Hyperthyroidism is the production of excess thyroid hormones by an overactive thyroid gland (speeding up body functions). The most common form of hyperthyroidism is Graves’disease, which is an autoimmune disorder (in which the immune system attacks the thyroid tissue). Less commonly, the condition is associated with enlarged nodules in the thyroid gland.
Symptoms and signs
The characteristic signs of hyperthyroidism include increased appetite, weight loss, increased sweating, heat intolerance, rapid heart rate, and protruding eyes (in people with Graves’ disease). In severe cases, the thyroid gland often becomes enlarged (goitre) and there is physical and mental hyperactivity and muscle wasting.
Diagnosis, treatment and outlook
The diagnosis of hyperthyroidism is confirmed by measuring the level of thyroid hormones present in the blood. The condition can be treated with drugs that inhibit the production of thyroid hormones (see antithyroid drugs) or by the removal of part of the thyroid gland. People suffering from hyperthyroidism may be given radioactive iodine to destroy part of the thyroid tissue. Many people recover fully after treatment, but their hormone levels need to be monitored regularly so that any further abnormal changes can easily be detected and treated. Treatment with radioactive iodine may result in development of hypothyroidism (underactivity of the thyroid gland).
Read more: Hyperthyroidism: diagnosis and treatment
Hyperthyroidism (Thyrotoxicosis) in detail - technical
Aetiology—Graves’ disease, which is caused by TSH receptor stimulating autoantibodies, is responsible for 60 to 80% of cases, and nodular thyroid disease (toxic multinodular goitre and toxic adenoma) accounts for most of the rest.
Clinical features—presents with a wide range of symptoms and signs including hyperactivity, palpitations, fatigue, weight loss (despite increased appetite), sinus tachycardia (or atrial fibrillation), tremor, and eye signs (including lid retraction and lid lag). Biochemical diagnosis of primary hyperthyroidism is confirmed by a low serum TSH and a high free T4 and/or T3, with autoimmune hyperthyroidism associated with the presence of thyroid peroxidase autoantibodies in most patients with Graves’ disease. β-blockers can rapidly relieve symptoms, but definitive treatment requires antithyroid drugs (usually carbimazole or propythiouracil), radio-iodine (131I), or surgery.
Thyroid-associated ophthalmopathy—this often causes anxiety and social embarrassment, but severe cases are a threat to vision and may require treatment with corticosteroids, radiotherapy, other immunosuppressive agents, or orbital decompression.
Thyrotoxic crisis or storm—this is the most dramatic presentation of hyperthyroidism and a medical emergency with high mortality. Manifestations include fever (>38.5 º C), delirium or coma, seizures, vomiting, diarrhoea and jaundice. Management requires (1) supportive treatment; (2) identification and treatment of any precipitating condition, including infection; (3) antithyroid treatment, e.g. loading dose of propylthiouracil, followed 1 h later by stable iodine (e.g. Lugol’s iodine or ipodate).
Thyrotoxicosis is defined as the state produced by excessive thyroid hormone. Hyperthyroidism exists when thyrotoxicosis is caused by thyroid overactivity but there are several types of thyrotoxicosis that are not due to hyperthyroidism, the most obvious being administration of excessive T4.
Bullet list 1 Indications for screening for hypothyroidism
- Congenital hypothyroidism
- Previous treatment for hyperthyroidism
- Previous neck irradiation (e.g. for lymphoma)
- Pituitary tumours, including follow-up after surgery or irradiation
- Treatment with lithium or amiodarone
- Subclinical hypothyroidism
- Antepartuma in type 1 diabetes
- Three months postpartum after a prior episode of postpartum thyroiditis
- Unexplained infertility
- Nonspecific symptoms in women over 40 years of age
- Refractory depression or bipolar affective disorder with rapid cycling
- Turner’s syndrome
- Down’s syndrome
- Autoimmune Addison’s disease
- Patients with a family history of thyroid autoimmunity
- Dementia or obesity without other evidence of thyroid disease
- Antepartum to detect unsuspected hypothyroidismb
- Breast cancer
a Also measure thyroid peroxidase antibodies; screen euthyroid antibody-positive women 3 months postpartum for postpartum thyroiditis.
b It is also uncertain whether all pregnant women should be checked for thyroid peroxidase antibodies as predictors of postpartum thyroiditis.
