Hyperthyroidism

doi:10.1016/S0140-6736(03)14073-1

The Lancet

Volume 362, Issue 9382, 9 August 2003, Pages 459-468

https://doi.org/10.1016/S0140-6736(03)14073-1 Get rights and content

Summary

Hyperthyroidism is a pathological syndrome in which tissue is exposed to excessive amounts of circulating thyroid hormone. The most common cause of this syndrome is Graves' disease, followed by toxic multinodular goitre, and solitary hyperfunctioning nodules. Autoimmune postpartum and subacute thyroiditis, tumours that secrete thyrotropin, and drug-induced thyroid dysfunction, are also important causes. The diagnosis of hyperthyroidism is generally straightforward, with raised serum thyroid hormones and suppressed serum thyrotropin in almost all cases. Appropriate treatment of hyperthyroidism relies on identification of the underlying cause. Antithyroid drugs, radioactive iodine, and surgery are the traditional treatments for the three common forms of hyperthyroidism. β-adrenergic blocking agents are used in most patients for symptomatic relief, and might be the only treatment needed for thyroiditis, which is transient. The more unusual causes of hyperthyroidism, including struma ovarii, thyrotropin-secreting tumours, choriocarcinoma, and amiodarone-induced thyrotoxicosis are, more often than not, a challenge to diagnose and treat.

Section snippets

Causation

Hyperthyroidism has many causes (table 1). Graves' disease, an autoimmune condition caused by stimulation by antibodies directed against the thyrotropin receptor, is the cause in most patients. The development of one or more autonomously functioning thyroid nodules that produce excessive quantities of thyroid hormone is also a common problem. Various forms of thyroiditis, in which thyroidal inflammation damages thyroid follicles, resulting in unregulated release of thyroid hormone into the

Epidemiology

Unsuspected and undiagnosed hyperthyroidism arose in roughly 0·5% of women in a large population-based British survey, done in the 1970s.³ In a more recent survey done in the USA,⁴ investigators noted hyperthyroidism in 0·5% of randomly selected individuals. An additional 0·8% had subclinical or mild hyperthyroidism, in which serum thyrotropin is low or undetectable, but circulating thyroid hormone is within the normal range. In this investigation, the percentage of individuals with values of

Clinical features

Typical symptoms of hyperthyroidism indicate the action of excess thyroid hormone in the cell, as well as enhanced -adrenergic activity. Patients usually have fatigue, nervousness or anxiety, weight loss, palpitations, and heat sensitivity. Women might have irregular menses and decreased fertility, although frank amenorrhoea is rare.⁶ Men can have reduced libido and sometimes painful gynaecomastia.⁷ Clinical findings almost always include tachycardia, warm moist skin, the presence of an

Laboratory diagnosis

Patients with hyperthyroidism often have non-specific changes in commonly requested laboratory tests. Indices of liver function are slightly raised in a minority of patients. Hypercalcaemia is present in about 10% of patients, because of increased bone turnover and subsequent suppression of parathyroid hormone in serum. Laboratory diagnosis of hyperthyroidism is usually straightforward (figure). Most patients have increased serum concentrations of unbound thyroxine and tri-iodothyronine, and

Causation

Graves' disease is an autoimmune disorder characterised by antibodies in the circulation that are directed against the thyrotropin receptor. These antibodies mimic the effects of pituitary thyrotropin, thereby stimulating thyroid growth and function. Whether the disease is triggered by abnormal clones of autoreactive T-cells, or abnormal antigen presentation by thyroid follicular cells either independently or in response to cytokines released by infiltrating T-cells,²⁰ is uncertain. The cause

Thyroidectomy

Although surgery was for many years the only treatment for Graves' disease, it is now used only in specific circumstances. These situations include patient preference, poor response to antithyroid drugs, especially in pregnancy; the presence of a very large goitre, and the presence of a co-existing potentially malignant thyroid nodule. A total or near total thyroidectomy is the procedure of choice to avoid recurrent hyperthyroidism, and should be done by a skilled thyroid surgeon.⁶⁶

Pregnancy

Pregnancy is complicated by Graves' disease in about one in 500 women.⁶⁹ Recognition of Graves' disease in pregnancy is important, since untreated hyperthyroidism is associated with miscarriage, premature labour, low birthweight, and eclampsia.⁷⁰ The diagnosis might not be obvious because hyperthyroid symptoms such as heat intolerance and palpitations are common in pregnancy. Also, laboratory testing is difficult because increased thyroid-binding globulin raises total serum thyroxine, and

Solitary toxic thyroid nodules

Solitary autonomous thyroid nodules that produce enough hormone to suppress secretion of thyrotropin from the pituitary, with consequent suppression of the contralateral thyroid lobe, are called toxic nodules. They usually grow to at least 3 cm in diameter before they result in overt hyperthyroidism.⁷⁴ Autonomous function has been linked to activating mutations in the thyrotropin receptor,⁷⁵ or further downstream in the stimulatory G_s protein pathway linked to cyclic AMP production.⁷⁶ These

Thyroiditis

Thyroiditis refers to any inflammatory condition of the thyroid. Results of several investigations have shown that thyroiditis, whether autoimmune,⁸⁶ infectious,⁸⁷ or toxic⁸⁸ affects apoptotic pathways leading to thyroid follicular cell death. This apoptosis leads to follicular disruption and release of hormonal stores into the circulation, resulting in hyperthyroidism. After the inflammatory process subsides, mild to moderate hypothyroidism generally follows, before complete recovery.

Subacute

Amiodarone-induced thyroiditis

Amiodarone is an iodinated antiarrhythmic that has several effects on thyroid function tests, thyroid hormone metabolism, and thyroid function.⁹² Some of these effects are due to the drug, and others are due to iodine released during drug metabolism. In the USA, roughly 3% of patients treated with amiodarone develop hyper-thyroidism, and the prevalence is much higher in areas of the world with iodine deficiency. Two subtypes of amiodarone-induced hyperthyroidism have been described: type 1,

Gestational thyrotoxicosis

Human chorionic gonadotropin has a structure similar to thyrotropin, and can therefore stimulate the thyroid when present in high concentrations in serum.⁹⁴ Thus, serum thyrotropin might be low at the end of the first trimester of pregnancy, a time when serum human chorionic gonadotropin values peak. Women with hyperemesis gravidarum, defined as severe nausea and vomiting with a weight loss of 5% or more, have higher serum human chorionic gonadotropin values than healthy pregnant women, and

Future directions

Treatments for patients with hyperthyroidism have not changed over half a century, and are aimed to inhibit, destroy, or remove the thyroid gland. Current research is directed towards genetic and molecular approaches to finding the causes of autoimmune hyperthyroidism (Graves' disease), and should ultimately produce targeted treatments that will cure these diseases non-invasively, without toxicity, and without permanent damage to the thyroid gland. In the words of EB Astwood, a pioneer of

Search strategy and selection criteria

We searched MEDLINE from 1995 to 2002, using the key words hyperthyroidism, thyrotoxicosis, thyroiditis, radioactive iodine therapy, and antithyroid drugs. English language articles only were selected. We also searched reference lists from older articles and book chapters for relevant articles.

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