Skip to content
Download PDF

Hyperthyroidism and Other Causes ofThyrotoxicosis

Chapter 396 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 396

Key Clinical Points

  1. Thyrotoxicosis is the state of thyroid hormone excess; it is not synonymous with hyperthyroidism (excessive thyroid function).
  2. Graves' disease is the most common cause of thyrotoxicosis, accounting for 60–80% of cases.
  3. Propylthiouracil (PTU) is preferred in the first trimester of pregnancy and during thyroid storm due to methimazole embryopathy risks.
  4. Thyroid storm has a high mortality rate (4–17%) and requires aggressive treatment with PTU, iodide, beta-blockers, and glucocorticoids.
  5. Graves' ophthalmopathy is associated with smoking and can worsen with radioiodine; teprotumumab is a specific monoclonal antibody treatment.
  6. Apathetic thyrotoxicosis in the elderly may present only with fatigue and weight loss rather than hyperadrenergic symptoms.
  7. Normal TSH and unbound T4/T3 levels effectively exclude thyrotoxicosis and Graves' disease.
  8. The NO SPECS scoring system (0–6) is used to evaluate the severity of Graves' ophthalmopathy.
  9. Subacute thyroiditis is characterized by a high ESR and a distinct clinical course involving a thyrotoxic phase followed by a hypothyroid phase.
  10. Methimazole is the preferred antithyroid drug in the US; PTU is reserved for first-trimester pregnancy or thyroid storm.

DEFINITION & OVERVIEW

• Definition (Harrison's 22e): Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function. • Clinical Presentation Factors: ◦ Severity of thyrotoxicosis ◦ Duration of disease ◦ Individual thyroid tissue susceptibility to excess hormone ◦ Patient age (e.g., elderly may present with 'apathetic thyrotoxicosis'—fatigue and weight loss). • Classification of Thyrotoxicosis: ◦ Primary Hyperthyroidism: Excessive hormone production by the thyroid gland. ◦ Thyrotoxicosis without Hyperthyroidism: Release of preformed hormone without increased synthesis (e.g., thyroiditis). ◦ Secondary Hyperthyroidism: Excessive hormone production driven by TSH or other factors (e.g., pituitary adenoma, hCG-secreting tumors).

EPIDEMIOLOGY

• Graves' Disease Prevalence: ◦ Accounts for 60–80% of thyrotoxicosis. ◦ Occurs in up to 3% of women; 1/10th as frequent in men. ◦ Risk factors: High iodine intake, postpartum period (3x increase), and immune reconstitution after HAART or checkpoint inhibitors. • Graves' Ophthalmopathy: Approximately one-third of patients with Graves' disease show clinical evidence of ophthalmopathy.

ETIOLOGY & PATHOPHYSIOLOGY

• Graves' Disease Pathogenesis: ◦ Caused by thyroid-stimulating immunoglobulins (TSIs) and TSH receptor antibodies (TRAb). ◦ TRAb can cross the placenta → risk of neonatal thyrotoxicosis. ◦ Coexisting autoantibodies: TPO and Tg antibodies in up to 80% of cases. • Ophthalmopathy Pathophysiology: ◦ Driven by cytokines (IFN-γ, TNF, IL-1) leading to fibroblast activation and glycosaminoglycan synthesis → muscle swelling. ◦ Resulting tissue expansion: Fibrosis, fat accumulation, and increased intraorbital pressure → proptosis, diplopia, and optic neuropathy. ◦ Mechanism: TSH-R is a thyroid autoantigen expressed in orbital tissues; also involves IGF-1R signaling.

Graves' Disease Risk Factors

• Genetic: Polymorphisms in HLA-DR, CTLA-4, CD25, CD40, PTPN22, FCRL3, and CD226. ◦ Monozygotic twins: 20–30% concordance (vs. <5% for dizygotic). ◦ Environmental: Stress, smoking (major risk for ophthalmopathy), and sudden iodine increase.

