Acquired Hypothyroidism In Children

Acquired hypothyroidism is thyroid hormone deficiency developing after the neonatal period in a child whose thyroid functioned normally at birth. It affects about 1 to 2% of children and adolescents, with a female to male ratio of about 2 to 4:1 and a peak around puberty.

Causes:

• Chronic autoimmune (Hashimoto) thyroiditis, the commonest cause where iodine is sufficient (over 90%), with anti-thyroid peroxidase and anti-thyroglobulin antibodies. It is associated with type 1 diabetes, coeliac disease, Addison disease, vitiligo, juvenile arthritis, Down syndrome (30 to 40% develop thyroid dysfunction), Turner syndrome (30 to 50%), Klinefelter and Williams syndromes, and the autoimmune polyglandular syndromes
• Iodine deficiency (endemic goitre) or excess
• Iatrogenic: thyroidectomy, radioiodine, neck irradiation (including craniospinal and total body irradiation), antithyroid drug overtreatment, and drugs (lithium, amiodarone, interferon alpha, tyrosine kinase inhibitors, immune checkpoint inhibitors)
• Central (secondary or tertiary) hypothyroidism: pituitary or hypothalamic disease (craniopharyngioma, germinoma, head injury, cranial irradiation, septo optic dysplasia, genetic hypopituitarism), with low or normal TSH
• Infiltrative disease (cystinosis, Langerhans cell histiocytosis, iron overload in thalassaemia)
• Subacute thyroiditis, during its hypothyroid phase
• Dyshormonogenesis and thyroid hormone resistance
• Consumptive hypothyroidism from hepatic haemangiomas (type 3 deiodinase)

Onset is insidious and symptoms may be missed for years. The characteristic feature in children is growth failure: slowing of height velocity (below the 25th centile for age), short stature with modest weight gain, and delayed bone age, which is the hallmark.

Other features:

• Goitre (diffuse, firm, rubbery, sometimes nodular; absent in atrophic thyroiditis)
• Fatigue, lethargy, cold intolerance, constipation, dry skin, brittle hair, puffy face, hoarse voice, delayed relaxation of deep tendon reflexes, bradycardia, hypotension, myalgia, carpal tunnel syndrome
• Poor school performance, poor concentration and low mood
• Puberty: delay in many; paradoxically, some girls develop early breast development and vaginal bleeding and some boys develop testicular enlargement without virilisation (Van Wyk-Grumbach syndrome), because high TSH cross reacts with the FSH receptor; it resolves on thyroxine
• Menstrual abnormalities in adolescent girls
• Pericardial effusion, hyperlipidaemia, anaemia, raised creatine kinase, slipped capital femoral epiphysis, hyperprolactinaemia, and pituitary hyperplasia that can mimic a pituitary tumour on MRI
• Myxoedema coma is extremely rare in children

Examination: height and weight plotted, height velocity, mid-parental height, thyroid palpation, pubertal staging, and signs of associated autoimmune disease.

• Serum TSH and free T4: primary hypothyroidism shows raised TSH (above about 4.5 to 5 mU/L, assay dependent) with low free T4 (overt) or normal free T4 (subclinical). In central hypothyroidism free T4 is low with low, normal or inappropriately normal TSH. Reference ranges are age specific
• Anti-TPO and anti-thyroglobulin antibodies (anti-TPO positive in over 90% of Hashimoto thyroiditis)
• Thyroid ultrasound: heterogeneous hypoechoic gland with increased vascularity in Hashimoto thyroiditis; indicated for a nodule or asymmetric goitre
• Bone age (left hand and wrist radiograph), delayed in proportion to the duration of hypothyroidism
• Lipids, creatine kinase, full blood count, liver function and prolactin as appropriate
• Screening for associated autoimmune disease: HbA1c or glucose, tissue transglutaminase IgA with total IgA, and morning cortisol or adrenal antibodies when indicated
• If central hypothyroidism is suspected: cortisol, IGF-1, prolactin, LH, FSH and MRI of the hypothalamic pituitary region. Start glucocorticoid replacement before levothyroxine when adrenal insufficiency coexists, to avoid adrenal crisis
• Karyotype in girls with short stature and hypothyroidism if Turner syndrome is suspected

Levothyroxine replacement. Give once daily on an empty stomach, 30 to 60 minutes before breakfast (or at bedtime, at least 3 hours after the last meal), with water. For young children, tablets can be crushed in a small volume of water. Separate from soy, iron, calcium and fibre by at least 4 hours. Typical doses (micrograms/kg/day):

• Age 1 to 5 years: 5 to 6
• Age 6 to 12 years: 4 to 5
• Adolescence with incomplete puberty or growth: 2 to 3
• Growth and puberty complete: 1.6 (range 1.5 to 2)

In severe long standing hypothyroidism, start at 25 to 50% of the full dose and increase every 2 to 4 weeks, to avoid hyperactivity, insomnia, headache, tachycardia and, rarely, pseudotumour cerebri and slipped capital femoral epiphysis.

Subclinical hypothyroidism: treat if TSH is persistently above 10 mU/L, or if TSH is 5 to 10 mU/L with symptoms, goitre, positive antibodies, dyslipidaemia or growth failure.

Otherwise recheck TSH and free T4 every 3 to 6 months, because 30 to 60% normalise spontaneously, especially with TSH under 10 and negative antibodies.

Monitoring. TSH and free T4 6 to 8 weeks after starting or changing the dose, then every 3 to 4 months until stable, then every 6 to 12 months. Aim for TSH in the lower half of the reference range (0.5 to 2.5 mU/L) with free T4 in the upper half. Adjust the dose as the child grows. In central hypothyroidism titrate to free T4 in the upper half of the range, not TSH. Bone age annually if growth is a concern.

Growth and puberty. Catch up growth begins within months. Final height is usually normal when treatment starts early, and may be reduced when it is delayed. Precocious puberty from long standing hypothyroidism regresses with replacement.

Drug interactions. Iron, calcium, aluminium antacids, sucralfate, proton pump inhibitors, bile acid sequestrants and soy reduce absorption. Rifampicin, carbamazepine and phenytoin increase clearance. In pregnancy, raise the dose by 25 to 30% as soon as pregnancy is confirmed.

Counselling. Treatment is usually lifelong in Hashimoto thyroiditis, though some adolescents recover; a trial off therapy can be considered once growth and puberty are complete. Check adherence if TSH stays high. After a missed dose, take it when remembered; a double dose the next day is safe. Screen yearly for associated autoimmune disease, particularly in Down and Turner syndromes.