The causes of thyrotoxicosis are shown in Bullet list 2. Graves’ disease is responsible for 60 to 80% of cases and nodular thyroid disease (toxic multinodular goitre and toxic adenoma) accounts for most of the rest. Destructive thyrotoxicosis is dealt with in the next section.
The prevalence of thyrotoxicosis in white people is 2 to 3% in women and 0.2 to 0.3% in men. The peak age of onset for Graves’ disease is between 20 and 50 years of age, whereas toxic multinodular goitre occurs more often in later life.
Graves’ disease is caused by TSH receptor stimulating antibodies, clearly demonstrated by the occurrence of transient, neonatal thyrotoxicosis in babies born to mothers with Graves’ disease whose antibody levels are high enough for transplacental transfer to affect the fetus. As with autoimmune hypothyroidism, genetic factors, including HLA-DR, CTLA4, and TSHR gene polymorphisms, are associated with the disease; the concordance rate in monozygotic twins is about 20% and much less in dizygotic twins. A high iodine intake, smoking, and stress have all been identified as environmental factors, but in many patients the genetic and environmental triggers remain elusive. Smoking is a major risk factor for the development of thyroid-associated ophthalmopathy. These eye signs are due primarily to swelling of the extraocular muscles, the result of fibroblast activation by cytokines released by infiltrating T cells and macrophages, leading to glycosaminoglycan accumulation, oedema, and fibrosis. The close correlation between ophthalmopathy and thyroid disease is best explained by a shared orbital and thyroid autoantigen (possibly the TSH receptor).
Bullet list 2 Causes of thyrotoxicosis
- Graves’ disease
- Toxic multinodular goitre
- Toxic adenoma
- Drugs: iodine excess (Jod–Basedow phenomenon), lithium, amiodarone
- Thyroid carcinoma or functioning metastases
- Activating mutation of the TSH receptor
- Activating mutation of the Gsα protein (McCune–Albright syndrome)
- Struma ovarii (ectopic thyroid tissue)
- Ingestion of excess thyroid hormone (factitious thyrotoxicosis)
- Subacute thyroiditis
- Silent thyroiditis
- Other causes of thyroid destruction: amiodarone, 131I or external irradiation (acute effect), infarction of an adenoma
- TSH-secreting pituitary tumour
- Chorionic gonadotropin-secreting tumours
- Gestational thyrotoxicosis
- Thyroid hormone resistance (usually euthyroid)
Toxic multinodular goitre evolves from a nontoxic sporadic goitre (see above) and is particularly likely when iodine intake increases, either gradually as a result of changes in the diet, or acutely when iodine-containing agents (amiodarone, some contrast media) are given. More than 50% of toxic adenomas are due to a somatic activating mutation in the genes encoding the TSH receptor or the associated Gsα protein, and a similar but unknown mechanism leading to constitutive activation of a clone of thyroid cells must underlie the remainder.
The typical features of thyrotoxicosis from any cause are shown in Bullet list 3, but their presence and severity depend on the duration of disease and the age of the patient. Occasionally there are paradoxical manifestations, such as the weight gain that can occur in up to 10% of patients when the increase in appetite exceeds the effects of increased metabolism, and apathetic or masked thyrotoxicosis in older patients which mimics depression. The most dramatic but rare presentation is thyrotoxic crisis or storm, with a mortality rate of 20 to 30% even with treatment. Patients typically are previously undiagnosed or partially treated and have an acute exacerbation of thyrotoxicosis precipitated by acute illness (infection, stroke, diabetic ketoacidosis) or trauma, especially directly to the thyroid (surgery or radio-iodine). Exact diagnostic criteria for thyrotoxic crisis are not agreed and its frequency is sometimes exaggerated. There is marked fever (>38.5 °C), delirium or coma, seizures, vomiting, diarrhoea, and jaundice, with death being caused by arrhythmias, heart failure, or hyperthermia.
