (does not extend beyond the capsule)

• Painless diffuse goiter (firm, rubbery)
• Hypothyroidism (slow onset, in ~20-85%)
• "Hashitoxicosis" - transient thyrotoxic phase in some patients
• Goiter may cause compressive symptoms
• Associated with other autoimmune conditions (T1DM, pernicious anemia, Addison's)
• Elevated anti-TPO antibodies (hallmark laboratory finding)

• Goitrogenic form (classic - enlarged gland)
• Atrophic form (no goiter, directly hypothyroid)
• Fibrosing variant (extensive fibrosis; can mimic Riedel's thyroiditis)

• Permanent hypothyroidism
• Increased risk of thyroid lymphoma (extranodal marginal zone B-cell lymphoma)
• Possible association with papillary thyroid carcinoma (controversial)

4. Silent (Painless) Thyroiditis / Chronic Lymphocytic Thyroiditis

• Lymphocytic infiltration with germinal centers
• Patchy follicular disruption and collapse
• No fibrosis, no Hürthle cell metaplasia (distinguishes it from Hashimoto thyroiditis)
• Thyroid grossly normal or mildly enlarged

• Painless goiter (key distinguishing feature)
• Mild transient hyperthyroidism → hypothyroidism → recovery (similar pattern to de Quervain but without pain)
• RAIU low during thyrotoxic phase (low uptake differentiates from Graves')
• ~30% may evolve into permanent hypothyroidism

5. Riedel's Thyroiditis (Invasive Fibrous Thyroiditis)

• Rare, chronic condition
• Extensive fibrosis involving the thyroid AND contiguous neck structures (muscles, nerves, vessels, trachea, esophagus)
• Fibrosis extends beyond the thyroid capsule (key distinction from Hashimoto's fibrosing variant)
• Hard, fixed thyroid mass clinically simulates thyroid carcinoma
• May be associated with fibrosis at other sites: retroperitoneum (retroperitoneal fibrosis), mediastinum, orbit, bile ducts

• Progressive compressive symptoms: dyspnea, dysphagia, hoarseness (recurrent laryngeal nerve involvement)
• Hypothyroidism if sufficient thyroid parenchyma is destroyed
• Hypoparathyroidism if parathyroids are encased

6. Drug-Induced Thyroiditis

7. Radiation Thyroiditis

• Occurs days to weeks after radioactive iodine (¹³¹I) treatment or external beam radiation to the neck
• Characterized by acute inflammation and tenderness of the thyroid
• Usually transient; thyroid function eventually declines toward hypothyroidism
• FNA not typically needed (diagnosis is clinical in context of recent radiation)

Comparative Summary: Key Distinguishing Features

• Harrison's Principles of Internal Medicine, 22nd Edition - Primary reference for clinical classification
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Histopathology and pathogenesis
• Robbins & Kumar Basic Pathology - Key concepts
• Current Surgical Therapy, 14th Edition - Clinical variants and surgical management

Graves' Disease

The Classic Triad

1. Thyrotoxicosis - with diffuse goiter
2. Infiltrative ophthalmopathy - exophthalmos/proptosis
3. Infiltrative dermopathy - pretibial myxedema (minority of patients)

Pathogenesis

Core Mechanism: TSH Receptor Autoantibodies

• TSI (~90% of patients): Binds to the TSH-R and mimics TSH action - stimulates adenylyl cyclase → ↑cAMP → continuous thyroid hormone synthesis and release, independent of TSH
• TSH-R blocking antibodies: Also present in some patients; cause hypothyroidism. Coexistence of stimulating and blocking antibodies in the same patient explains occasional episodes of hypothyroidism
• TPO and Tg antibodies: Present in up to 80% of patients (coexisting lymphocytic thyroiditis); no direct correlation between TSI level and thyroid hormone levels

Genetic Susceptibility

Pathogenesis of Ophthalmopathy

1. Activated CD4+ T cells infiltrate the retro-orbital space and secrete cytokines (IFN-γ, TNF, IL-1)
2. Cytokines stimulate orbital fibroblasts → proliferation and synthesis of hydrophilic glycosaminoglycans (hyaluronic acid, chondroitin sulfate) that trap water
3. Progressive edema and swelling of extraocular muscles
4. Fatty infiltration (increased adipocytes) expands retrobulbar volume
5. Mononuclear cell (predominantly T-cell) infiltration of connective tissue
6. Late: irreversible fibrosis of extraocular muscles

Pathogenesis of Dermopathy

Morphology

Thyroid Gland

• Symmetrically enlarged (can exceed 80 g; normal ~25 g)
• Soft, beefy deep-red parenchyma; intact capsule