CLINICAL FEATURES

• General Thyrotoxicosis Features: ◦ Metabolic: Weight loss with increased appetite (5% may gain weight due to overeating). ◦ Neuropsychiatric: Hyperactivity, nervousness, irritability, insomnia, impaired concentration. ◦ Neuromuscular: Fine tremor, hyperreflexia, muscle wasting, proximal myopathy; hypokalemic periodic paralysis (common in Asian males). ◦ Integumentary: Warm/moist skin, sweating, heat intolerance, palmar erythema, onycholysis, hair thinning/alopecia. ◦ Gastrointestinal: Decreased transit time → increased stool frequency, diarrhea, mild steatorrhea. ◦ Reproductive/Endocrine: Oligomenorrhea/amenorrhea (women); impaired sexual function/gynecomastia (men). ◦ Bone/Mineral: Osteopenia from direct hormone effect; hypercalcemia in up to 20% of patients. • Graves' Specific Features: ◦ Ophthalmopathy: Proptosis, periorbital edema, scleral injection, chemosis, lid retraction (due to sympathetic overactivity). ◦ Dermopathy: <5% of cases; noninflamed, indurated plaques (pretibial myxedema) on lower legs. ◦ Acropachy: <1% of cases; a form of clubbing strongly associated with dermopathy. • Table 396-2 Summary: ◦ Symptoms: Hyperactivity/irritability, heat intolerance, palpitations, fatigue, weight loss, diarrhea, polyuria, oligomenorrhea. ◦ Signs: Tachycardia (atrial fibrillation in elderly), tremor, goiter, warm skin, muscle weakness, lid retraction, gynecomastia.

Graves' Ophthalmopathy (NO SPECS)

• Clinical Presentation: ◦ Early: Grittiness, discomfort, excess tearing. ◦ Advanced: Proptosis, diplopia (5–10%), optic nerve compression → papilledema and vision loss. ◦ NO SPECS Scoring System: ◦ 0 = No signs/symptoms ◦ 1 = Lid retraction or lag ◦ 2 = Soft tissue involvement (periorbital edema) ◦ 3 = Proptosis (>22 mm) ◦ 4 = Extraocular muscle involvement (diplopia) ◦ 5 = Corneal involvement ◦ 6 = Sight loss

DIFFERENTIAL DIAGNOSIS

• Mimics: Panic attacks, mania, pheochromocytoma, malignancy-related weight loss. ◦ Exclusion: Normal TSH and unbound T4/T3 levels rule out thyrotoxicosis. ◦ Graves' Diagnosis: Confirmed by biochemical thyrotoxicosis + diffuse goiter + ophthalmopathy + TRAb positivity. ◦ Alternative Confirmation: Radionuclide scan (distinguishes Graves' from thyroiditis, adenoma, or factitious) or color-flow Doppler ultrasound.

DIAGNOSTIC APPROACH

  1. Initial Screening: Measure TSH, unbound T4, and T3.
  2. Interpretation of Results (Decision Pathway): ◦ Step 1: Assess TSH and T4. ◦ TSH low + T4 high → Proceed to Step 2. ◦ TSH low + T4 normal → Measure T3 → ◦ If T3 high → T3 toxicosis. ◦ If T3 normal → Subclinical hyperthyroidism (Follow up in 6–12 weeks). ◦ TSH normal or increased + T4 high → TSH-secreting pituitary adenoma or thyroid hormone resistance syndrome. ◦ TSH and T4 both normal → No further tests. ◦ Step 2: Identify Specific Cause (for TSH low, T4 high): ◦ Check for Graves' features (Diffuse goiter, TRAb+, ophthalmopathy, dermopathy). ◦ If Yes → Graves' disease. ◦ If No → Proceed to Step 3. ◦ Step 3: Nuclear Imaging/Palpation: ◦ Is there a multinodular goiter or toxic adenoma? ◦ If Yes → Toxic nodular hyperthyroidism. ◦ If No → Perform radionuclide scan. ◦ If uptake is low → Destructive thyroiditis, iodine excess, or factitious thyrotoxicosis. ◦ If uptake is not low → Rule out other causes (e.g., hCG stimulation).