Bullet list 3 Clinical features of thyrotoxicosis of any cause
- Hyperactivity, irritability, altered mood
- Heat intolerance, sweating
- Fatigue, weakness
- Weight loss with increased appetite
- Diarrhoea, steatorrhoea
- Oligomenorrhoea, amenorrhoea, loss of libido
- Sinus tachycardia, atrial fibrillation in older patients
- Fine tremor
- Warm, moist skin
- Palmar erythema, onycholysis, pruritus, urticaria, diffuse pigmentation
- Diffuse alopecia
- Muscle weakness and wasting, proximal myopathy, hyper-reflexia
- Eyelid retraction or lag
- Rarely: chorea, periodic paralysis (usually in Asian men), psychosis, impaired consciousness
The differential diagnosis of thyrotoxicosis includes any cause of weight loss, anxiety, and phaeochromocytoma, but simple biochemical testing can readily distinguish thyrotoxicosis from these conditions. Once the diagnosis of thyrotoxicosis is made, it is essential to determine the cause (see Bullet list 2), as this determines treatment. Graves’ disease is usually clinically distinctive; there is a small to moderate, diffuse, firm goitre and around one-half of these patients have signs of thyroid-associated ophthalmopathy (Table 1). There may be evidence of another autoimmune disorder, in the patient or his/her family, with the same associations as autoimmune hypothyroidism described above. Less than 5% of patients have pretibial myxoedema, which is better called thyroid dermopathy as it can occur anywhere, especially after trauma. These patients almost always have moderate to severe ophthalmopathy and 10 to 20% have clubbing (thyroid acropachy). Thyroid dermopathy most commonly occurs as nonpitting plaques with a pink or purple colour but no inflammatory signs. Nodular and generalized forms, the latter mimicking elephantiasis, also occur. Hyperplasia of lymphoid tissue, including splenomegaly and thymic enlargement, is sometimes found in Graves’ disease.
|Table 1 Clinical features of thyroid-associated ophthalmopathy|
|Signs and symptoms||Assessment||Approximate frequencya (%)|
|Lid lag, lid retraction||Measure lid fissure width||50–60|
|Grittiness, discomfort, excessive tearing, retrobulbar pain, periorbital oedema||Self-assessment score by patient; activity score by clinician||40|
|Proptosis||Exophthalmometry or CT/MRI-based measurement||20|
|Extraocular muscle dysfunction (typically causing diplopia looking up and out)||Hess chart or similar; CT/MRI scan to detect muscle size||10|
|Corneal involvement, causing exposure keratitis||Rose bengal or fluorescein staining||<5|
|Loss of sight due to optic nerve compression||Visual acuity and fields, colour vision; CT/MRI scan||<1|
a In patients with Graves’ disease. Patients often have multiple signs and in 5–10% of them signs are unilateral.
The absence of these features of Graves’ disease and the presence of a multinodular goitre strongly suggest toxic multinodular goitre, although nodular thyroid disease is so common that occasional patients with Graves’ disease may cause confusion when their thyrotoxicosis arises in a pre-existing multinodular gland. In toxic adenoma, the solitary thyroid nodule is usually readily palpable. Other, rare causes of thyrotoxicosis can usually be easily identified from the history and biochemical investigations.