• Follicular epithelial cells are tall and crowded → form small papillae projecting into lumen (note: lack fibrovascular cores, distinguishing from papillary carcinoma)
• Colloid is pale with scalloped margins (being actively resorbed)
• Lymphoid infiltrates (predominantly T cells) with scattered germinal centers throughout the interstitium

• Iodine pre-treatment: causes involution of epithelium and colloid accumulation (blocks thyroglobulin secretion)
• Propylthiouracil: exaggerates epithelial hypertrophy by stimulating TSH secretion

• Generalized lymphoid hyperplasia; thymic enlargement (especially in young patients)
• Cardiac hypertrophy; ischemic changes if pre-existing coronary artery disease
• Orbital: edema, glycosaminoglycan deposition, T-cell infiltration, muscle fibrosis
• Skin: dermal thickening from glycosaminoglycan deposition and lymphocytic infiltration

Clinical Features

Symptoms and Signs of Thyrotoxicosis

Graves-Specific Features

• Occurs in ~50% of patients; in 10%, may occur without clinical hyperthyroidism
• Lid retraction → staring appearance (also present in other thyrotoxicoses via sympathetic overactivity)
• Proptosis/exophthalmos (forward displacement of eyeball)
• Periorbital and conjunctival edema, chemosis
• Diplopia (restrictive extraocular myopathy)
• Optic neuropathy (severe cases) → vision loss
• Corneal exposure and injury
• Onset is within the year before or after diagnosis of thyrotoxicosis in 75% of patients

• Scaly, thickened, indurated skin over the shins
• May appear as pigmented papules or nodules with an "orange peel" texture
• Present in a minority of patients

Cardiovascular Complications

• Sinus tachycardia (most common), supraventricular tachycardia, atrial fibrillation
• Bounding pulse, widened pulse pressure
• High-output cardiac failure in elderly or those with pre-existing disease
• Atrial fibrillation converts to sinus rhythm in ~75% after achieving euthyroidism

Other Systemic Effects

• Bone: Increased bone resorption → osteopenia; mild hypercalcemia (up to 20%); increased fracture risk
• Reproductive: Oligomenorrhea/amenorrhea; impaired sexual function; gynecomastia
• Hair/skin: Fine hair; diffuse alopecia (up to 40%, may persist months after treatment)
• Neuromuscular: Hyperreflexia, proximal myopathy; hypokalemic periodic paralysis (especially in Asian males)

Laboratory Findings

Treatment

1. Antithyroid Drugs (Thionamides)

• Methimazole (preferred) or propylthiouracil (PTU) (preferred in first trimester pregnancy, thyroid storm)
• Mechanism: Block thyroid peroxidase → inhibit thyroid hormone synthesis. PTU also blocks peripheral T4→T3 conversion
• PTU has additional advantage of blocking T4→T3 conversion (useful in thyroid storm)
• Remission (~50%) may be achieved after 12-18 months of therapy
• Beta-blockers (propranolol, atenolol) control adrenergic symptoms (tachycardia, tremor, anxiety)

2. Radioiodine Ablation (¹³¹I)

• Destroys thyroid tissue; most common definitive therapy in the US
• Eventually leads to hypothyroidism requiring lifelong thyroid hormone replacement
• Contraindicated in pregnancy and breastfeeding; may worsen pre-existing severe ophthalmopathy

3. Thyroidectomy

• Indicated for: large compressive goiters, patients who cannot receive radioiodine, those failing antithyroid drugs, suspected concurrent malignancy, young patients or those planning pregnancy
• Pre-operative iodine (Lugol's solution) is given to reduce gland vascularity

Treatment of Ophthalmopathy

• Smoking cessation (smoking is a major risk factor for worsening TED)
• Corticosteroids for active/moderate-severe disease
• Orbital radiation
• Teprotumumab (anti-IGF-1R monoclonal antibody): targeted therapy that reduces TSH-R/IGF-1R complex signaling in orbital fibroblasts; approved for active Graves' ophthalmopathy
• Surgical orbital decompression (severe cases)

Relationship to Hashimoto Thyroiditis

• Both involve autoimmune reactions to thyroid antigens with lymphocytic infiltrates and germinal centers
• Both share genetic susceptibility genes (CTLA4, PTPN22, IL2RA)
• Hyperthyroidism can supervene on Hashimoto thyroiditis ("Hashitoxicosis"), and Graves' patients can spontaneously develop hypothyroidism
• Both diseases co-occur in families; both associated with systemic autoimmune diseases (SLE, pernicious anemia, type 1 diabetes, Addison's disease)

