12.5 Hypothyroidism, Subclinical Disease & Thyroid Nodules

4. Hypothyroidism & Subclinical Thyroid Dysfunction

Primary vs. Secondary (Central) Hypothyroidism

• Primary Hypothyroidism: Elevated serum TSH with decreased free T4. Commonest aetiology in iodine-sufficient countries is Hashimoto's thyroiditis (autoimmune lymphocytic destruction, high anti-TPO titres, associated with other autoimmune diseases and a 40- to 60-fold increased risk of primary thyroid lymphoma).
• Secondary / Central Hypothyroidism: Inappropriately low or normal serum TSH in the presence of a low free T4. Results from pituitary pathology (macroadenoma, Sheehan's syndrome, lymphocytic hypophysitis) or hypothalamic disease. Critical Rule: In central hypothyroidism, always evaluate the hypothalamic-pituitary-adrenal (HPA) axis and treat adrenal insufficiency with hydrocortisone BEFORE initiating levothyroxine; thyroxine accelerates hepatic cortisol clearance and precipitates fatal acute Addisonian crisis.

Levothyroxine Pharmacotherapy & Target Monitoring

• Pure synthetic thyroxine (T4); half-life ~7 days. Administer on an empty stomach with water 30–60 minutes before breakfast (absorption impaired by iron, calcium, aluminium antacids, proton pump inhibitors, and dietary fibre).
• Standard Adult Dose: $\sim 1.6\text{ mcg/kg/day}$ (usually $100\text{–}125\text{ mcg/day}$). Target: normalization of serum TSH ($0.5\text{–}2.5\text{ mU/L}$).
• Ischaemic Heart Disease / Frail Elderly: Start at a low dose of $25\text{ mcg once daily}$, titrating upwards slowly by 25 mcg increments every 4–6 weeks to prevent unmasking angina or precipitating myocardial infarction/arrhythmias.
• Pregnancy Requirements: Fetal brain development is completely dependent on maternal transplacental T4 during the first trimester (fetal thyroid begins synthesis at 12–14 weeks). Oestrogen elevates thyroxine-binding globulin (TBG) and placental deiodinases increase T4 clearance. Women with established hypothyroidism must increase their levothyroxine dose by 25–50% (typically 2 extra tablets per week) immediately upon confirming pregnancy, targeting a first-trimester TSH $< 2.5\text{ mU/L}$ with 4-weekly TSH surveillance.
• Myxoedema Coma: Decompensated end-stage hypothyroidism presenting with hypothermia ($< 35^\circ\text{C}$), bradycardia, hypoventilation, hyponatraemia, hypotension, and obtundation. Emergency management: IV hydrocortisone 100 mg (prior to thyroid hormone), IV levothyroxine loading ($200\text{–}400\text{ mcg}$) or IV liothyronine (T3), slow passive rewarming (avoid active external rewarming: precipitates peripheral vasodilation and shock), and supportive mechanical ventilation.

Subclinical Thyroid Disease

• Subclinical Hypothyroidism: Elevated TSH with normal free T4 and free T3.
  • Indications to Treat (NICE Guidelines):
    1. Serum $\text{TSH} \ge 10.0\text{ mU/L}$ (high rate of progression to overt disease; adverse cardiovascular and lipid risk).
    2. Serum $\text{TSH } 5.5\text{–}10.0\text{ mU/L}$ in patients aged $< 65$ years with persistent hypothyroid symptoms, positive anti-TPO antibodies, or pregnant/planning conception.
    3. In asymptomatic elderly patients ($> 80$ years), conservative observation ("watch and wait") is recommended; treatment does not improve clinical outcomes and increases the risk of atrial fibrillation and bone demineralisation.
• Subclinical Hyperthyroidism: Suppressed TSH ($< 0.1\text{ mU/L}$) with normal free T4 and free T3. Carries a 3-fold increased risk of atrial fibrillation and accelerated osteoporosis (loss of trabecular and cortical bone density). Treat with antithyroid drugs or radioiodine if $\text{TSH} < 0.1\text{ mU/L}$ and age $\ge 65$ years, or presence of established cardiac disease, osteoporosis, or high fracture risk.

5. Thyroid Nodules & Malignancies

Ultrasound Stratification: British Thyroid Association (BTA U1–U5)

• U1 (Normal): No focal lesions.
• U2 (Benign): Purely cystic, spongiform/honeycomb, hyperechoic nodule with peripheral halo.
• U3 (Indeterminate): Equivocal solid features without high-risk signs.
• U4 (Suspicious): Solid, hypoechoic, lobulated margin, microcalcifications.
• U5 (Malignant): Marked hypoechogenicity, taller-than-wide shape, irregular/infiltrative margins, microcalcifications, disrupted rim calcification, abnormal cervical lymphadenopathy. Fine-needle aspiration cytology (FNAC) is indicated for U3–U5 lesions.

