Hyperthyroidism in Children

Definition

Hyperthyroidism is a clinical syndrome resulting from hypermetabolism due to excessive synthesis and secretion of thyroid hormones (T4 and T3) by the thyroid gland. Thyrotoxicosis is the clinical state of excess thyroid hormone, which can occur without hyperthyroidism (e.g., thyroiditis, factitious).

Etiology in Children

Graves' Disease (GD): (Most common cause, 80–95%). Autoimmune disorder, often with a family history of autoimmune thyroid disease. Peak incidence in adolescence.
Neonatal Graves' Disease:
- Transient: Transplacental passage of maternal TSH-Receptor Antibodies (TRAb). Resolves in 3–6 months as maternal IgG decays.
- Persistent: Activating mutation of the TSHR gene (non-autoimmune).
Toxic Nodular Goiter (Rare in children):
- Toxic Adenoma (Single "hot" nodule): Somatic activating mutation of TSHR.
- McCune-Albright Syndrome: Somatic activating mutation of the GNAS1 gene (constitutive cAMP activation).
Hashitoxicosis: Transient thyrotoxic phase (due to hormone release from follicular destruction) during the evolution of Hashimoto's thyroiditis.
Exogenous: Factitious ingestion of thyroid hormone.
Iodine-Induced (Jod-Basedow effect): Rare in children.

Pathophysiology (Graves' Disease)

GD is caused by TSH-Receptor Antibodies (TRAb), specifically Thyroid-Stimulating Immunoglobulins (TSI).

These antibodies bind to the TSH receptor (TSHR) on thyroid follicular cells.
They mimic TSH action, activating adenylate cyclase and the cAMP pathway.
This leads to unregulated, continuous thyroid hormone synthesis (T4, T3) and release, as well as glandular hyperplasia (goiter).
The normal hypothalamic-pituitary-thyroid axis negative feedback is overridden; pituitary TSH secretion is suppressed.

Clinical Features

Symptoms are often insidious in children.

Neurobehavioral: Decline in school performance, short attention span, hyperactivity, emotional lability, anxiety, and insomnia.
Goiter: Diffuse, symmetrical, firm, and non-tender. A vascular bruit may be audible.
Systemic/Metabolic: Weight loss (or poor weight gain) despite polyphagia, heat intolerance, excessive sweating (diaphoresis), and fatigue.
Cardiovascular: Tachycardia (key sign, check sleeping pulse rate), palpitations, widened pulse pressure, systolic hypertension, and rarely, high-output cardiac failure.
Neuromuscular: Fine tremor (e.g., of outstretched hands), proximal muscle weakness.
Ophthalmopathy (Specific to Graves'): Occurs in approx 50% of children.
- Signs: Stare (Dalrymple sign), lid lag (von Graefe's sign), lid retraction.
- Symptoms: Grittiness, photophobia, excessive tearing.
- True Infiltrative Disease: Proptosis (exophthalmos), periorbital edema, chemosis, and ophthalmoplegia (diplopia).
Pediatric-Specific Growth: Accelerated linear growth and advanced bone age (due to direct T4 effect on chondrocytes).
Skin: Warm, moist skin (vasodilation). Pretibial myxedema is extremely rare in children.

Investigations & Diagnosis

Biochemical Confirmation of Thyrotoxicosis
- Primary Screening: Suppressed TSH (<0.01 mIU/L) with elevated Free T4 (FT4).
- T3 Toxicosis: Suppressed TSH, normal FT4, but elevated Total T3 (TT3). (Often seen early in GD).
Etiological Diagnosis
- Thyroid Autoantibodies:
  - TRAb (TSHR-Ab): High levels are diagnostic for Graves' disease. Differentiates GD from thyroiditis or toxic nodules.
  - Anti-TPO (Thyroperoxidase) Ab: Positive in approx 80% of GD (and most Hashimoto's).
  - Anti-Thyroglobulin (Anti-Tg) Ab: Less specific.
- Thyroid Ultrasound (USG) with Doppler:
  - Modality of choice in children (avoids radiation).
  - Graves': Diffusely enlarged, hypoechoic gland with markedly increased vascularity ("thyroid inferno" on Doppler).
  - Nodule: Identifies solitary or multiple nodules.
- Radionuclide Uptake Scan (I123 or Tc99m-pertechnetate):
  - Used if USG/antibodies are non-diagnostic.
  - Graves': Diffuse, increased uptake.
  - Toxic Nodule: Focal "hot" nodule with suppression of remaining gland.
  - Thyroiditis: Low or absent uptake (critical differentiator).
Baseline & Other Tests
- CBC with differential: Baseline before starting Anti-Thyroid Drugs (ATDs) (to check for neutropenia).
- LFTs (AST/ALT, Bilirubin): Baseline before ATDs (MMI/PTU hepatotoxicity).
- Bone Age: Often advanced.