Flowchart 396-2 Logic Path Summary: • Path A (Primary): TSH low, T4 high → Graves' features? → Yes → Graves' disease. • Path A2 (Nodular): TSH low, T4 high → Graves' features? → No → Multinodular/Adenoma? → Yes → Toxic nodular hyperthyroidism. • Path A3 (Destructive): TSH low, T4 high → Graves' features? → No → Multinodular/Adenoma? → No → Low radionuclide uptake? → Yes → Destructive thyroiditis, iodine excess, or factitious. • Path A4 (Other): TSH low, T4 high → Graves' features? → No → Multinodular/Adenoma? → No → Low radionuclide uptake? → No → Rule out other causes (e.g., hCG). • Path B1 (T3 Toxicosis): TSH low, T4 normal → Measure T3 → High → T3 toxicosis. • Path B2 (Subclinical): TSH low, T4 normal → Measure T3 → Normal → Subclinical hyperthyroidism → Follow up in 6–12 weeks. • Path C (Secondary): TSH high/normal, T4 high → Secondary Hyperthyroidism (Pituitary adenoma or resistance).

Table 396-1: Causes of Thyrotoxicosis

• Primary Hyperthyroidism: Graves' disease, Toxic multinodular goiter, Toxic adenoma, Functioning thyroid carcinoma metastases, TSH receptor mutation, Gα mutation (McCune-Albright), Struma ovarii, Drugs (Jod-Basedow). ◦ Thyrotoxicosis without Hyperthyroidism: Subacute thyroiditis, Silent thyroiditis, other destruction causes (amiodarone, cytokines, TKIs, checkpoint inhibitors, radiation, infarction), factitious. ◦ Secondary Hyperthyroidism: TSH-secreting pituitary adenoma, Thyroid hormone resistance syndrome, Chorionic gonadotropin-secreting tumors, Gestational thyrotoxicosis.

Table 396-3: Causes of Thyroiditis

• Acute: Bacterial (Staph, Strep, Enterobacter), Fungal (Aspergillus, Candida, Coccidioides, Histoplasma, Pneumocystis). ◦ Subacute: Viral (granulomatous), Mycobacterial, Drug-induced (interferon, amiodarone, TKIs, checkpoint inhibitors). ◦ Chronic: Autoimmunity (focal, Hashimoto's, atrophic), Riedel's, Parasitic (echinococcosis, strongyloidiasis, cysticercosis), Traumatic.

MANAGEMENT & TREATMENT

  1. Initial Medical Therapy: ◦ Antithyroid drugs (thionamides): Methimazole or Carbimazole. ◦ Beta-blockers: Propranolol (20–40 mg every 6 h) or atenolol to control adrenergic symptoms; also used in thyrotoxic periodic paralysis.
  2. Antithyroid Drug Regimens: ◦ Titration: Adjust dose based on unbound T4 levels; review every 4–6 weeks. ◦ Block-Replace: Keep antithyroid drug constant, adjust T4 to maintain normal T4. ◦ Dosage: Carbimazole/Methimazole (2.5–10 mg daily); Propylthiouracil (50–100 mg daily).
  3. Special Drug Indications: ◦ Propylthiouracil (PTU): Use in 1st trimester of pregnancy or thyroid storm. ◦ Methimazole: Preferred in US; avoid in first trimester due to hepatotoxicity risk.
  4. Radioiodine (131I) and Surgery: ◦ Used for definitive treatment or relapses. ◦ Pre-treatment: Antithyroid drugs + beta-blockers for 1 month before 131I if high risk of crisis. ◦ Timing: Carbimazole/Methimazole stop 2–3 days before 131I; PTU stop longer period due to radioprotective effect.
  5. Monitoring & Safety: ◦ Agranulocytosis (<1%): Stop thionamides immediately if fever, sore throat, or mouth ulcers occur; do not restart. ◦ Side Effects: Rash, urticaria, fever, arthralgia (1–5%). ◦ Follow-up: Monitor for relapse during first year and annually thereafter.