• Robbins, Cotran & Kumar Pathologic Basis of Disease - Pathogenesis and morphology (primary reference)
• Robbins & Kumar Basic Pathology - Key concepts and histology
• Harrison's Principles of Internal Medicine, 22nd Edition - Clinical features, ophthalmopathy mechanism, treatment
• Cummings Otolaryngology - Ophthalmopathy and surgical management

Classification and Explanation of Thyroid Neoplasms

Overview and Classification

THYROID NEOPLASMS
│
├── BENIGN
│   └── Follicular Adenoma
│       ├── Nonfunctional (cold nodule)
│       └── Toxic adenoma (functional/warm nodule)
│
└── MALIGNANT (Carcinomas)
    │
    ├── Derived from FOLLICULAR EPITHELIUM (~95%)
    │   ├── 1. Papillary Thyroid Carcinoma (PTC) - >85%
    │   ├── 2. Follicular Thyroid Carcinoma (FTC) - 5-15%
    │   ├── 3. Noninvasive Follicular Thyroid Neoplasm with
    │   │      Papillary-like Nuclear Features (NIFTP)
    │   ├── 4. Poorly Differentiated Carcinoma
    │   └── 5. Anaplastic (Undifferentiated) Carcinoma - <5%
    │
    └── Derived from PARAFOLLICULAR C CELLS (~5%)
        └── 6. Medullary Thyroid Carcinoma (MTC)

Molecular Pathogenesis Overview

Part I: Benign Neoplasm - Follicular Adenoma

Definition and General Features

Pathogenesis

• Toxic adenomas: Somatic gain-of-function mutations causing constitutive activation of the TSH receptor signaling pathway:
  • TSHR mutations (most common) - stimulate thyrocytes to secrete hormone independent of TSH
  • GNAS mutations (Gα-s subunit, less common)
  • Present in >50% of toxic adenomas
• Nonfunctional adenomas: Mutations in RAS (<20%) and PTEN - same mutations also seen in follicular carcinoma

Morphology

• Gross: Solitary, spherical, well-circumscribed, compresses adjacent thyroid tissue; intact well-defined fibrous capsule
• Microscopy:
  • Uniform follicles containing colloid; little variation in cell size, shape, or nuclear morphology
  • Mitotic figures rare
  • Hürthle (oxyphil) cell change may occur (brightly eosinophilic granular cytoplasm)
  • Hallmark: complete intact encapsulation - NO capsular or vascular invasion (this is the critical distinction from follicular carcinoma)

Clinical Features

• Painless solitary nodule discovered on routine examination
• Nonfunctional: cold nodule on radionuclide scan (takes up less iodine than normal parenchyma)
• Toxic adenoma: warm or hot nodule on scan; associated thyrotoxicosis
• Treatment: surgical excision

Part II: Malignant Neoplasms - Thyroid Carcinomas

Frequency

• Solitary nodule (vs. multinodular)
• Patient age <30 years or male sex
• History of ionizing radiation exposure
• Cold (non-functioning) nodule on radionuclide scan

1. Papillary Thyroid Carcinoma (PTC)

Pathogenesis

Morphology

• Solitary or multifocal lesions
• May be well-circumscribed and encapsulated OR infiltrate adjacent parenchyma with ill-defined margins
• Papillary foci visible on cut surface

1. Branching papillae - fibrovascular stalks covered by single-to-multiple layers of cuboidal epithelial cells (crowded, sometimes pleomorphic)
2. Ground-glass (Orphan Annie eye) nuclei - finely dispersed chromatin imparts an optically clear/empty appearance. In addition:
   • Intranuclear pseudoinclusions - invaginations of cytoplasm into nucleus
   • Nuclear grooves - linear longitudinal grooves in the nuclear membrane
   • These nuclear features are diagnostic of PTC even in the absence of papillary architecture
3. Psammoma bodies - concentrically calcified laminated structures, usually within cores of papillae. Almost never found in follicular or medullary carcinomas.

Clinical Features

• Most common incidentally detected thyroid mass (greatly increased detection with widespread use of ultrasound)
• Often presents as a thyroid nodule or neck lymphadenopathy
• Lymphatic spread is characteristic - metastases to regional cervical lymph nodes are common (but do not worsen prognosis significantly)
• Hematogenous spread less common
• Cold nodule on scintigraphy
• Elevated thyroglobulin (used for postoperative monitoring)

2. Follicular Thyroid Carcinoma (FTC)

Pathogenesis

Morphology - Key Distinction from Adenoma

Capsular invasion and/or vascular invasion - adenomas have none; carcinomas must demonstrate at least one.