In Graves’ disease, there is thyroid hypertrophy and hyperplasia. The follicles show considerable folding, contain little colloid, and are composed of tall columnar cells. Gland vascularity increases. There is a focal and diffuse lymphocytic infiltrate and lymphoid hyperplasia may occur in the lymph nodes, spleen, and thymus. These changes are all reversed by antithyroid drugs. Toxic multinodular goitre comprises a mixture of areas of follicular hyperplasia and nodules filled with colloid. There is a variable degree of fibrosis, haemorrhage, and calcification. Toxic adenomas are encapsulated and cellular, sometimes with little evidence of follicle formation, and occasionally containing unusual cell forms suggesting malignant change. However, capsular invasion is absent and this is the cardinal feature which distinguishes a follicular adenoma from carcinoma.
Measuring the serum TSH is the simplest way to exclude primary thyrotoxicosis. A normal or slightly raised TSH level can rarely be associated with secondary hyperthyroidism in the case of a TSH-secreting pituitary adenoma. A low TSH level is not always the result of thyrotoxicosis see Table 2), therefore the diagnosis of thyrotoxicosis must be confirmed by measuring thyroid hormone levels.
|Table 2 Causes of abnormal serum TSH concentrations|
|TSH level||Cause||Free thyroid hormone levels|
|Sick euthyroid syndrome||↓ or N|
|Dopamine antagonists (acute effect)||N|
|TSH-secreting pituitary adenoma||↑|
|Thyroid hormone resistance syndrome||↑|
|Adrenal insufficiency||↓ or N|
|Recently treated hyperthyroidism||N|
|Thyroid-associated ophthalmopathy without Graves’ disease||N|
|Excessive thyroxine treatment||N or ↑|
|Sick euthyroid syndrome||↓ or N|
|First trimester of pregnancy||N or ↑|
|Pituitary or hypothalamic disease||N or ↓|
|Anorexia nervosa||N or ↓|
|Dopamine, somatostatin (acute effect)||N|
N, normal; TSH, thyroid-stimulating hormone; ↑, increased; ↓, decreased.
Free hormone assays are preferable to those for total hormone, to eliminate binding protein effects (see Table 3).
|Table 3 Conditions in which there is altered binding of thyroid hormones to binding proteins|
|Increased binding||Genetic variation in TBG|
|Oestrogens (pregnancy, oral contraception, hormone replacement therapy, tamoxifen)|
|Other drugs (perphenazine, opiates, 5-fluorouracil, clofibrate, mitotane)|
|Acute intermittent porphyria|
|Decreased binding||Genetic variation in TBG|
|Steroids (testosterone, anabolic steroids, glucocorticoids)|
|Acute severe illness|
|Decreased binding||Any cause of hypoalbuminaemia|
|Increased binding||Genetic variation|
|Increased binding||Genetic variation|
|Competition for binding sites|
|Salicylates and nonsteroidal anti-inflammatory drugs|
|Nonesterified fatty acids|
TBG, thyroid-binding globulin.
Measuring free T4 alone is adequate in most cases of thyrotoxicosis, which can be confirmed by the presence of a suppressed TSH and elevated free T4 level. However, in up to 5% of patients, only free T3 levels are elevated (T3 toxicosis), especially during the earliest phase of the disorder. Therefore, if both free T3 and T4 are not measured routinely by a laboratory, it is essential to request free T3 analysis in any sample showing a suppressed TSH but normal free T4 level. Rarely, the free T4 is elevated but the free T3 is normal. This arises when Graves’ disease or nodular thyroid disease is precipitated by the administration of excess iodine (the Jod–Basedow phenomenon).