Primary Thyroid Malignancies: Histopathological & Clinical Classification

Thyroid Malignancy Spectrum:
- Differentiated Epithelial:
  • Papillary Carcinoma (~80%): BRAF / RET-PTC → Psammoma bodies, Orphan Annie nuclei → Lymphatic spread → Excellent prognosis
  • Follicular Carcinoma (~10%): RAS / PAX8-PPARg → Requires capsular/vascular invasion → Haematogenous spread (bone/lung)
- Neuroendocrine C-Cell:
  • Medullary Carcinoma (~5%): RET proto-oncogene (MEN 2A/2B) → Calcitonin / Amyloid stroma → Screen for phaeochromocytoma!
- Undifferentiated:
  • Anaplastic Carcinoma (<2%): p53 mutations, elderly → Rapidly enlarging, compressive, highly aggressive → Dismal prognosis
- Lymphoid:
  • Thyroid Lymphoma (<2%): Hashimoto's thyroiditis background → CD20+ B-cell lymphoma → Chemo/radiotherapy responsive

• Papillary Thyroid Carcinoma (PTC): Most prevalent thyroid cancer ($70\text{–}80%$). Associated with prior childhood head/neck radiation exposure and BRAF V600E mutations. Pathognomonic histology: Psammoma bodies (concentric lamellated calcospherites), Orphan Annie eye nuclei (large, pale, ground-glass cleared nuclei), and nuclear grooves. Spreads primarily via lymphatic drainage to regional cervical lymph nodes. Overall 20-year survival exceeds $90\text{–}95%$. Management: total thyroidectomy, central compartment node dissection, postoperative radioiodine ($^{131}\text{I}$) ablation, and suppressive levothyroxine; serum thyroglobulin is the primary tumour marker for recurrence surveillance.
• Follicular Thyroid Carcinoma (FTC): Second most common ($10\text{–}15%$). More frequent in iodine-deficient regions; linked to RAS mutations and *PAX8-PPAR\gamma$ translocations. Crucial Diagnostic Rule: FNAC cannot differentiate a benign follicular adenoma from follicular carcinoma because cytologic features are identical. Histological proof of capsular invasion or vascular invasion on permanent surgical histology is strictly required to establish malignancy. Spreads primarily via haematogenous dissemination to bones (osteolytic metastases) and lungs. Treated with total thyroidectomy, radioiodine ablation, and thyroglobulin monitoring.
• Medullary Thyroid Carcinoma (MTC): Neuroendocrine malignancy derived from calcitonin-secreting parafollicular C cells (neural crest origin). Accounts for ~5% of thyroid cancers. 75% sporadic; 25% familial as part of MEN 2A, MEN 2B, or familial MTC driven by germline activating missense mutations in the RET proto-oncogene on chromosome 10. Pre-Surgical Safety Rule: Must screen for phaeochromocytoma (plasma/urinary metanephrines) and primary hyperparathyroidism prior to neck surgery; if a phaeochromocytoma is detected, it must be resected first to prevent fatal intraoperative hypertensive crisis. Histology: sheets of neuroendocrine cells in dense stroma containing amyloid deposits (derived from procalcitonin; stains with Congo red, displaying apple-green birefringence under polarized light). Tumour markers: calcitonin and carcinoembryonic antigen (CEA). Does NOT concentrate iodine; radioiodine-131 is completely ineffective.
• Anaplastic Thyroid Carcinoma (ATC): Highly aggressive, undifferentiated tumour occurring almost exclusively in elderly patients ($> 65$ years). Features inactivating mutations in TP53. Presents as a rapidly expanding, stony-hard, fixed neck mass causing acute local invasion: stridor, dysphagia, and recurrent laryngeal nerve palsy (hoarseness). Histology reveals pleomorphic spindle and giant cells with extensive necrosis. Median survival is 3 to 6 months; therapy is largely palliative (airway protection, external beam radiation, targeted BRAF inhibitors like dabrafenib/trametinib if BRAF-mutated).
• Primary Thyroid Lymphoma: Predominantly diffuse large B-cell lymphoma (DLBCL) or MALT lymphoma. Arises almost exclusively in the background of chronic autoimmune Hashimoto's thyroiditis (40- to 60-fold increased relative risk). Presents as a rapidly enlarging goitre with compressive symptoms in an elderly woman with known Hashimoto's. Core needle or surgical biopsy reveals dense sheets of CD20+ atypical lymphoid cells. Highly sensitive to systemic chemotherapy (CHOP) and radiotherapy; surgery is rarely indicated.