31. Thyrotoxicosis

1. Definition

• Thyrotoxicosis → clinical syndrome of excess circulating thyroid hormones
• Hyperthyroidism → excess synthesis or secretion of hormone by the thyroid itself
• Thyrotoxicosis without hyperthyroidism → thyroiditis, factitious intake
• Overt → suppressed thyroid-stimulating hormone (TSH), raised free thyroxine (T4) or triiodothyronine (T3)
• Subclinical → suppressed TSH, normal free T4 and T3; risk of atrial fibrillation and osteoporosis

2. Epidemiology

• United Kingdom → 27 in 1000 women, 3 in 1000 men
• Graves' disease → 4 times more common in women, age 20–40 years

3. Aetiology and risk factors

• Graves' disease, toxic multinodular goitre, solitary toxic nodule → over 95% of cases

Thyrotoxicosis with hyperthyroidism

• Graves' disease → most common cause
• Toxic multinodular goitre (Plummer's disease) → elderly, iodine-deficient areas
• Solitary toxic nodule (adenoma)
• Iodine-induced → Jod-Basedow phenomenon in a nodular gland
• Rare → TSH-secreting pituitary adenoma, hydatidiform mole, choriocarcinoma, struma ovarii, metastatic follicular carcinoma

Thyrotoxicosis without hyperthyroidism

• Thyroiditis → de Quervain's (subacute), postpartum, silent, early Hashimoto's
• Drug-induced → amiodarone, interferon
• Factitious → excess levothyroxine

Triggers of Graves' disease

• Smoking, stress, iodine, radiation
• Genes → HLA-DR3, CTLA-4; 80% concordance in identical twins

4. Pathogenesis

Graves' disease

1. TSH receptor antibodies (TRAb) bind and stimulate the TSH receptor
2. Diffuse hyperplasia and hypertrophy of follicles → diffuse vascular goitre
3. Excess T4 and T3 secretion → raised metabolic rate, sensitivity to catecholamines
4. Same antibodies act on orbital fibroblasts → inflammation, oedema, fibrosis → orbitopathy

Toxic nodular disease

• Activating mutations of the TSH receptor gene → autonomous nodules
• Nodules work independent of TSH → TSH suppressed, rest of the gland switched off
• Not autoimmune → no remission with drugs

Thyroiditis

• Destruction of follicles → release of stored hormone → transient thyrotoxicosis, low uptake on scan

5. Classification

• By cause → Graves', toxic multinodular goitre, toxic nodule, thyroiditis, drug-induced, factitious
• By severity → overt, subclinical
• Amiodarone-induced:
  • Type 1 → iodine-induced excess synthesis in an abnormal gland
  • Type 2 → destructive thyroiditis in a normal gland; responds to steroids

6. Clinical picture

Symptoms

• Weight loss with increased appetite
• Heat intolerance, sweating
• Palpitations, dyspnoea
• Anxiety, irritability, tremor, fatigue
• Diarrhoea
• Oligomenorrhoea
• Elderly → few symptoms; atrial fibrillation or heart failure alone

Signs

• Tachycardia, atrial fibrillation
• Fine tremor, warm moist skin, hyperreflexia, proximal myopathy
• Lid lag, lid retraction → sympathetic overactivity, any cause
• Goitre:
  • Diffuse with bruit or thrill → Graves'
  • Nodular → toxic multinodular goitre
  • Single nodule → toxic nodule

Graves'-specific signs

• Ophthalmopathy → exophthalmos, chemosis, lid retraction, periorbital oedema, ophthalmoplegia, diplopia, corneal ulcers; usually bilateral
• Pretibial myxoedema (dermopathy)
• Thyroid acropachy → finger clubbing
• Vitiligo, alopecia, other autoimmune disease

7. Diagnosis

Laboratory

• TSH → suppressed (except pituitary adenoma)
• Free T4 and T3 → raised
• TRAb → raised in 90% of Graves' disease; specificity 99%
• Anti-thyroid peroxidase (TPO) antibodies → autoimmune thyroid disease, thyroiditis
• Full blood count and liver function tests → baseline before antithyroid drugs

