Hyperthyroidism

Hyperthyroidism is a clinical state resulting from excess circulating thyroid hormone. It arises from a range of underlying causes with distinct pathophysiology and treatment implications.

The causes include Graves disease, toxic multinodular goitre, toxic adenoma, subacute thyroiditis, and, less commonly, excessive exogenous thyroid hormone intake or, rarely, a thyrotropin secreting pituitary adenoma.

Accurate identification of the specific cause is essential, given the fundamentally different treatment approaches required. These range from antithyroid medication and definitive treatment for autonomous thyroid hormone overproduction to purely symptomatic management for the transient hyperthyroidism of thyroiditis.

Pathophysiology and classification

• Graves disease, the commonest cause of hyperthyroidism overall, reflects autoimmune stimulation of the thyroid stimulating hormone receptor by thyroid stimulating immunoglobulins, addressed in full detail under that specific condition.
• Toxic multinodular goitre and toxic adenoma reflect autonomous, thyroid stimulating hormone independent thyroid hormone production from hyperfunctioning nodules.
• In toxic multinodular goitre, one or more hyperfunctioning nodules lie within an otherwise structurally abnormal (multinodular) gland. In a solitary toxic adenoma, a single discrete hyperfunctioning nodule lies within an otherwise normal thyroid gland.
• These conditions typically develop over years in longstanding nodular thyroid disease. They are particularly relevant in older patients and in regions with historical iodine deficiency.
• Thyroiditis related hyperthyroidism occurs in subacute thyroiditis, and also in postpartum thyroiditis and the initial phase of Hashimoto thyroiditis in a proportion of patients.
• It reflects release of preformed thyroid hormone from an inflamed, damaged thyroid gland rather than genuine excess synthesis. The process is fundamentally different, generally self limiting and transient. Antithyroid medication is not required, as there is no ongoing excess hormone synthesis.

• The typical constellation of hyperthyroid symptoms, shared across the various underlying causes, comprises weight loss despite normal or increased appetite, heat intolerance, palpitations, tremor, anxiety and irritability, and increased sweating. In a substantial proportion of women there is oligomenorrhoea or amenorrhoea.
• Characteristic examination findings are tachycardia, atrial fibrillation, warm, moist skin, fine tremor, and lid lag or lid retraction.
• Atrial fibrillation is particularly important in older patients, where it may be the presenting or most prominent feature.
• Lid lag and lid retraction reflect sympathetic overactivity affecting the levator palpebrae superioris. They are distinct from the autoimmune orbital involvement of Graves ophthalmopathy.
• Specific features point toward the underlying cause. Graves disease causes ophthalmopathy, dermopathy and a diffusely enlarged, sometimes bruit positive goitre.
• A palpable multinodular or solitary nodular goitre supports toxic nodular disease. A preceding painful, tender thyroid gland with a viral prodrome supports subacute thyroiditis.
• Elderly patients frequently present with a more subtle, "apathetic" pattern. Weight loss, atrial fibrillation and depression or apathy predominate over the classically recognised adrenergic features. Keep a lower threshold for thyroid function testing in this population when these sometimes atypical features are present.

• The essential initial biochemical assessment is thyroid stimulating hormone, free thyroxine and free triiodothyronine.
• Thyroid stimulating hormone is suppressed in essentially all causes of genuine hyperthyroidism. The rare exception is a thyrotropin secreting pituitary adenoma, where it is inappropriately normal or elevated despite excess thyroid hormone.
• Free thyroxine and free triiodothyronine are both elevated in overt hyperthyroidism. Isolated triiodothyronine toxicosis (elevated triiodothyronine with normal free thyroxine) occurs in a proportion of cases, particularly early Graves disease and toxic nodular disease.
• Thyroid stimulating hormone receptor antibody testing supports a diagnosis of Graves disease specifically.
• Radioactive iodine uptake scanning gives functional information that distinguishes between the underlying causes. Diffusely increased uptake supports Graves disease. Focal or patchy increased uptake, corresponding to hyperfunctioning nodules, supports toxic multinodular goitre or toxic adenoma.
• Characteristically low or absent uptake supports thyroiditis, given release of preformed hormone rather than increased synthesis and trapping. It also supports exogenous thyroid hormone excess.
• Thyroid ultrasound characterises any nodular disease present, supporting assessment of toxic nodular goitre or adenoma.
• Inflammatory markers are elevated in subacute thyroiditis. They help distinguish this cause where the characteristic painful thyroid presentation suggests it.
• Screen for Graves ophthalmopathy (clinical assessment and, where indicated, orbital imaging) in any patient with confirmed or suspected Graves disease, given the specific implications for management detailed under that condition.

• Antithyroid medication is used for genuine, ongoing excess thyroid hormone synthesis (Graves disease and toxic nodular disease). It reduces thyroid hormone synthesis. Titrate the dose to clinical and biochemical response over subsequent weeks to months.
• The options are carbimazole, typically starting at 20 to 40 mg once daily, or propylthiouracil. Propylthiouracil is particularly preferred in the first trimester of pregnancy and in thyroid storm, given its additional peripheral conversion blocking activity.
• Beta blockade (propranolol 10 to 40 mg three to four times daily, or a longer acting agent, titrated to symptomatic and heart rate response) gives rapid, effective symptomatic control of the adrenergic features (tachycardia, tremor, anxiety) while definitive treatment takes effect.
• Beta blockade is an important, generally well tolerated adjunct across the great majority of hyperthyroid presentations, regardless of the underlying cause.
• Definitive treatment options are radioactive iodine ablation or surgical thyroidectomy. Consider them for Graves disease not achieving durable remission with antithyroid medication.
• They are also the generally preferred definitive approach for toxic multinodular goitre and toxic adenoma, given the low likelihood of spontaneous remission in these autonomous nodular conditions.
• Individualise the choice between radioactive iodine and surgery according to goitre size, patient preference, presence of significant ophthalmopathy, and other relevant clinical factors. Radioactive iodine carries a recognised risk of ophthalmopathy exacerbation, addressed further under Graves ophthalmopathy.
• Thyroiditis related hyperthyroidism is managed with beta blockade for symptomatic relief alone. There is no genuine excess hormone synthesis, so antithyroid medication is neither appropriate nor effective.
• The hyperthyroid phase is generally self limiting over several weeks. It is often followed by a transient hypothyroid phase before thyroid function returns to normal in the majority of cases.
• Thyroid storm is a rare, life threatening exacerbation of hyperthyroidism. It is characterised by severe hypermetabolic decompensation with high fever, marked tachycardia or arrhythmia, and altered consciousness.
• Thyroid storm requires emergency, intensive combination treatment, managed in an intensive care setting given the substantial associated mortality if not promptly and fully treated. Treatment comprises:
  • High dose propylthiouracil.
  • Iodine solution, given after antithyroid medication to avoid providing additional substrate for hormone synthesis.
  • High dose corticosteroids, which reduce peripheral thyroid hormone conversion and provide relative adrenal support given the physiological stress of this state.
  • Beta blockade, and aggressive general supportive care.
• Monitor thyroid function regularly throughout treatment, whatever approach is selected. Also monitor for antithyroid medication adverse effects.
• Agranulocytosis with carbimazole is rare but important. Educate patients to present urgently, and to have a blood count checked, with any significant febrile illness or sore throat during treatment.