Hashimoto Thyroiditis

Epidemiology

• Most common cause of diffuse goiter and hypothyroidism in iodine-replete countries (responsible for ~85% of hypothyroid cases in those areas)
• Prevalence of hypothyroidism in iodine-replete populations: 1-2%
• Peak age: 45-65 years (also reported in 3rd-5th decades)
• Female predominance: female-to-male ratio of 10:1 to 20:1
• Clusters in families; co-occurs with Graves disease and other autoimmune diseases

Pathogenesis

1. CD8+ cytotoxic T cells - kill thyroid epithelial cells directly via MHC-restricted mechanisms
2. CD4+ Th1 cytokine-mediated damage - IFN-γ production recruits and activates macrophages, which destroy follicles
3. Antithyroid antibodies - anti-thyroid peroxidase (anti-TPO, also called antimicrosomal antibody) and anti-thyroglobulin antibodies are present in nearly all patients. These may contribute via antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent mechanisms, though it remains unclear if they are the cause or consequence of injury.

• ~40% concordance in monozygotic twins
• ~50% of asymptomatic siblings carry antithyroid antibodies
• Associated with polymorphisms in CTLA4 (an inhibitor of T-cell responses) and other immune-regulatory genes

Morphology / Histology

• Thyroid is usually diffusely and symmetrically enlarged
• Microscopy (classic features):
  • Widespread mononuclear inflammatory infiltrate: lymphocytes, plasma cells, macrophages
  • Well-developed germinal centers (lymphoid follicle formation)
  • Thyroid follicles are atrophic
  • Hürthle (oxyphil) cell metaplasia - follicular epithelial cells with abundant eosinophilic, granular cytoplasm due to numerous mitochondria (metaplastic response to injury)
  • Interstitial fibrosis (variable, may be abundant)
• Fibrosing variant - forms a massive, firm goiter; can be difficult to distinguish from Riedel thyroiditis

Clinical Features

Laboratory Findings

• Anti-TPO antibodies (antimicrosomal): elevated in 70-90% of patients - most sensitive marker
• Anti-thyroglobulin antibodies: also commonly elevated
• TSH: elevated in hypothyroid phase; suppressed in hashitoxicosis phase
• Free T4/T3: low in hypothyroid phase; elevated transiently in hashitoxicosis
• Inflammatory cytokines elevated

Thyroid Nodules and Cancer Risk

• Hürthle cell metaplasia leads to associated thyroid nodules (most are benign Hürthle cell nodules)
• FNAB findings: follicular epithelial cells, colloid, lymphocytes, Hürthle cells - classified as Bethesda II (benign)
  • Predominance of Hürthle cells may be Bethesda III (AUS) or IV (Hürthle cell neoplasm)
  • Can cause false-positive FNAB suspicious for papillary thyroid cancer (Bethesda V)
• Any discrete palpable nodule not part of diffuse goiter should be evaluated with FNA regardless of the Hashimoto diagnosis
• Increased risk of B-cell non-Hodgkin lymphoma (primary thyroid lymphoma) - a rapidly enlarging mass within a Hashimoto gland warrants urgent biopsy
• Possible increased predisposition to papillary thyroid carcinoma (controversial)

Treatment

1. Asymptomatic / Euthyroid

• Observation; no treatment required

2. Hypothyroidism

• Levothyroxine (T4) replacement - resolves hypothyroid symptoms and typically reduces goiter size
• Dose titrated to normalize TSH

3. Persistent Symptoms Despite Adequate Hormone Replacement

• Many symptoms (fatigue, myalgia, dry eyes) may be autoimmune-mediated and do not resolve with T4 alone
• Total thyroidectomy is an option in this setting: removes the antigenic target, reduces the systemic inflammatory response, and lowers anti-TPO titers and pro-inflammatory cytokines
• The Norwegian Trial on Surgery for Hashimoto Disease (prospective RCT) demonstrated improved health-related quality of life, reduced fatigue, and normalization of anti-TPO titers in surgically treated patients vs. controls

4. Compressive Goiter / Surgical Indications

• Surgery for large, symptomatic, or refractory goiter
• Thyroid lobectomy + isthmusectomy for unilateral disease; total thyroidectomy for bilateral or extensive disease
• Intraoperative nerve monitoring recommended (inflamed, firm gland increases risk of recurrent laryngeal nerve traction injury)
• Enlarged reactive central compartment lymph nodes are common; frozen section can exclude metastatic thyroid cancer

5. Radioiodine (I-131)

• Typically contributes little useful information to the workup (I-123 scanning also not usually helpful)

Associated Conditions and Variants