Hashimoto Thyroiditis

Epidemiology

• Prevalence of hypothyroidism in iodine-replete populations: 1-2%; Hashimoto accounts for ~85% of those cases
• Mean annual incidence: up to 4 per 1000 women, 1 per 1000 men
• Female:male ratio = 10:1 to 20:1
• Peak presentation: 30-65 years of age (mean diagnosis age ~60 years)
• Subclinical hypothyroidism found in 6-8% of women (10% over age 60) and 3% of men
• Annual risk of progressing to overt hypothyroidism is ~4% when subclinical hypothyroidism is combined with positive TPO antibodies
• Robbins & Kumar Basic Pathology, p. 731; Harrison's Principles of Internal Medicine 22E, p. 3072

Types

1. Goitrous (classic) form - diffuse thyroid enlargement
2. Atrophic form - minimal residual thyroid tissue, represents the end stage with extensive fibrosis
3. Fibrosing variant - marked fibrosis with IgG4-positive plasma cell infiltration; can mimic Riedel thyroiditis
4. Hashitoxicosis - transient thyrotoxicosis from follicular disruption at disease onset

• Current Surgical Therapy 14e, p. 885

Pathogenesis

Fig: Pathogenesis of Hashimoto thyroiditis - breakdown of peripheral tolerance results in thyrocyte injury via cytotoxic T cells, cytokines, and activated macrophages (Robbins & Kumar Basic Pathology)

1. CD8+ cytotoxic T cells - directly kill thyroid epithelial cells via MHC class I recognition
2. CD4+ Th1 cytokines - secretion of IFN-γ recruits and activates macrophages, which destroy follicles; TNF-α and IL-1 are also implicated
3. Autoantibodies - anti-TPO (antimicrosomal) and antithyroglobulin antibodies are present in nearly all patients and may cause damage via antibody-dependent cell-mediated cytotoxicity (ADCC) or complement activation; though whether these are cause or consequence of injury remains debated

• ~40% concordance in monozygotic twins
• ~50% of asymptomatic siblings have antithyroid antibodies
• HLA-DR3, DR4, DR5 (Caucasians) are the strongest genetic risk factors
• Polymorphisms in CTLA-4 (T-cell inhibitor) and PTPN22 increase susceptibility
• Associated with Down syndrome (chromosome 21 gene) and Turner syndrome
• Shared genetic risk with type 1 DM, Addison's disease, pernicious anemia, vitiligo

• Robbins & Kumar Basic Pathology, p. 731-732; Harrison's 22E, p. 3072-3073

Morphology / Histology

Fig: Surgically excised diffuse goiter from a patient with Hashimoto thyroiditis causing compressive symptoms (Current Surgical Therapy 14e)

• Widespread lymphocytic infiltrate with lymphocytes, plasma cells, macrophages
• Well-developed germinal centers (lymphoid follicle formation)
• Atrophic thyroid follicles with scant colloid
• Hürthle (oxyphil) cell metaplasia - follicular epithelium replaced by cells with abundant eosinophilic granular cytoplasm packed with mitochondria (a metaplastic response to injury)
• Increased interstitial fibrosis
• Robbins & Kumar Basic Pathology, p. 732; Harrison's 22E, p. 3072

Clinical Features

• Painless, diffuse, firm thyroid enlargement (goiter) - most common presentation
• Symptoms of hypothyroidism (weight gain, fatigue, cold intolerance, constipation, dry skin, bradycardia, delayed reflexes)
• Less commonly, transient thyrotoxicosis (Hashitoxicosis) at disease onset due to follicular disruption releasing preformed hormone
• Globus sensation, profound fatigue, muscle/joint pain, poor sleep, dry mouth/eyes - these may persist even with adequate thyroid hormone replacement (thought to be autoimmune-related)
• Compressive symptoms in large goiters: dyspnea, dysphagia, cough, hoarseness

1. Euthyroid phase (compensation: TSH rises, T4 normal = subclinical hypothyroidism)
2. Overt hypothyroidism (TSH typically >10 mIU/L, free T4 falls)
3. Atrophic end stage

• Higher incidence of thyroid lymphoma (primary thyroid lymphoma almost always arises in a background of Hashimoto thyroiditis)
• Increased incidence of papillary thyroid carcinoma (disputed; may cause false-positive FNAB results)
• Current Surgical Therapy 14e, p. 885-886; Harrison's 22E, p. 3072

Diagnosis

• Positive TPO antibodies + elevated TSH usually clinch the diagnosis without biopsy
• FNAB findings: Bethesda III (AUS), IV (Hürthle cell neoplasm), or V (suspicious for PTC) may occur due to Hürthle cell changes causing false-positive results
• Schwartz's Principles of Surgery 11e; Current Surgical Therapy 14e

Treatment

Medical

• Euthyroid, asymptomatic patients: no treatment required; monitor TSH
• Hypothyroidism: levothyroxine (LT4) replacement
  • Starting dose: 1.6 mcg/kg/day (weight-based)
  • Titrate to normalize TSH
• Subclinical hypothyroidism: treat if TSH >10 mIU/L, or if symptomatic, pregnant, or TPO antibody-positive with progressive rise in TSH
• Hashitoxicosis: beta-blockers for symptom control; antithyroid drugs generally not needed (transient)
• Persistent symptoms despite adequate LT4 replacement (fatigue, pain, cognitive symptoms) do not routinely improve with additional thyroid hormone; thought to be autoimmune-mediated

Surgical

1. Thyroid nodule with indeterminate or malignant FNAB (Bethesda III-VI)
2. Unilateral or bilateral thyromegaly with mass effect/compressive symptoms (tracheal compression, dysphagia, hoarseness)
3. Persistent symptoms despite adequate thyroid hormone replacement (emerging evidence)

• Disease limited to one lobe: lobectomy + isthmusectomy
• Most patients: total thyroidectomy

• Current Surgical Therapy 14e, p. 886; Harrison's 22E

Hashimoto Variants & Related Conditions

Key Associations & Complications

• Primary thyroid lymphoma (MALT type) - nearly always in Hashimoto background; suspect with rapid gland enlargement
• Papillary thyroid carcinoma - possible increased risk (TSH-driven); Hashimoto can cause false-positive FNAB
• Hashimoto encephalopathy - rare steroid-responsive encephalopathy with high antithyroid antibodies, often euthyroid
• Polyglandular autoimmune syndromes (Type 2 includes Hashimoto + Addison's + T1DM)
• Increased prevalence in iodine-replete populations; iodine excess can accelerate thyroid autoimmunity