Although it is possible to measure TSH receptor stimulating antibodies and thus prove the existence of Graves’ disease in a thyrotoxic patient, these assays are cumbersome or expensive, and therefore, at present, are not widely used. Almost as much information can be gained by measuring thyroid peroxidase antibodies which are present in around 75% of patients with Graves’ disease. In cases of diagnostic uncertainty, a thyroid scintiscan will demonstrate a diffuse goitre with high isotope intake in Graves’ disease and reveal nodular thyroid disease, as well as ectopic thyroid tissue in the extremely rare struma ovarii. In destructive and factitious thyrotoxicosis, the thyroid scan shows virtually no isotope uptake and the diagnosis of factitious thyrotoxicosis can be confirmed by measuring serum thyroglobulin levels, which are suppressed in contrast to the raised levels in all other causes of thyrotoxicosis. When a TSH-secreting pituitary adenoma is suggested biochemically, the diagnosis is made by demonstrating both an elevated level of the α-subunit common to glycoprotein hormones including TSH and a pituitary tumour on CT, or preferably MRI. Prolonged thyrotoxicosis can cause several nonspecific biochemical abnormalities, especially abnormal liver function tests, hypercalciuria, and elevated serum levels of ferritin. Less commonly, serum calcium and phosphate may be raised, glucose intolerance or diabetes may occur, and rarely there may be a microcytic anaemia or thrombocytopenia.
Definitive diagnosis is the most important determinant of treatment selection for thyrotoxicosis. In particular, antithyroid drugs only achieve a cure in Graves’ disease. When due to a subacute or silent thyroiditis, discussed below, spontaneous resolution of thyrotoxicosis is expected and symptomatic treatment with β-blockers such as propranolol, 20 to 80 mg 3 times daily, is indicated. Although β-blockers will rapidly alleviate symptoms in all types of hyperthyroidism, definitive treatment is also necessary, and when euthyroidism is restored β-blockers can be gradually withdrawn.
There are three types of treatment for Graves’ disease: antithyroid drugs, radio-iodine (131I), and surgery. Local policy and patient age dictate the order of their use. For young or middle-aged adults, antithyroid drugs are generally used initially in Europe and Japan, whereas radio-iodine is preferred in North America. Surgery is particularly useful in patients with a large goitre, but is less frequently used in North America than elsewhere. The local availability of an experienced surgeon is crucial. There is more international agreement over the preferential use of radio-iodine for a recurrence after antithyroid drugs and as first-line treatment in older people with Graves’ disease.
The main antithyroid drugs used in Europe are carbimazole and its active metabolite methimazole, whereas propylthiouracil is preferred in North America. There is little to choose between them in normal practice, as all exert their principal action by inhibiting iodide oxidation and organification by thyroid peroxidase. Propylthiouracil additionally inhibits the activity of type I deiodinase, reducing T3 formation in many tissues, but this activity is only of clinical importance in very severe hyperthyroidism, and more frequent dosing is necessary with this drug.
Two regimens are used to avoid antithyroid drug-induced hypothyroidism and achieve the best chance of remission, which occurs in 40 to 60% of patients and is inversely proportional to dietary iodine intake. The first method is to titrate the dose of antithyroid drug, giving carbimazole (or methimazole) 20 mg 2 or 3 times daily, and then lowering the dose every 3 to 4 weeks or so, based on free T4 measurements, until a maintenance dose of 5 to 10 mg once daily is achieved. Equivalent starting and maintenance doses of propylthiouracil are 100 to 200 mg 3 times daily and 50 mg once or twice daily. Maximum remission rates occur after 18 to 24 months of treatment.
The second regimen is to start with the same dose of antithyroid drug but then to add 100 µg T4 daily after 3 to 4 weeks when free T4 levels are usually becoming normal, rather than lowering the dose of drug. Thereafter the patient is maintained on 40 mg carbimazole or methimazole once daily (alternatively, 100 to 150 mg propylthiouracil 3 times daily) and T4, the latter being adjusted if necessary 4 weeks after starting to achieve normal free T4 levels. The block–replace regimen achieves the same remission rate as the titration regimen within 6 months; continuation beyond this time is not necessary but can be used if a patient wishes to ensure euthyroidism for a particular period of time. Patients with the biggest goitres almost always relapse after antithyroid drug treatment, but unfortunately there are no reliable predictors of which other patients will relapse and therefore it is usual practice to follow patients closely (e.g. every 3 months) in the first year after stopping treatment. Thereafter, an annual check of thyroid function is warranted as recurrence occurs in 10 to 20% 1 to 5 years after treatment, and autoimmune hypothyroidism may supervene in around 15%.