Pregnancy & Breastfeeding

• First Trimester: Use PTU due to methimazole embryopathy risk. ◦ Second/Third Trimester: Switch to Methimazole. ◦ Radioiodine: Contraindicated in pregnancy and breastfeeding; safe to conceive 6 months after treatment.

COMPLICATIONS & PROGNOSIS

• Thyroid Storm: High mortality (4–17%); requires aggressive PTU, iodide, beta-blockers, and glucocorticoids. ◦ Relapse Risk: Higher in younger patients, males, smokers, those with large goiters, or persistent TRAb. ◦ Remission: 30–60% achieved by 12–18 months with titration regimen.

KEY PEARLS & HIGH-YIELD POINTS

• Thyrotoxicosis eq Hyperthyroidism. ◦ Thyrotoxicosis = hormone excess. ◦ Hyperthyroidism = excessive thyroid function. ◦ Most common cause of thyrotoxicosis is Graves' disease (60–80%). ◦ T3 Toxicosis: TSH low, T4 normal, T3 high; often seen with iodine excess. ◦ Subacute Thyroiditis: High ESR and a distinct clinical course (thyrotoxic → hypothyroid → recovery). ◦ Pregnancy Rule: PTU for 1st trimester/Thyroid storm; Methimazole otherwise. ◦ Agranulocytosis: Stop thionamides immediately if fever or sore throat occurs; do not restart.

Reference Tables

TABLE 396-1 Causes of Thyrotoxicosis Primary Hyperthyroidism Graves’ disease Toxic multinodular goiter Toxic adenoma…

Harrison's 22e, p.3033

  • Primary Hyperthyroidism
  • Graves’ disease
  • Toxic multinodular goiter
  • Toxic adenoma
  • Functioning thyroid carcinoma metastases
  • Activating mutation of the TSH receptor
  • Activating mutation of Gα (McCune-Albright syndrome)
    S
  • Struma ovarii
  • Drugs: iodine excess (Jod-Basedow phenomenon)
  • Thyrotoxicosis without Hyperthyroidism
  • Subacute thyroiditis
  • Silent thyroiditis
  • Other causes of thyroid destruction: drugs (amiodarone, cytokines, tyrosine
    kinase inhibitors, immune checkpoint inhibitors), radiation, infarction of adenoma
  • Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue
  • Secondary Hyperthyroidism
  • TSH-secreting pituitary adenoma
  • Thyroid hormone resistance syndrome: occasional patients may have features of
    thyrotoxicosis
  • Chorionic gonadotropin-secreting tumorsa
  • Gestational thyrotoxicosisa

TABLE 396-2 Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency)

SYMPTOMS SIGNSa
Hyperactivity, irritability, dysphoria
Heat intolerance and sweating
Palpitations
Fatigue and weakness
Weight loss with increased appetite
Diarrhea
Polyuria
Oligomenorrhea, loss of libido		 Tachycardia; atrial fibrillation in the
elderly
Tremor
Goiter
Warm, moist skin
Muscle weakness, proximal myopathy
Lid retraction or lag
Gynecomastia

TABLE 396-3 Causes of Thyroiditis Acute Bacterial infection: especially Staphylococcus, Streptococcus, and Enterobacter…

Harrison's 22e, p.3038

  • Acute
  • Bacterial infection: especially Staphylococcus, Streptococcus, and Enterobacter
  • Fungal infection: Aspergillus, Candida, Coccidioides, Histoplasma, and
    Pneumocystis
  • Radiation thyroiditis after 131I treatment
  • Amiodarone (may also be subacute or chronic)
  • Subacute
  • Viral (or granulomatous) thyroiditis
  • Silent thyroiditis (including postpartum thyroiditis)
  • Mycobacterial infection
  • Drug-induced (interferon, amiodarone, tyrosine kinase inhibitors, immune
    checkpoint inhibitors)
  • Chronic
  • Autoimmunity: focal thyroiditis, Hashimoto’s thyroiditis, atrophic thyroiditis
  • Riedel’s thyroiditis
  • Parasitic thyroiditis: echinococcosis, strongyloidiasis, cysticercosis
  • Traumatic: after palpation