Management (Medical Therapy)

Symptomatic Control (Beta-Blockers)
- Used for initial symptomatic relief (tachycardia, tremor, anxiety) while awaiting ATD effect.
- Propranolol: 0.5–2 mg/kg/day (divided TID).
- Also inhibits peripheral conversion of T4 to T3 (at higher doses).
- Tapered off once the patient is biochemically euthyroid.
Anti-Thyroid Drugs (ATDs) - Thionamides
- Inhibit thyroid peroxidase (TPO), blocking organification and coupling steps.
- Methimazole (MMI):
  - First-line drug of choice in children.
  - Dose: 0.2–1.0 mg/kg/day (Max 30–45 mg) given once daily (improves adherence).
  - Less hepatotoxicity risk than PTU.
- Propylthiouracil (PTU):
  - Dose: 5–10 mg/kg/day (divided TID).
  - Black Box Warning (BBW) for severe hepatotoxicity/liver failure.
  - Reserved only for:
    - Neonatal Graves' disease (also rapidly blocks T4 → T3 conversion).
    - First trimester of pregnancy.
- Minor MMI allergic reactions (if desensitization fails).
- Monitoring ATD Therapy:
  - FT4/TT3 monitored every 4-6 weeks until euthyroid, then 3-4 monthly.
  - TSH is NOT used for initial titration as it remains suppressed for months.
- Side Effects:
  - Minor (5%): Rash, urticaria, arthralgia (treat with antihistamines).
  - Major (0.2–0.5%): Agranulocytosis (ANC <500/mm3). Counsel family to stop ATD and seek immediate care (CBC) if fever or sore throat occurs.
  - Major (Rare): Hepatotoxicity (monitor LFTs if symptomatic), ANCA-positive vasculitis.

Management (Definitive Therapy & Complications)

Indications for Definitive Therapy

Pediatric remission rates on ATDs (18–24 months course) are low (approx. 30–50%)
Definitive therapy is required for:
- ATD failure (relapse or persistent disease after 18–24 months).
- Major ATD toxicity (agranulocytosis, hepatotoxicity).
- Poor adherence to medical therapy.
- Very large goiter (>80g) or compressive symptoms.
- Patient/family preference.
Definitive Options
1. Radioactive Iodine (RAI; I131):
  - Highly effective (ablates the gland). Preferred definitive option in North America for older children (>10 years).
  - Cautions: Generally avoided <10 years (though safety data >5y is good), pregnancy, severe ophthalmopathy (may worsen it).
  - Outcome: Inevitable permanent hypothyroidism requiring lifelong L-thyroxine.
2. Total Thyroidectomy:
  - Preferred for: Children <10 years, very large goiters, suspected malignancy, severe/progressive ophthalmopathy, or patient refusal of RAI.
  - Prerequisites: Must be rendered euthyroid with ATDs and given pre-operative Lugol’s iodine (to reduce gland vascularity).
  - Complications: Permanent hypothyroidism (guaranteed), risk of hypoparathyroidism, recurrent laryngeal nerve injury (voice change). Requires high-volume pediatric thyroid surgeon.
Complication: Thyroid Storm (Thyrotoxic Crisis)
- A life-threatening medical emergency (high mortality) precipitated by infection, trauma, surgery, or ATD non-adherence.
- Diagnosis (Burch-Wartofsky score): Hyperpyrexia (>103oF), severe tachycardia (out of proportion to fever), arrhythmia, CHF, altered sensorium (agitation, delirium, coma), and severe GI distress.
PICU Management (The "5 Bs"):
1. Block Synthesis: PTU (preferred) or MMI (high dose, oral/NGT).
2. Block Release: Iodide (SSKI or Lugol's) at least 1 hour AFTER ATD. (Blocks hormone release - Wolff-Chaikoff effect).
3. Block Periphery: Propranolol (IV or oral) for adrenergic symptoms.
4. Block Conversion (T4 → T3): IV Hydrocortisone (also treats relative adrenal insufficiency) and high-dose PTU.
5. Block Enterohepatic circulation: Cholestyramine (uncommon).
6. Supportive Care: Cooling blankets, hydration, treat the precipitant