The side effects of antithyroid drugs are shown in Bullet list 4; most occur in the first 3 months of treatment and there is a moderate dose dependency. Substituting propylthiouracil for carbimazole or vice versa usually reverses the common side effects but further antithyroid drugs should be avoided if bone marrow disturbance develops. Lower doses of antithyroid drugs can be used in areas of low iodine intake. Lithium and potassium perchlorate have antithyroid actions and are alternatives when antithyroid drugs are not tolerated, but these drugs are difficult to use, their side effects are serious, and they are given as a last resort. Anticoagulation with warfarin should be considered in all patients with atrial fibrillation; only 50% of patients revert to sinus rhythm when euthyroidism is restored. In the remainder, attempts at cardioversion should be made, ideally when hyperthyroidism has been definitively treated with radio-iodine. Digoxin is useful to control atrial fibrillation acutely but higher doses than normal are needed in the thyrotoxic state.
Bullet list 4 Side effects of antithyroid drugs
- Rash (typically maculopapular)
- Fever, sometimes with malaise
- Gastrointestinal symptoms
- Abnormal taste and smell
- Aplastic anaemia
- Lupus-like syndrome, vasculitis
- Hypoglycaemia due to the insulin autoimmune syndrome
a All patients must be warned in writing, before treatment commences, to seek medical advice and stop medication if features suggesting agranulocytosis (fever, mouth ulcers, sore throat) develop.
Accurate dosimetry for radio-iodine administration, based on uptake tests, has now largely fallen out of favour as the results have been little or no better than more empirical methods of dose calculation. Typical 131I doses are 400 to 600 MBq in uncomplicated Graves’ disease, but local policies vary, not least because less 131I is needed when iodine intake is low. Around 5 to 10% of patients treated this way require a second dose of 131I, while hypothyroidism rates are 10 to 20% after 1 year and 5 to 10% annually thereafter. Close follow-up is needed in the first year after treatment, and an annual test of thyroid function thereafter is recommended. Transient cytoplasmic, rather than nuclear, damage may cause hypothyroidism in the first 2 to 3 months after 131I treatment, which then resolves. It is usual to delay a second dose of 131I for at least 4 to 6 months after the first, as hyperthyroidism is controlled only slowly by radiation-induced nuclear damage. Antithyroid drugs or β-blockers are useful in the interim.
Radio-iodine is contraindicated in pregnancy and breastfeeding. There are no teratogenic risks if men or women attempt conception 6 months or more after treatment. Overall mortality rates from cancer are not increased by radio-iodine, although there is a theoretical risk of an increase in the frequency and aggressiveness of thyroid cancer in children and adolescents, which makes many endocrinologists reluctant to use 131I in this group, unless other treatments fail or are rejected. Another concern is the precipitation of thyrotoxic crisis by 131I, but in practice this must be rare. To minimize the risk, antithyroid drugs can be given for up to 4 weeks or more prior to radio-iodine, particularly in older people who are at special risk. Thyroid-associated ophthalmopathy may appear or worsen after radio-iodine, especially if the patient smokes. A 3-month tapering course of prednisolone, starting with 40 mg daily at the time of 131I administration, will prevent such worsening but an extended course of antithyroid drugs, with scrupulous maintenance of euthyroidism, may well be preferable until the orbital disease becomes inactive.