Imaging

• Ultrasound → increased vascularity in Graves', reduced in thyroiditis; nodules
• Scintigraphy (technetium-99m or iodine-123):
  • Diffuse increased uptake → Graves' disease
  • Patchy uptake → toxic multinodular goitre
  • Single hot focus, rest suppressed → toxic nodule
  • Low uptake → thyroiditis, iodine excess, factitious
• Toxic nodule → no fine-needle aspiration cytology (FNAC); hot nodules are rarely malignant and cytology is unhelpful (Thy3f)
• CT or MRI of the orbits → orbitopathy

8. Differential diagnosis

• Anxiety disorder
• Phaeochromocytoma
• Menopause
• Diabetes mellitus, malignancy → weight loss
• Sympathomimetic drugs, cocaine

9. Treatment

Conservative

• Beta-blockers (propranolol 40–120 mg/day) → tachycardia, tremor; also reduce T4 to T3 conversion
• Antithyroid drugs:
  • Carbimazole → first choice in the United Kingdom
  • Propylthiouracil → first trimester of pregnancy, thyroid storm; blocks T4 to T3 conversion; risk of liver failure
  • Regimens → dose titration, or block and replace (carbimazole 40 mg + levothyroxine after 4–6 weeks)
  • Euthyroid in 4–8 weeks; continued 12–18 months for remission
  • Relapse after stopping → about 60%; higher in men, smokers, large goitre, high TRAb
  • Side effects → rash, arthralgia, agranulocytosis
• Radioactive iodine (RAI, iodine-131):
  • Given as a drink; works in up to 4 months
  • Relapse → 15–20%
  • Contraindicated → pregnancy, breastfeeding, pregnancy planned within 6 months, close contact with young children
  • Severe eye disease → avoid; worsens in 15%; mild stable disease → give with steroid cover
  • Late hypothyroidism common
• Toxic nodular disease → drugs only to prepare for RAI or surgery
• Subclinical disease → treat if ≥ 65 years, cardiac risk, osteoporosis risk, symptoms

Surgical

• Indications:
  1. Large goitre with compression
  2. Suspicious or malignant nodule
  3. Severe or active ophthalmopathy
  4. Pregnancy, breastfeeding, planned pregnancy
  5. Children
  6. Failure, relapse, side effects or poor compliance with drugs
  7. Need for rapid control
• Operations:
  • Graves' disease → total thyroidectomy; cure in all; replaced subtotal thyroidectomy
  • Toxic multinodular goitre → total thyroidectomy
  • Solitary toxic nodule → lobectomy on the side of the nodule
• Preoperative preparation:
  1. Euthyroid with antithyroid drugs → avoids thyroid storm
  2. Beta-blocker for tachycardia
  3. Lugol's iodine 0.3 mL 3 times daily for 10 days in Graves' disease → less vascular gland (Wolff-Chaikoff effect)
  4. No iodine in toxic nodular goitre → may worsen thyrotoxicosis (Jod-Basedow)
  5. Vocal cord check, calcium and vitamin D
• After total thyroidectomy → lifelong levothyroxine

Pregnancy

• Graves' → 1 in 500 pregnancies
• Propylthiouracil in the first trimester, carbimazole after
• RAI contraindicated; surgery in the second trimester if needed
• TRAb cross the placenta → foetal and neonatal thyrotoxicosis

10. Complications

Of the disease

• Atrial fibrillation, cardiac failure
• Osteoporosis, muscle wasting
• Loss of vision → corneal ulceration, optic nerve compression
• Thyroid storm:
  • Triggers → surgery, trauma, infection, iodinated contrast, RAI, stopping drugs
  • Fever, marked tachycardia, arrhythmia, heart failure, vomiting, diarrhoea, agitation, coma
  • Treatment → beta-blocker, propylthiouracil, potassium iodide (1 h after the thionamide), hydrocortisone, cooling, intensive care

Of thyroidectomy in Graves' disease

• Bleeding → 1%
• Hypoparathyroidism → temporary in up to 30%; permanent in up to 5–10% (0.6–6% in high-volume centres)
• Recurrent laryngeal nerve injury → 1–2%; bilateral about 1 in 500
• External branch of the superior laryngeal nerve → loss of high pitch
• Hypothyroidism → expected after total thyroidectomy