• Minimally invasive FTC: Limited capsular penetration; excellent prognosis (>90% 10-year survival)
• Widely invasive FTC: Extensive vascular and soft tissue invasion; 50% mortality within 10 years

• Uniform follicles with colloid (resembles adenoma - diagnosis CANNOT be made on cytology alone)
• On FNA: indeterminate (cannot distinguish from adenoma) - requires surgical excision
• Capsular invasion: Tumor cells penetrate through (not just indent) the fibrous capsule
• Vascular invasion: Tumor cells within endothelium-lined vascular spaces

Clinical Features

• Slowly enlarging painless nodule; cold nodule on scintigraphy
• Hematogenous spread is characteristic (NOT lymphatic) - metastases to bone, lungs, liver, brain
• Regional lymph nodes typically NOT involved (unlike PTC)
• Rarely, well-differentiated lesions may take up radioactive iodine (warm nodule)
• Serum thyroglobulin used for monitoring recurrence after total thyroidectomy

3. NIFTP - Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features

• Entirely follicular growth pattern (no papillae) but shows PTC-like nuclear features (enlarged nuclei, chromatin clearing, membrane irregularities)
• No invasion (no capsular, vascular, or intrathyroidal invasion) - if present, reclassified as "invasive encapsulated follicular variant of PTC"
• Historically called "noninvasive encapsulated follicular variant of PTC"
• Changed because: retrospective studies showed essentially zero risk of recurrence or metastasis → removing "carcinoma" from the name avoids unnecessary overtreatment
• Driven by RAS mutations (similar to follicular adenoma/carcinoma)

4. Poorly Differentiated and Anaplastic (Undifferentiated) Thyroid Carcinoma

Pathogenesis

• Arise de novo or, more commonly, by progression from a well-differentiated PTC or FTC (dedifferentiation/transformation)
• Retain driver mutations from precursor tumors (e.g., RAS, PIK3CA) PLUS additional mutations:
  • TP53 loss-of-function mutations - most important, believed to drive anaplastic transformation
• Molecular alterations: RAS, BRAF, PIK3CA, TP53

Morphology

• Tumor necrosis and/or increased mitotic activity
• Solid, insular (nested), or trabecular growth patterns
• Still retains some thyroid follicular cell markers

• No resemblance to follicular cells - loss of thyroid follicular differentiation markers
• Variable morphology:
  • Epithelioid (may resemble squamous cell carcinoma)
  • Spindled (resembles sarcoma)
  • Pleomorphic giant cells
• Foci of residual papillary or follicular carcinoma may be present (evidence of origin)

Clinical Features

• Rapidly enlarging bulky neck mass - usually the presenting feature
• Symptoms from invasion: dyspnea, dysphagia, hoarseness, cough
• Disease usually spread beyond thyroid into adjacent neck structures or metastasized to lungs at presentation
• Anaplastic carcinoma: one of the most aggressive human cancers - death in <1 year in most cases
• Poorly differentiated carcinomas fare somewhat better with surgery, external beam radiotherapy, and radioactive iodine

5. Medullary Thyroid Carcinoma (MTC)

Pathogenesis

• RET proto-oncogene activating mutations are central to both familial and sporadic MTC:
  • Familial (30%): Germline RET mutations → MEN-2A, MEN-2B, or familial MTC without MEN
  • Sporadic (70%): Acquired somatic RET mutations (~50% of sporadic cases)
• RET tyrosine kinase receptor is constitutively activated → unregulated cell proliferation of C cells

Morphology

• Sporadic: solitary nodule
• Familial: bilateral, multicentric
• Larger lesions: areas of necrosis and hemorrhage, may extend through capsule; pale gray to tan, infiltrative

• Polygonal to spindle-shaped cells arranged in nests, trabeculae, or even gland-like structures
• Amyloid deposits in stroma - derived from altered calcitonin polypeptides - DISTINCTIVE FEATURE
• Calcitonin demonstrable by immunohistochemistry within tumor cells AND in stromal amyloid
• Electron microscopy: membrane-bound electron-dense granules (neuroendocrine secretory granules)
• Familial cases: multicentric C-cell hyperplasia in surrounding thyroid parenchyma (precursor lesion) - not seen in sporadic lesions

Clinical Features

• Sporadic: neck mass ± compressive symptoms (dysphagia, hoarseness)
• Hormonal syndromes: diarrhea (VIP secretion), carcinoid-like features (serotonin), Cushing's syndrome (ACTH secretion)
• Serum calcitonin: key diagnostic and monitoring marker
• RET mutation screening of relatives enables early detection in familial cases
• MEN-2 kindred carriers of RET mutations are offered prophylactic thyroidectomy in childhood - often the only histologic finding is C-cell hyperplasia

Comparative Summary Table

• Robbins & Kumar Basic Pathology - Primary reference (pp. 735-739)
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Supplementary detail (pp. 1003-1010)