Surgery for Graves’ disease consists of subtotal or near total thyroidectomy, and in the best centres achieves cure in more than 98% of patients but with a hypothyroidism rate similar to radio-iodine. Lower rates of hypothyroidism are inevitably associated with a higher recurrence rate. Patient preference is the main determinant of when surgical treatment is used to treat relapses after antithyroid drugs. Euthyroidism must be achieved with a further course of these drugs prior to surgery to avoid thyrotoxic crisis. Stable iodine (e.g. Lugol’s iodine three drops 3 times daily) is often also given for 7 to 10 days prior to surgery to block hormone synthesis acutely. Specific complications of surgery include haemorrhage leading to laryngeal oedema, damage to the recurrent laryngeal nerves, and hypoparathyroidism. These problems occur in less than 1% of patients in experienced hands and the last two problems are often transient.
The management of thyroid-associated ophthalmopathy is summarized in Bullet list 5. Symptoms and signs are usually mild to moderate, although still capable of creating considerable anxiety and disturbance of social function. Severe ophthalmopathy is fortunately rare (1–5% of cases) and requires specialist ophthalmological management. Signs usually stabilize 12 to 18 months after onset, and may improve thereafter in 30 to 50% of patients, although improvement is less likely for marked proptosis or diplopia. Corrective surgery for diplopia or cosmetic problems should only be considered in this stable phase. Thyroid dermopathy is left untreated and may resolve spontaneously. Surgical removal usually worsens the situation and, when troublesome, the best treatment is topical, high-potency corticosteroids.
Bullet list 5 Treatment of thyroid-associated ophthalmopathy
- Reassurance and explanation
- Avoid hypothyroidism and hyperthyroidism
- Stop smoking
- Protect eyes from dust and bright light
- Artificial tears; simple eye ointment at night
- Sleep with more pillows or the head of the bed elevated
- Stick-on prisms
- Corticosteroids (e.g. prednisolone 40–80 mg daily, tapered over >3 months)
- Radiotherapy (10 fractionated doses of 2 Gy)
- Immunosuppressive agents (azathioprine, cyclosporin A)
- Intravenous immunoglobulin
- Orbital decompression (usually transantral)
- Surgery to extraocular muscle
- Cosmetic eyelid surgery
Toxic multinodular goitre is usually managed by radio-iodine treatment. Antithyroid drugs will control the hyperthyroidism but relapse is inevitable when the drugs are stopped. Long-term use of antithyroid drugs may be indicated in the very old or frail, or when incontinence poses an insuperable problem for the safe disposal of excreta after 131I. The therapeutic dose of 131I used for toxic multinodular goitre is generally higher than for Graves’ disease (500–800 MBq) because there is uneven uptake of the isotope and usually a large goitre. Surgery is sometimes used as an alternative in patients with a retrosternal goitre or if there is any suspicion of a malignancy. Toxic adenoma is also usually treated with 131I and the rate of subsequent hypothyroidism is low because the function of the normal thyroid tissue is suppressed at the time the patient is hyperthyroid and therefore receives little irradiation. When there is a large (>5 cm) nodule or in young patients (<20 years) surgical excision is preferable and subsequent hypothyroidism is uncommon. Treatment of rare forms of primary hyperthyroidism is by surgical removal of the source of thyroid hormone or by radio-iodine. TSH-secreting pituitary adenomas causing secondary hyperthyroidism are usually treated by trans-sphenoidal surgery, with radiotherapy for any residual tumour. Octreotide can also be used to lower TSH secretion.
Thyrotoxic crisis is a medical emergency (Bullet list 6).
Although spontaneous remission occurs in Graves’ disease, its exact frequency is unknown and is unlikely to be more than 10%, with no guarantee of persistence. Remission does not occur in other types of hyperthyroidism. Mortality rates in untreated hyperthyroidism are also uncertain but are probably around 30%. Even after successful treatment, there is a threefold increased risk of death from osteoporotic fracture and a 1.3-fold increased risk of death from cardiovascular disease and stroke. It is important that the patient with Graves’ disease understands that the course of ophthalmopathy is independent of the thyroid disorder; eye signs appear 1 or more years before or after the onset of hyperthyroidism in one-quarter of patients and progression of the orbital disease frequently occurs despite restoration of euthyroidism.
