Hyperthyroidism and Graves disease — formative SAQs

SAQ 1 (10 marks)

A thirteen-year-old girl presents over four months with palpitations, a tremor, a five-kilogram weight loss despite an increased appetite, heat intolerance, anxiety and declining school performance. Her mother has noticed that her eyes look prominent. Examination reveals a heart rate of 110 beats per minute, a bounding pulse with a blood pressure of 130/60 mmHg, a fine tremor, lid retraction and mild proptosis, and a diffuse, smooth goitre with an audible bruit. Her thyroid function shows a TSH of less than 0.05 mU/L, a free T4 of 38 pmol/L and a positive TSH-receptor antibody. [1] [3]

a) Give the diagnosis and explain how the clinical and biochemical picture arises from the underlying autoimmune mechanism. (3 marks) [1]

b) Outline the immediate and long-term pharmacological management, naming the first-line antithyroid drug, the role of the beta-blocker, the two dosing regimens, and the reason propylthiouracil is avoided. (3 marks) [1] [6] [9]

c) Describe the two drug dangers that must be explained to the family at every prescription, their presenting features, and the immediate response. (2 marks) [9]

d) Discuss the prognosis after a two-to-three-year course of antithyroid drugs, the relapse rate, and the factors that predict relapse. (2 marks) [5] [6]

SAQ 2 (10 marks)

A two-week-old boy is reviewed on the postnatal ward. His mother has a history of Graves disease treated with radioactive iodine three years ago and is now on thyroxine. The infant is tachycardic at 175 beats per minute, irritable, feeding voraciously but gaining weight poorly, and has a small goitre. Cord-blood thyroid function shows a suppressed TSH with a raised free T4, and the maternal and neonatal TSH-receptor antibody titres are both markedly elevated. [11]

a) Name the diagnosis, explain its mechanism, and explain why the mother's current hypothyroid state did not protect the baby. (3 marks) [11]

b) Outline the natural history and the management of this neonatal condition, including the expected duration and the drugs used. (2 marks) [11]

c) Compare this presentation with thyroid storm in an older child, describing the clinical features, the precipitants, and the four-pronged management. (3 marks) [1] [3]

d) Explain how you would distinguish Graves disease from subacute thyroiditis in an older thyrotoxic child, using the antibody, the radioiodine uptake and the inflammatory markers. (2 marks) [1] [3]

Marking guide

SAQ 1. The diagnosis is Graves disease, the commonest cause of childhood hyperthyroidism. A stimulating TSH-receptor antibody binds and constitutively activates the TSH receptor on the thyroid follicular cell, bypassing the pituitary negative-feedback brake, driving unregulated T4 and T3 synthesis, follicular hypertrophy and increased vascularity — hence the diffuse goitre with a bruit. The hormone excess up-regulates beta-adrenergic receptors, producing the tachycardia, tremor, anxiety, heat intolerance and wide pulse pressure, and accelerates metabolism, producing weight loss with increased appetite. The eye signs — proptosis, lid retraction and lag — are antibody-driven (the antibody acts on retro-orbital fibroblasts and adipocytes, causing glycosaminoglycan accumulation and orbital swelling) and are unique to Graves. The suppressed TSH with a raised free T4 and a positive TSH-receptor antibody confirms the diagnosis. [1] [3]

The management is layered. Carbimazole or methimazole is first-line (starting around 0.25 to 1 mg/kg per day methimazole equivalent, titrated to the free T4), because it is dosed once daily, is more effective, and carries a lower risk of liver failure than propylthiouracil. A beta-blocker (propranolol roughly 0.5 to 2 mg/kg per day in divided doses) bridges the beta-adrenergic symptoms within hours while the thionamide takes effect over weeks. The two regimens are the titration regimen (preferred in children: start standard, taper to the lowest euthyroid dose) and the block-and-replace regimen (high-dose thionamide plus replacement levothyroxine). Propylthiouracil is avoided except in thyroid storm and first-trimester pregnancy because it carries a real risk of fulminant liver failure in children. [1] [6] [9]

The two drug dangers are agranulocytosis (fever, sore throat, mouth ulcers or sepsis — stop the drug, check the neutrophil count, start antibiotics if infected) and hepatotoxicity (jaundice, dark urine, abdominal pain or fatigue — stop the drug, check liver function, switch agents). Every family must be warned at every prescription to present with fever or abdominal symptoms. [9]

After a two-to-three-year course, roughly half to two-thirds of children relapse, predicted by a large goitre, a high TSH-receptor antibody titre, severe biochemical disease at diagnosis and young age at onset. The response to relapse is a shared decision between prolonged or indefinite medical therapy and definitive radioactive iodine or surgery. [5] [6]

SAQ 2. The diagnosis is neonatal thyrotoxicosis from transplacentally acquired maternal TSH-receptor antibody. The antibody crosses the placenta and drives the fetal and neonatal thyroid, producing tachycardia, irritability, poor weight gain, a goitre and, in severe cases, heart failure and craniosynostosis. The mother's current hypothyroid state did not protect the baby because the risk travels with the antibody, not the thyroid status — radioactive iodine ablated her gland but left her antibody-positive, and that antibody still crossed the placenta. [11]

The condition is transient, resolving as the maternal antibody clears over three to six months. Management is methimazole (or propylthiouracil if breastfeeding considerations demand), a beta-blocker for symptom control, and supportive care, with the dose tapered as the antibody clears. Every infant of a mother with a history of Graves disease — treated or untreated — has thyroid function and a TSH-receptor antibody checked at birth and is monitored through the first months. [11]

Thyroid storm in an older child is the decompensated extreme of thyrotoxicosis: hyperpyrexia, severe tachycardia or arrhythmia, heart failure, agitation, delirium or coma, triggered by non-adherence, infection, surgery or diabetic ketoacidosis. It is a clinical diagnosis, treated before the laboratory confirms it, with the four-pronged regimen: propylthiouracil (which blocks T4-to-T3 conversion), iodine (given at least an hour after the thionamide to block release), a beta-blocker with corticosteroids, and supportive PICU care. [1] [3]

Graves disease is distinguished from subacute thyroiditis by a positive TSH-receptor antibody and a high diffuse radioiodine uptake in Graves, against a negative antibody, a low uptake, a painful tender goitre and raised inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) in subacute thyroiditis. Subacute thyroiditis is self-limited and managed with a beta-blocker and analgesia, not thionamides. [1] [3]