Special problems in pregnant women
Graves’ disease during pregnancy is often treated with propylthiouracil, as carbimazole and methimazole have been associated with fetal aplasia cutis, but some dispute the significance of this association. The block–replace regimen is contraindicated in pregnancy, as preferential placental transfer of antithyroid drug will cause fetal hypothyroidism. Instead, the dose of antithyroid drug should be titrated to the lowest dose that results in maternal free T4 levels in the upper part of the reference range. TSH receptor stimulating antibodies decline during pregnancy and it is usually possible to stop treatment at the beginning of the third trimester. Subtotal thyroidectomy can be performed in the second trimester for women intolerant of antithyroid drugs.
Transplacental passage of TSH receptor antibodies causes fetal and neonatal thyrotoxicosis in 1 to 5% of mothers with Graves’ disease and can be predicted by demonstrating a high level of these antibodies in the maternal circulation at the beginning of the third trimester. Poor intrauterine growth and a high fetal heart rate also suggest this diagnosis. Fetal thyrotoxicosis is treated by giving the mother antithyroid drugs and the neonate requires treatment for 1 to 3 months after delivery. Failure to treat intrauterine and neonatal thyrotoxicosis causes low birth weight, premature closure of the sutures, and intellectual impairment. Breastfeeding is safe with low doses of antithyroid drugs, but when high doses are needed (e.g. 20 mg or more carbimazole daily) thyroid function should be checked every 1 to 2 weeks in the baby. Patients with Graves’ disease who have entered remission prior to or during pregnancy have an increased risk of relapse around 3 to 6 months after delivery and should be offered thyroid function testing at this time.
Bullet list 6 Treatment of thyrotoxic crisis (‘thyroid storm’)
- ◆ Antithyroid treatment
- • Propylthiouracil 600 mg as a loading dose; then 250 mg every 6 h, given orally, by nasogastric tube, or per rectum
- • Stable iodine given 1 h after starting propylthiouracil (e.g. Lugol’s iodine five drops every 6 h); ipodate 500 mg every 12 h is an alternative with additional deiodinase blocking activity
- • Propranolol 40 mg orally or 2 mg intravenously every 4 h to control heart rate; careful monitoring necessary in heart failure
- • Severe cases may respond to plasmapheresis or dialysis
- ◆ Supportive treatment
- • Oxygen
- • External cooling
- • Intravenous saline
- • Dexamethasone 2 mg every 6 h
- • Diuretics and digoxin for heart failure
- ◆ Identify and treat underlying precipitant (including trauma, infection, diabetic ketoacidosis, and myocardial infarction)
- • Broad-spectrum antibiotics if infection suspected
Areas of uncertainty or needing further research
The pathogenesis of thyroid-associated ophthalmopathy is poorly understood, and this remains an obstacle to developing better treatments. Outcome after antithyroid drug treatment in Graves’ disease cannot yet be predicted, but improved assays for TSH receptor antibodies may permit better assessment in the near future. Antithyroid drugs modulate the autoimmune response favourably in those patients whose Graves’ disease remits, indicating the potential for more specific immunotherapy aimed at the cause of the disease, which would be preferential to present treatments which merely block or destroy the thyroid.
The evolution of hyperthyroidism is gradual and patients with multinodular goitre in particular are now recognized at the stage of subclinical hyperthyroidism, i.e. with a low or suppressed TSH but normal free T3 and T4 levels. Their optimum management is uncertain. There is a twofold to threefold increased risk of atrial fibrillation over 10 years in subclinical thyrotoxicosis, as well as deleterious effects on bone mineral density, but no clinical trials have been performed to show a clear benefit from early intervention. Many endocrinologists simply follow such patients carefully, electing to treat when overt hyperthyroidism is shown by an abnormal free T3 level (T3 usually increases before T4). However, in older patients with known cardiac disease there is an increasing tendency to use radio-iodine for sustained subclinical hyperthyroidism.